16.1.1 protocol and protocol amendments · property of novartis vaccines and diagnostics...

16.1.1 Protocol and Protocol Amendments

GSK Biologicals 27 FEB 17

Confidential ePublished V72_60 Final CSR 021 of 3966

Novartis Vaccines and Diagnostics Protocol V72_6014 MAY 13 Version 1.0 Confidential Page 1 of 92

PRO-01 TEMP 06 / Atlas No. 293620Version No. 1 / Version Date: August, 20 2012

CLINICAL STUDY PROTOCOL V72_60 Version 1.0

A Phase 3, Open Label, Randomized, Controlled, Multi-Center Study to Evaluate the Safety and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine

When Administered concomitantly with Routine Vaccines to Healthy Infants in Taiwan.

Property of Novartis Vaccines and Diagnostics

Confidential

May not be used, divulged, published or otherwise disclosed without writtenconsent of Novartis Vaccines and Diagnostics

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Confidential ePublished V72_60 Final CSR Page 1022 of 3966



PROTOCOL SYNOPSIS V72_60 VERSION 1.0

Name of SponsorNovartis Vaccines and Diagnostics

Protocol number:

V72_60

Health authority trial registration number(s):TBD

Title of Study:A Phase 3, Open Label, Randomized, Controlled, Multi-Center Study to Evaluate the Safety and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine When Administered concomitantly with Routine Vaccinates to Healthy Infants in Taiwan.

Study Period: 11 months Clinical Phase: Phase 3

Rationale: N. meningitidis is an important cause of bacterial meningitis and septicemia in infants and young adults. Meningococcal disease can be caused by serogroups A, B, C, W-135 and Y. Currently, no vaccine is available to protect against serogroup B, which accounts for approximately 50% of confirmed meningococcal disease cases reported in Taiwan. Therefore, there exists an urgent need for an effective vaccine that protects against meningococcal disease caused by serogroup B.

Novartis Vaccines & Diagnostics (NVD) has developed a Meningococcal B Recombinant Vaccine (rMenB+OMV NZ; Bexsero). Data provided from clinical studies conducted with rMenB+OMV NZ confirm that the vaccine has a similar safety profile to other licensed pediatric vaccines and is able to elicit a robust immune response against the selected meningococcal B strains. On 14th of January 2013, NVD received EU marketing authorisation for Bexsero for use in individuals from 2 months of age and older.

Immunogenicity results of rMenB+OMV NZ in infants and toddlers (V72P13 and V72P13E1) with concomitant routine vaccines - including diphtheria (D), tetanus (T), acellular pertussis (aP), poliovirus types 1, 2, 3 (IPV), Hepatitis B (HepB), Haemophilus influenzae type b (Hib), 7-valent pneumococcal conjugate vaccine (PCV), measles, mumps, rubella (MMR) and varicella - support a 3-dose schedule (at 2, 4, 6 months) for rMenB+OMV NZ in infants followed by a booster at 12 months.

The aim of the proposed study is to assess the safety and immunogenicity of a 3-dose schedule (at 2, 4, 6 months) of rMenB+OMV NZ followed by a booster at 12 months when concomitantly administered with routine vaccines (i.e. combined DTaP-IPV-Hiband 13-valent PCV at 2, 4, 6 months; HepB at 6 months of age; MMR and varicella at 12 months of age) in healthy infants in Taiwan.

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Protocol number:

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Objectives:

Immunogenicity Objectives

PrimaryTo demonstrate the sufficiency of the immune response to rMenB+OMV NZ vaccine, when given concomitantly with routine vaccines (i.e DTaP-IPV-Hib, HepB and PCV-13) to healthy infants at 2, 4, 6 months of age, as measured by percentage of subjects with serum bactericidal activity (SBA) titer ≥ 1:5 against the indicator strains H44/76, 5/99 and NZ98/254 at 1 month after the third vaccination (at 7 months of age).

Key SecondaryTo demonstrate the sufficiency of the immune response to a booster dose of rMenB+OMV NZ vaccine when given concomitantly with routine vaccines (i.e. MMR and varicella) to healthy toddlers at 12 months of age that were previously primed with 3-doses of rMenB+OMV NZ, as measured by percentage of subjects with SBA titer ≥ 1:5 against the indicator strains H44/76, 5/99 and NZ98/254 at 1 month after the booster dose (at 13 months of age).

Other SecondaryTo assess bactericidal antibodies against meningococcal B in healthy infants receivingrMenB+OMV NZ concomitantly with routine vaccines (Group A) or routine vaccines alone (Group B) at 2, 4, 6 and 12 months of age, as measured by SBA geometric mean titers (GMTs), geometric mean ratios between post and pre-vaccination (baseline) titers(GMRs) and percentage of subjects with SBA titer ≥ 1:5 against indicator strains H44/76, 5/99, NZ98/254 and strain M10713 at baseline (2 months of age), 1 month after the third vaccination (7 months of age), prior to the booster dose (12 months of age) and at 1 month after the booster dose (13 months of age).

Safety ObjectivesTo assess the safety and tolerability of 3 doses of rMenB+OMV NZ given at 2, 4, 6 months of age, followed by a booster dose at 12 months of age when concomitantly administered with routine vaccines (i.e. combined DTaP-IPV-Hib and PCV-13 at 2, 4, 6 months; HepB at 6 months of age; MMR and varicella at 12 months of age) and of routine vaccines alone in terms of percentages and numbers of subjects with:

- Solicited local and systemic adverse events reported from Day 1 (day of vaccination) through Day 7 after each vaccination. (Fever, Rash and

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Parotid/salivary gland swelling will be collected for an extended period of 28 days after MMR and varicella vaccination).

- Any unsolicited adverse events (AEs) reported from Day 1 through Day 7 after each vaccination.

- SAEs, medically attended AEs, AEs leading to withdrawal from the study (see definitions in the Safety Assessment Table 2) throughout the entire study.

Methodology:

This is a Phase 3, randomized, controlled, open-label, multi-center study in healthy infants aged approximately 2 months at time of enrollment.

Approximately 225 healthy infants will be randomized in a 2:1 ratio to receive rMenB+OMV NZ concomitantly with routine vaccines (Group A) or routine vaccinesalone (Group B) according to Table 1.

Study procedures

At study-related Visit 1 (Day 1, 2 months of age), approximately 5 mL blood samplewill be obtained for serologic evaluation just prior to administration of the first dose of study vaccines. In addition, the first Diary Card will be provided.

At Days 3 and 7, reminder calls to subject’s parent/legal representative for completion of the Diary Card will be made by study staff.

At study-related Visit 2 (Day 61, 4 months of age), the first Diary Card will be collected and the subject will receive the second dose of study vaccines. In addition, a second Diary Card will be provided.


At study-related Visit 3 (Day 122, 6 months of age) the second Diary Card will be collected and the subject will receive the third dose of study vaccines. In addition, a third Diary Card will be provided.

At Days 124 and 128, reminder calls to subject’s parent/legal representative for

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completion of the Diary Card will be made by study staff.

At study-related Visit 4 (Day 152, 7 months of age) the third Diary Card will be collected and approximately 5 mL blood sample will be obtained for serologic evaluation. In addition, a fourth Diary Card will be provided.

At study-related Visits 5 (Day 213, 9 months of age) and 6 (day 274, 11 months of age), Safety Phone Calls will be performed by study staff to collect information relating to unsolicited adverse events and concomitant medications associated with those events.

At study-related Visit 7 (Day 305, 12 months of age), the fourth Diary Card will be collected and approximately 5 mL blood sample will be obtained for serologic evaluation just prior to the booster dose of study vaccines. In addition, a fifth Diary Card will be provided.

At Days 307, 311 and 318 reminder calls to subject’s parent/legal representative for completion of the Diary Card will be made by study staff.

At study-related Visit 8 (Day 335, 13 months of age) the fifth Diary Card will be collected and approximately 5 mL blood sample will be obtained for serologic evaluation.

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Name of Sponsor

Novartis Vaccines and Diagnostics

Protocol number:

V72_60


Table 1: Randomization groups and visits schedule

Part of Interim analysis at 7 monthsGroup Subjects(n) 2 months

(Visit 1)4 months(Visit 2)

6 months(Visit 3)

7 months(Visit 4)

9 months(Visit 5)

11 months(Visit 6)

12 months(Visit 7)

13 months(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-HibPCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-HibPCV-13

rMenB+OMV NZ

DTaP-IPV-HibPCV-13

HepB (3rd dose)*

Blood Draw

Safety Call

Safety Call rMenB+OMV NZ

MMRVaricella

Blood Draw

Blood Draw

B 75 DTaP-IPV-HibPCV-13

Blood Draw

DTaP-IPV-HibPCV-13

DTaP-IPV-HibPCV-13

HepB (3rd dose)*

Blood Draw

Safety Call

Safety Call MMRVaricella

Blood Draw

Blood Draw

*According to the Taiwanese Immunization Program Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively.In addition, BCG vaccine will be administered ≤ 24 hours after birth

.

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Safety assessments will be made according to Table 2.

Table 2: Relevant Medical History and Safety Assessments

From birth to the start of the study (Day 1)

1. Medical History (Any significant past diagnoses including allergies, hospitalizations, surgeries requiring in-patient hospitalization and any other conditions requiring medication)

2. All medications (with the exception of minerals, supplements, vitamins, local anaesthetic cream and emollients)

3. All vaccinations

30 minutes after each vaccinationImmediate reactions:

- Signs or symptoms of anaphylaxis- Immediate local and systemic reactions

For 7 days after each vaccination

1. Body Temperature- Daily Body Temperature- Fever (fever is defined as body temperature ≥ 38.0 °C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics

2. Solicited Local Adverse Events (Injection site erythema, induration, tenderness and swelling)

3. Solicited Systemic Adverse Events (Change in eating habits, sleepiness, irritability, persistent crying, vomiting, diarrhea and rash. In addition to these, parotid/salivary gland swelling** will be collected after the administration of MMR and varicella vaccines)

4. All Adverse Events (including medically attended adverse events§, adverse events leading to premature withdrawal from the study and serious adverse events#)

5. All medications (with the exception of minerals, supplements, vitamins, local

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anaesthetic cream and emollients)

6. All vaccinations (except the study vaccines)

From Day 8 after each vaccination to next vaccination or to 30 days after last vaccination

1. Serious Adverse Events2. Medically attended Adverse Events3. Adverse Events leading to premature withdrawal from the study4. Fever and Solicited Adverse Events persisting beyond Day 75. All medications for treatment of Adverse Events recorded in this period

(with the exception of minerals, supplements, vitamins, local anesthetic cream and emollients)


Additional assessments from Day 8 to Day 28 after MMR + varicella vaccines

1. Body Temperature - Daily temperature- Fever (defined as temperature ≥38°C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics

2. Solicited reactions for MMR + varicella:- Parotid/salivary gland swelling**- Rash

*Medically attended fever: any fever for which a medical visit was sought.** As part of the study evaluations for MMR + varicella given at 12 months of age parents should be encouraged to see a doctor if subjects develop parotid/salivary gland swelling and obtain a diagnosis.§Medically attended adverse events: any adverse event requiring a medical visit (medical visit: a visit by a doctor or a nurse entitled to conduct medical visit [according to local regulations]).#Serious Adverse Events are defined in Protocol Section 6.6.2.

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Number of Subjects planned: To obtain 120 evaluable subjects it is estimated thatapproximately 150 eligible subjects will need to be enrolled in Group A, to allow for a dropout rate of approximately 20%. Taking into account a randomization ratio between group A:B of 2:1, 75 eligible subjects will need to be enrolled in group B.

Subject Population: Healthy male and female infants approximately 2 months of age

Subject Characteristics and Main Criteria for Inclusion and Exclusion:

Healthy male and female infants approximately 2 months of age. The full list of inclusion and exclusion criteria is included in Protocol section 4.0

Vaccines:

Novartis Vaccines and Diagnostics will supply all required study vaccines to subjects.

Study vaccines used in this study

▫ Novartis meningococcal Recombinant B with Outer Membrane Vesicles Vaccine (rMenB+OMV NZ)

▫ GSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + Hib®)▫ Pfizer 13-valent pneumococcal conjugate vaccine (Prevenar-13®)

▫ GSK Hepatitis B vaccine (Engerix-B®)▫ GSK Measles, Mumps and Rubella vaccine (Priorix®)

▫ GSK Varicella vaccine (Varilrix®)All vaccines are to be administered by intramuscular (IM) injection on pre-specified locations in the anterolateral area of the left and right thigh.

Antigen dose, vaccine presentation and vaccine administration are further specified in Protocol section 5.0.

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Immunogenicity Endpoints

Primary

The percentage of subjects with SBA titer 1:5 at 1 month following the third vaccination (at 7 months of age) against the indicator strains H44/76, 5/99 and NZ98/254.

Key Secondary

The percentage of subjects with SBA titer 1:5 at 1 month following the booster vaccination (13 months of age) against the indicator strains H44/76, 5/99 and NZ98/254.

Other Secondary

SBA GMTs, GMRs and percentage of subjects with SBA titer 1:5 against the indicator strains H44/76, 5/99, NZ98/254 and strain M10713 at baseline (2 months of age), 1 month after the third vaccination (7 months of age), prior to the booster dose (12 months of age) and at 1 month after the booster dose (13 months of age).

Safety EndpointsLocal (i.e., injection site erythema, induration, tenderness and swelling) and systemic (i.e. change in eating habits, sleepiness, irritability, persistent crying, vomiting, diarrhea, rash, fever [temperature ≥ 38.0 °C] and medically attended fever) adverse events will be assessed for 7 days (including the day of vaccination) post each vaccination according to Table 2.

All AEs occurring during the 7 days (including the day of vaccination) post each vaccination will be collected on a Diary Card. SAEs, medically attended AEs and AEs that result in a subject’s withdrawal from the study will be collected throughout the entire study period.

After the administration of MMR and varicella vaccines (with and without rMenB+OMV NZ) at 12 months of age, rash, , parotid/salivary gland swelling, fever [temperature ≥ 38.0°C], medically attended fever and use of antipyretic medication will be assessed for a prolonged period up to day 28 following MMR and varicella vaccination.

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Statistical Analysis of Primary Objectives and Secondary Objectives:The percentage of subjects with SBA titer ≥1:5 will be presented as point estimates along with the associated 95% Clopper-Pearson confidence intervals (CIs) at baseline (2 months of age, Visit 1), 1 month after the third injection (7 months of age, Visit 4), prior to the booster dose (12 months of age, Visit 7) and at 1 month after the booster dose (13 months of age, Visit 8) for the meningococcal B indicatorstrains H44/76, 5/99 and NZ98/254.

The criterion for the primary objective for a sufficient immune response at Visit 4 (i.e., 1 month after the third injection) is that the lower limit of the two-sided 95% CI for the percentage of subjects with SBA titer ≥ 1:5 is ≥ 70%.

The criterion for the secondary objective for a sufficient immune response at Visit 8 (1 month after booster) is that the lower limit of the two-sided 95% CI for the percentage of subjects with SBA titer ≥ 1:5 is ≥ 75%.

In addition, for each strain (H44/76, 5/99, NZ98/254 and M10713) the GMTs at baseline, at 7 months of age, at 12 month of age and at 13 month of age and geometric mean of the post vaccination to pre-vaccination (baseline) ratio (GMRs) and their associated 95% CIs, median, minimum and maximum antibody levels will be determined using descriptive analyses and presented together with number of subjects for each vaccine group.

All statistical analyses will be performed on the logarithmically (base 10) transformed titers or concentrations.

The proposed sufficiency thresholds are based on previous Novartis Vaccines studies V72P13 and V72P13E1.

Sample Size and Power Considerations:Sample size for this study was calculated under considerations and assumptionsbased on the antibody response of infants observed in the Novartis Vaccines study V72P13 where infants enrolled received 3 doses of the rMenB+OMV NZ vaccine at 2, 4 and 6 months of age. The percentage of subjects with a SBA titer ≥ 1:5 at 1 month after the third vaccination reported in V72P13 study was 100% (99%-100%) for strain 44/76, 84% (82%-86%) for strain NZ98/254, and 100% (99%-100%) for

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strain 5/99.

We assume that the infants in this study will have antibody responses similar to those observed in V72P13, with the percentage of subjects with SBA titer ≥ 1:5ranging from 84% for strain NZ98/254 and 99% for strains 44/76 and 5/99.

Table 3 shows the power that the proportion of subjects with SBA titer ≥ 1:5 one month after the third dose of the rMenB+OMV NZ vaccine is > the threshold, π0, assuming that the true proportions are 0.84, 0.99, and 0.99, respectively, for strains NZ98/254, 44/76, 5/99, with evaluable number of subjects (N = 120) and threshold (π0 = 0.70). The exact test of binomial proportions with two-sided alpha of 0.05 was used to calculate the power.

Table 3: Power that the Proportion of Subjects with SBA titer ≥1:5 is greater than 0.70 (threshold π0) for a Given Strain, True Underlying Proportion, and Sample Size

Strain

πk(proportion of

subjects with SBA titer ≥ 1:5)

π0(Threshold)

Evaluable Sample Size for Group A

Power

NZ98/254 0.84 0.70 120 94%44/76 0.99 0.70 120 99%5/99 0.99 0.70 120 99%

A sample size of 120 evaluable infants was chosen for infants receiving rMenB+OMV NZ together with routine vaccines (Group A). We assume a true proportion of subjects with SBA titer ≥1:5 of 0.84, 0.99 and 0.99 for the NZ98/254, 44.76, and 5/99 strains, respectively, one month after the third injection. With this sample size of 120 evaluable subjects, using an exact test for a single binomial proportion and a 2-sided alpha (Type I error) of 0.05, the power to reject the null hypothesis associated with the primary objective and demonstrate sufficiency of response (i.e., > 0.70) is 94%, 99% and 99%, respectively.

Assuming the results for the three strains are independent, the overall power to demonstrate sufficiency of response is equal to 92%, the product of the 3 individual powers.

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Infants randomized to the control arm will receive routine vaccines only. The control arm of this study has been chosen for safety evaluation purpose and to assess the prevalence of bactericidal meningococcal B antibodies over the study period in infants not receiving rMenB+OMV NZ vaccine. To avoid unnecessary blood draws in infants, a randomization ratio of 2:1 was chosen.

Considering a non ‘per protocol rate’ of approximately 20%, a total of 225 infants are request to be enrolled in to the study (150 in rMenB+OMV NZ + routine vaccines arm and 75 in routine vaccines only arm).

The primary and secondary objectives will be assessed based on both, the Full Analysis Set (FAS) and in the Per Protocol Set (PPS) which will include subjects who received all vaccinations, provide blood draws within an acceptable window, and who have no other major protocol deviations.

Interim Analysis: An interim analysis for the primary immunogenicity and safetyendpoint will be done after all subjects completed the Study Visit 4, one month after the third vaccination (at 7 months of age). Further details regarding the interim analysis are contained in Protocol section 7.5.

Data Monitoring Committee: No Data Monitoring Committee will be convened for this study.

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Table 4: Times and Events Table

Study Related Visit# 1 RCm RC 2 RC RC 3 RC RC 4 5SCn

6SC

7 RC RC RC 8

Months of Age 2 4 6 7 9 11 12 13Study Day 1 3 7 61 63 67 122 124 128 152 213 274 305 307 311 318 335Time Window (min/max)

n/a

0/+2

0/+2

-4/+

7

2 da

ys (0

/+2)

from

Vis

it 2

6 da

ys (0

/+2)

from

Vis

it 2

61 d

ays (

-4/+

7) fr

omV

isit

2

2 da

ys (0

/+2)

from

Vis

it 3

6 da

ys (0

/+2)

from

Vis

it 3

30 d

ays (

-4/+

7) fr

omV

isit

3

61 d

ays (

-7/+

14) f

rom

Vis

it 4

61 d

ays (

-7/+

14) f

rom

Vis

it 5

183

days

(-7/

+14)

from

Vis

it 3

2 da

ys (0

/+2)

from

Vis

it 7

6 da

ys (0

/+2)

from

Vis

it 7

13 d

ays (

0/+2

)fr

om V

isit

7

30 d

ays (

-4/+

7)fr

om V

isit

7

Informed Consent Xa

Inclusion/Exclusion Xa

Medical History Xa

Physical Exam/ Assessmentb

Xa Xa Xa Xa X

Serology Blood Draw(5 ml)c

Xa X Xa X

rMenB + OMV NZ Vaccination(Group A only)

X X X X

Routine Vaccination(Group A and B) X X X X

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6SC

7 RC RC RC 8

30 minutes post injection hypersensitivity reactions assessmentd

X X X X

Diary Card Dispensede X X X X XReminder Phone Call to Complete Diary Cardf

X X X X X X X X X

Telephone Contact for Review of Safety Datag X X

Assess Local/SystemicAdverse eventsh X X X X

Diary Card Reviewedi X X X XAssess AEs and SAEsj X X X X X XConcomitant Medicationk X X X X X X X

Study Terminationl Xa. Procedure to be performed prior to vaccinationb. Physical examination must be performed by a qualified health professional in accordance with local regulations and licensing requirements designated

within the Site Responsibility Delegation Log. See section 6.2 for components of physical examination by visit.c. Maximal blood drawn refers to volume drawn at each specified visit. See section 3.5.1 for greater detail regarding blood sampling volumes.d. A 30 minutes post injection hypersensitivity reactions measurement will be performed under site staff supervision during each vaccination visit.e. Subjects/subject’s legal guardians will receive instruction on Diary Card completion. A Diary Card will be dispensed at this visit. See section 3.2.5.3 for

more detail.f. Subject’s parents(s)/legal guardian(s) will be reminded at telephone contact visits to complete Diary Cards and return them at the next clinic visit.

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g. Subject’s parents(s)/legal guardian(s) will be interviewed by site staff using a scripted interview for collection of safety data. These safety data will be transcribed in source documents by the individuals performing the interviews.

h. Beginning in the evening (approximately 6 hours) following study vaccine administration on Day 1, and daily thereafter through Day 8 (or Day 28 for booster dose), solicited local and systemic adverse events including other reactions (i.e. body temperature measurements and use of antipyretics) will be reported daily by the subject’s parents(s)/ legal guardian(s) on a Diary Card.

i. Review of safety data captured on Diary Cards will be completed at these visits. Subject’s parents(s)/legal guardian(s) will be asked to return to the study clinic with the Diary Card completed. See section 3.2.5.5 for greater detail about Diary Card review.

j. All unsolicited AEs will be captured Day 1through Day 7 on Diary Card by the subject’s parent(s)/legal guardian(s). From Day 8 (or Day 28 for booster dose) after each vaccination to next vaccination/last visit, only SAEs, Medically Attended AEs, AEs leading to premature withdrawal and solicited local/systemic reaction persisting beyond Day 7 (or Day 28 for booster dose) will be collected.

k. Collect concomitant medications and vaccination history according to the study procedures outlined throughout section 3.2.5 and 5.4.l. Any subject who terminates the study during the Post-Vaccination period is recommended to undergo study-related procedures as outline in section 3.8.m. RC = Reminder Call for completion of Diary Card. See section 3.2.5.4 for greater detail.n. SC = Safety Call. See section 3.2.5.6 for greater detail.

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TABLE OF CONTENTS

PROTOCOL SYNOPSIS V72_60 VERSION 1.0............................................................ 2TABLE OF CONTENTS .............................................................................................. 17

LIST OF ABBREVIATIONS........................................................................................ 221.0 BACKGROUND AND RATIONALE............................................................... 24

2.0 OBJECTIVES.................................................................................................... 262.1 Immunogenicity Objective(s) ......................................................................... 26

2.2 Safety Objectives ........................................................................................... 263.0 STUDY DESIGN AND INVESTIGATIONAL PLAN ...................................... 28

3.1 Overview of Study Design ............................................................................. 283.1.1 Study Period........................................................................................... 31

3.2 Study Procedures ........................................................................................... 313.2.1 Informed Consent/Assent ....................................................................... 31

3.2.2 Screening Procedures ............................................................................. 313.2.3 Enrollment ............................................................................................. 32

3.2.4 Randomization ....................................................................................... 323.2.5 Visit Procedures ..................................................................................... 33

3.2.5.1 Pre-vaccination Procedures................................................................. 33

3.2.5.2 Vaccination Procedures ...................................................................... 343.2.5.3 Post-vaccination Procedures ............................................................... 34

3.2.5.4 Reminder Telephone Calls.................................................................. 363.2.5.5 Clinic Visits After Vaccination........................................................... 36

3.2.5.6 Safety Calls ........................................................................................ 373.2.5.7 “For cause” Visits............................................................................... 37

3.2.5.8 Termination Visits .............................................................................. 373.3 Blinding Procedures....................................................................................... 38

3.4 Data Collection .............................................................................................. 383.4.1 Data Collected From Subjects ................................................................ 38

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3.4.2 Electronic Case Report Forms ................................................................ 40

3.5 Laboratory Assessments................................................................................. 403.5.1 Processing, Labeling and Storage of Serum Samples for Serology.......... 40

3.5.2 Pregnancy Testing .................................................................................. 403.5.3 Safety Laboratory Assessments .............................................................. 40

3.5.4 Cell Mediated Immunity Assessments .................................................... 403.5.5 Culture/PCR/Genotyping Assessments ................................................... 41

3.6 Stopping/Pausing Guidelines.......................................................................... 413.7 Premature Withdrawal and Early Study Termination...................................... 41

3.8 Early Termination Visit.................................................................................. 434.0 SELECTION OF STUDY POPULATION......................................................... 45

4.1 Inclusion Criteria ........................................................................................... 454.2 Exclusion Criteria .......................................................................................... 45

4.3 Criteria for Delay of Vaccination and/or Blood Sampling .............................. 464.4 Criteria for Repeat Vaccination in the Study .................................................. 47

5.0 TREATMENT OF SUBJECTS.......................................................................... 485.1 Study Vaccine(s)............................................................................................ 485.2 Non-Study Vaccines ...................................................................................... 52

5.3 Vaccines Preparation and Administration....................................................... 525.4 Prior and Concomitant Medications and Vaccines.......................................... 54

5.5 Vaccine Supply, Labeling, Storage, and Tracking .......................................... 556.0 MEASUREMENTS........................................................................................... 58

6.1 Appropriateness of Measurements.................................................................. 586.2 Demographics, Medical History and Physical Examination............................ 58

6.3 Immunogenicity Measurements...................................................................... 596.4 Efficacy Measurements.................................................................................. 59

6.5 Solicited Safety Measurements ...................................................................... 596.6 Unsolicited Safety Measurements .................................................................. 61

6.6.1 Adverse Events ...................................................................................... 61

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6.6.1.1 Adverse Events of Special Interest...................................................... 63

6.6.2 Serious Adverse Events .......................................................................... 636.6.3 Methods for Assessing and Recording AEs and SAEs ............................ 64

6.6.4 Pregnancies ............................................................................................ 656.7 Safety Laboratory Measurements ................................................................... 66

6.8 Other Measurements ...................................................................................... 666.9 Data Monitoring Committee........................................................................... 66

7.0 ENDPOINTS AND STATISTICAL ANALYSES ............................................. 677.1 Endpoints....................................................................................................... 67

7.1.1 Primary Endpoint(s) ............................................................................... 677.1.2 Secondary Immunogenicity Endpoints.................................................... 67

7.1.3 Secondary Efficacy Endpoints................................................................ 677.1.4 Safety Endpoints .................................................................................... 67

7.1.5 Other Endpoints ..................................................................................... 697.1.6 Exploratory Endpoints............................................................................ 69

7.2 Success Criteria ............................................................................................. 697.2.1 Success Criteria for Primary Objectives.................................................. 697.2.2 Success Criteria for Key Secondary Immunogenicity Objectives ............ 70

7.2.3 Success Criteria for Secondary Efficacy Objectives................................ 707.2.4 Success Criteria for Safety Objectives .................................................... 70

7.3 Analysis Sets ................................................................................................. 707.3.1 All Enrolled Set...................................................................................... 71

7.3.2 Exposed Set........................................................................................... 717.3.3 Full Analysis Set (FAS) Efficacy/Immunogenicity Set ........................... 71

7.3.4 Per Protocol (PP) Population, Efficacy/Immunogenicity Set ................... 717.3.5 Safety Set ............................................................................................... 72

7.3.6 Other Analysis Sets ................................................................................ 727.3.7 Subgroups .............................................................................................. 72

7.3.8 Protocol Deviations ................................................................................ 72

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7.4 Analysis Plan ................................................................................................. 74

7.4.1 Analysis of Demographic and Baseline Characteristics........................... 747.4.2 Analysis of Primary Objectives .............................................................. 74

7.4.2.1 Statistical Hypotheses for Primary Objectives ........................................ 747.4.2.2 Analysis Populations for Primary Objectives ...................................... 75

7.4.2.3 Statistical Methods for Primary Objectives ......................................... 757.4.2.4 Sample Size and Power Considerations of Primary Objectives ........... 75

7.4.2.5 Analysis of Safety Objectives ............................................................. 767.4.2.5.1 Analysis of Extent of Exposure .................................................... 76

7.4.2.5.2 Analysis of Solicited Local and Systemic Adverse Events and Other Reactions 77

7.4.2.5.3 Analysis of Spontaneously Reported Adverse Events................... 797.4.2.5.4 Analysis of Safety Laboratory Values .......................................... 79

7.4.3 Analysis of Key Secondary Immunogenicity Objectives......................... 797.4.4 Analysis of Key Secondary Efficacy Objectives ..................................... 82

7.4.5 Analysis of Key Secondary Other Objectives ......................................... 827.4.6 Analysis of Non-Key Objective .............................................................. 82

7.5 Planned Interim Analysis ............................................................................... 82

8.0 SOURCE DOCUMENTATION, STUDY MONITORING, AND AUDITING.. 848.1 Source Documentation................................................................................... 84

8.2 Study Monitoring and Source Data Verification............................................. 859.0 DATA MANAGEMENT................................................................................... 86

9.1 Data Entry and Management .......................................................................... 869.2 Data Clarification........................................................................................... 86

9.3 Data Coding Procedures................................................................................. 869.4 Data Protection .............................................................................................. 86

10.0 RECORD RETENTION.................................................................................... 8711.0 USE OF INFORMATION AND PUBLICATION ............................................. 88

12.0 ETHICS............................................................................................................. 89

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12.1 Regulatory and Ethical Compliance ............................................................... 89

12.2 Informed Consent Procedures ........................................................................ 8912.3 Responsibilities of the Investigator and IRB/EC............................................. 89

12.4 Protocol Adherence........................................................................................ 9112.5 Protocol Amendments.................................................................................... 91

13.0 REFERENCE LIST ........................................................................................... 92

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LIST OF ABBREVIATIONS

AE Adverse EventAP (Statistical) Analysis PlanBCDM Biostatistics and Clinical Data ManagementCFR Code of Federal RegulationsCHMP Committee for Medicinal Products for Human UseCI Confidence IntervalCRF Case Report FormCRO Contract Research OrganizationDCF Data Clarification FormDTaP Diphteria, Tetanus, acellular PertussiseCRF Electronic Case Report FormEDC Electronic Data CaptureEMA European Medicines AgencyEU European UnionFAS Full Analysis SetFDA Food and Drug AdministrationFSFV First Subject First VisitGCP Good Clinical PracticesGMR Geometric Mean RatioGMT Geometric Mean TiterhSBA Human Serum Bactericidal Assay HepB Hepatitis BHib Haemophilus Influenzae Type BIB Investigator’s BrochureICF Informed Consent FormICH International Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human UseID Identification (Subject ID)IM IntramuscularIPV Inactivated Polio VirusIRB Institutional Review BoardLSLV Last Subject Last VisitMedDRA Medical Dictionary for Regulatory ActivitiesMMR Measles, Mumps, Rubella NVD Novartis Vaccines & DiagnosticsNZ New ZealandOMV Outer Membrane VesiclesPCV Pneumococcal Conjugate VirusPPS Per Protocol Set

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SAE Serious Adverse EventSBA Serum Bactericidal Activity SC SubcutaneouslySDA Source Data AgreementSUSAR Serious Unexpected Suspected Adverse ReactionSOP Standard Operating ProcedureVSAE Vaccine Serious Adverse EventWHO World Health Organization

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1.0 BACKGROUND AND RATIONALE

Meningococcal meningitis and sepsis are diseases that can result in death within hours, despite the availability of effective antibiotics. The diseases are caused by Neisseria meningitidis, a gram-negative, encapsulated bacterium classified into five major pathogenic serogroups (A, B, C, Y, and W-135) on the basis of the chemical composition of distinctive capsular polysaccharides.

Each year approximately 500,000 cases and 50,000 deaths are caused by Neisseria meningitidis globally (World Health Organization (WHO), 2002). The disease is most common in children and young adults. The global incidence of serogroup B has been estimated between 20,000 and 80,000 cases per year, accounting for 2,000-8,000 deaths annually (Girard et al., 2006). In Taiwan, meningococcal serogroup B is the major serogroup associated with meningococcal disease and accounts for approximately 50% of confirmed meningococcal disease cases (Chiou et al., 2006).

The incidence of meningococcal serogroup B disease can increase dramatically during an epidemic, as demonstrated in Latin American countries (Cuba, Brazil and Chile), in Norway and in France (Girard et al., 2006; Rouaud et al., 2006). New Zealand experienced an epidemic of group B meningococcal disease with incidence rates of up to 10 times higher than usual where rates increased from 1.6 cases per 100,000 population in 1990 to 17.4 per 100,000 in 2001. In contrast to serogroup A and C epidemics, which usually resolve in 1 to 3 years, serogroup B epidemics begin slowly but may persist for 10 years or longer, as seen in Cuba, Norway, areas of Chile, and New Zealand (Girard et al., 2006)

Since the 1960s, vaccines consisting of purified polysaccharide antigens have been developed against four (A, C, Y, and W-135) of the five pathogenic serogroups. The use of capsular polysaccharide as the basis of a vaccine for prevention of meningococcal B diseases has proven problematic. The meningococcal B capsular polysaccharide is identical to a widely distributed human carbohydrate (α[2→8] N-acetyl neuraminic acid or polysialic acid), which, being a self-antigen, is poorly immunogenic in humans. The recent sequencing of the meningococcal B genome provided a unique opportunity to discover and test gene products that have been left undetected by conventional biochemical and microbiological approaches (Pizza et al. Science 2000). Making use of a novel genome mining approach based on the meningococcal B sequence information, Novartis Vaccines & Diagnostics (NVD) has developed a Meningococcal B Recombinant Vaccine (rMenB+OMV NZ). Data provided from clinical studies conducted with rMenB+OMV NZ confirm that the vaccine has a similar safety profile to other licensed pediatric vaccines and is able to elicit a robust immune response against selected

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meningococcal B strains. On 14th of January 2013, NVD received EU marketing authorisation for Bexsero for use in individuals from 2 months of age and older.

A comprehensive review of rMenB+OMV NZ is contained in the Investigator’s Brochure (IB) supplied by NVD; this document should be reviewed prior to initiating the study.

Rationale of the study

The study described in this clinical study protocol is a Phase 3 study. The aim of the proposed study is to evaluate the safety and immunogenicity of Novartis rMenB+OMV NZ vaccine when administered concomitantly with routine infant vaccines to healthy infants in Taiwan. The Novartis rMenB+OMV NZ vaccine will be administered in a 3 dose schedule (at 2, 4 and 6 months of age), followed by a booster at 12 months age. This study is intended to support licensure of rMenB+OMV NZ vaccine in Taiwan.

To allow for a descriptive comparison of the study results with the results of clinicalstudies V72P13 and V72P13E1, the primary and key secondary objective of this study are identical to the primary objectives of V72P13 (3-dose schedule at 2, 4 and 6 months of age) and extension study V72P13E1 (booster dose at 12 months of age), respectively.

The trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and applicable regulatory requirement(s).

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2.0 OBJECTIVES

2.1 Immunogenicity Objective(s)

Primary Immunogenicity Objective

To demonstrate the sufficiency of the immune response to rMenB+OMV NZ vaccine, when given concomitantly with routine vaccines (i.e DTaP-IPV-Hib, HepB and PCV-13) to healthy infants at 2, 4, 6 months of age as measured by percentage of subjects with serum bactericidal activity (SBA) titer ≥ 1:5 against the indicator strains H44/76, 5/99 and NZ98/254 at 1 month after the third vaccination (at 7 months of age).

Key Secondary Immunogenicity Objective

To demonstrate the sufficiency of the immune response to a booster dose of rMenB+OMV NZ vaccine when given concomitantly with routine vaccines (i.e. MMR and varicella) to healthy toddlers at 12 months of age that were previously primed with 3-doses of rMenB+OMV NZ, as measured by percentage of subjects with SBA titer ≥ 1:5 against the indicator strains H44/76, 5/99 and NZ98/254 at 1 month after the booster dose (at 13 months of age).

Other Secondary Immunogenicity Objective

To assess bactericidal antibodies against meningococcal B in healthy infants receivingrMenB+OMV NZ concomitantly with routine vaccines (Group A) or routine vaccines alone (Group B) at 2, 4, 6 and 12 months of age, as measured by SBA geometric mean titers (GMTs), and geometric mean ratios between post and pre-vaccination (baseline) titers (GMRs) and percentage of subjects with SBA titer ≥ 1:5 against indicator strainsH44/76, 5/99, NZ98/254 and strain M10713 at baseline (2 months of age), 1 month after the third vaccination (7 months of age), prior to the booster dose (12 months of age) and at 1 month after the booster dose (13 months of age).

2.2 Safety Objectives

To assess the safety and tolerability of 3 doses of rMenB+OMV NZ given at 2, 4, 6 months of age, followed by a booster dose at 12 months of age when concomitantly administered with routine vaccines (i.e. combined DTaP-IPV-Hib and PCV-13 at 2, 4, 6 months; HepB at 6 months of age; MMR and varicella at 12 months of age) and of routine infant vaccines alone in terms of percentages and numbers of subjects with:


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Parotid/salivary gland swelling will be collected for an extended period of 28 daysafter MMR and varicella).


- SAEs, medically attended AEs, AEs leading to withdrawal from the study throughout the entire study.

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3.0 STUDY DESIGN AND INVESTIGATIONAL PLAN

3.1 Overview of Study Design

Introduction of study design and rationale

This is a Phase 3, open-label, randomized, controlled, multi-center study to evaluate the safety and immunogenicity of NVD rMenB+OMV NZ vaccine when administered concomitantly with routine vaccines to healthy infants in Taiwan. The rMenB+OMV NZ vaccine will be administered in a 3 dose schedule (at 2, 4 and 6 months of age), followed by a booster at 12 months age. Concomitantly, infants will receive routine vaccines, i.e.diphtheria (D), tetanus (T), acellular pertussis (aP), poliovirus types 1, 2, 3 (IPV), Hepatitis B (HepB), Haemophilus influenzae type b (Hib), 13-valent pneumococcal conjugate vaccine (PCV-13), measles, mumps, rubella (MMR) and varicella. For safety comparison and to assess the prevalence of bactericidal meningococcal B antibodies over the study period in infants not receiving rMenB+OMV NZ vaccine infants will receive routine vaccines alone as a control. The results of this study are intended to support licensure of rMenB+OMV NZ in Taiwan.

All staff participating in the study will be trained in a uniform fashion and all participating sites will be monitored to ensure consistency in study execution across all centers.

At the enrollment visit (Visit 1), the investigator, or a person designated by the investigator, should fully inform the subject’s parent(s) or guardian(s) of all pertinent aspects of the trial and the subject’s parent(s)/legal guardian’s written informed consent will be obtained. After obtaining written informed consent from the subject’s parents/legal guardians, a physical examination will be performed and medical historyobtained. A brief physical assessment will be performed prior to each subsequent injection.

Subjects will only be enrolled after their eligibility for participation is confirmed. After meeting enrollment criteria, approximately 225 subjects will be randomized to receive rMenB+OMV NZ vaccine + routine vaccines (Group A) or routine vaccines alone (Group B) in a 2:1 ratio.

Vaccination procedures

Subjects that have been enrolled in this study will receive the study vaccines in an open-label fashion, i.e. the subject’s parent(s)/legal guardian(s) and study staff will not be blinded for the group to which the subject is assigned. Subjects randomized to Group Awill receive 4 vaccinations of rMenB+OMV NZ concomitantly with routine vaccines

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according to the Taiwanese immunization program at 2, 4, 6 and 12 months of age.Subjects assigned to the control group (Group B) will receive routine vaccines alone at 2, 4, 6 and 12 months of age. All vaccines will be administered to the subjects by designated nurse(s) or physician(s).

Post-vaccination evaluations

After each vaccination, the safety of the vaccines will be evaluated using routine procedures:

▫ Immediate local and systemic adverse events or signs/symptoms of anaphylaxis will be collected for 30 minutes after each vaccination by study personnel.

▫ Body temperature, fever (body temperature ≥ 38.0 °C), medically attended fever, solicited local and systemic adverse events, any adverse events and any medication taken by the subject will be collected for 7 days (extended to 28 days after MMR + varicella vaccination) after each vaccination using a Diary Card.

▫ All serious adverse events, medically attended adverse events, adverse events leading to premature withdrawal from the study, all solicited adverse events and fever persisting beyond Day 7 and any medication for treatment of adverse events will be collected throughout the entire study using Diary Cards.

▫ Safety Phone calls will be performed when subjects are approximately 9 and 11 months of age to collect information relating to unsolicited adverse events and concomitant medications associated with those events.

Prior to the first vaccination (at 2 months of age), 1 month after the third vaccination (at 7 months of age), prior to the booster vaccination (at 12 months of age) and 1 month after the booster vaccination (at 13 months of age) a blood sample will be taken from allsubjects to evaluate bactericidal antibodies against meningococcal B.

Vaccinations and blood samples will be completed according to Table 3.1-1.

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Novartis Vaccines and Diagnostics Protocol V72_6014 MAY13 Version 1.0 Confidential Page 30 of 92


Table 3.1-1: Summary of study related events

Part of Interim analysis at 7 monthsGroup Subjects

(n)2 months(Visit 1)

4 months(Visit 2)

6 months(Visit 3)

7 months(Visit 4)

9 months(Visit 5)

11 months(Visit 6)

12 months(Visit 7)

13 months(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-HibPCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-HibPCV-13

rMenB+OMV NZ

DTaP-IPV-HibPCV-13

HepB (3rd dose)*

Blood Draw

Safety Call Safety Call rMenB+OMV NZ

MMRVaricella

Blood Draw

Blood Draw


Blood Draw

DTaP-IPV-HibPCV-13

DTaP-IPV-HibPCV-13

HepB (3rd dose)*

Blood Draw

Safety Call Safety Call MMRVaricella

Blood Draw

Blood Draw

*According to the Taiwanese Immunization Program Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively.In addition, BCG vaccine will be administered ≤ 24 hours after birth.

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3.1.1 Study Period

Expected duration of the study for an individual subject is approximately 11 months.

3.2 Study Procedures

The sections that follow provide an overview of the procedures that are to be followed in enrolling, evaluating, and following subjects who participate in this clinical trial.

3.2.1 Informed Consent/Assent

"Informed consent" is the voluntary agreement of an individual or his/her legal guardian to participate in research. Consent must be given with free will of choice, and without undue inducement. The individual that gives informed consent must have sufficient knowledge and understanding of the nature of the proposed research, the anticipated risks and potential benefits, and the requirements of the research to be able to make an informed decision.

Informed consent following local IRB guidance must be obtained before conducting any study-specific procedure (i.e., all of the procedures described in the protocol). The process of obtaining informed consent should be documented in the subject source documents in addition to maintaining a copy of the signed and dated informed consent.

If the subject’s guardian/parent is unable to read, an impartial witness should be present during the entire informed consent discussion. An impartial witness is defined as a person who is independent from trial conduct, who cannot be unfairly influenced by those involved with the trial, who attends the informed consent process if the subject's legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject. After the written informed consent form and any other written information to be provided to subject’s guardian/parent, is read and explained to the subject’s guardian/parent and after the subject’s guardian/parent has verbally consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject’s guardian/parent and that informed consent was freely given by the subject’s guardian/parent.

3.2.2 Screening Procedures

After the subject’s guardian/parent has consented for the subject to participate in the study and informed consent is signed, the subject will be given a unique screening number

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which is documented in the Screening Log. Screening procedures will include the following:

- Review of demographic data from the subject, including: date of birth, gender, height, weight and race (refer to section 6.2 for details)

- Review of the subject’s medical history (refer to section 6.2 for details)

- Review of prior and concomitant medication, including all vaccinations from birth to start of the study (refer to section 5.4 for details)

- General physical examination (refer to section 6.2 for details)- Review of eligibility criteria (refer to sections 4.1 and 4.2 for the complete list)

Eligibility to be enrolled in the study will be evaluated at Visit 1 (Day 1)

In the event that the individual is determined ineligible for study participation, he/she is considered a “screen failure”. The reason for screen failure must be documented in the Screening Log. If the individual is determined to be eligible for the study, he/she should be assigned an enrollment number and enrolled into the study as described in section 3.2.3.

3.2.3 Enrollment

After an individual is determined to be eligible for study participation, the subject will be enrolled in the electronic data capture (EDC) system; using the screening number assigned by the EDC system and then randomized. At randomization, the subject will automatically be assigned a unique Subject ID. The Subject ID consists of a 5 digit number resulting from the combination of the site number, the subject’s order of randomization at the site.

3.2.4 Randomization

Enrolled subjects will be randomly assigned to study group A or B in a pre-specified ratio of 2:1 and according to web-based randomization. The list of randomization assignments is produced by a validated system used by the NVD Biostatistics and Clinical Data Management (BCDM) department.

If for any reason, after signing the informed consent form (ICF), the subject (who has passed screening) fails to be randomized, the reason for not being randomized should berecorded in source documents as specified in the source data agreement. The information on these subjects, who are randomization failures, should be kept distinct in the source documentation from screen failures, which are described in section 3.2.2.

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Additional subjects may be randomized into the study at the discretion of the sponsor in the case of any subject who:

▫ Is randomized but does not receive any study vaccine.

▫ Has consent for participation in the study but who is withdrawn for reasons other than an adverse event.

3.2.5 Visit Procedures

3.2.5.1 Pre-vaccination Procedures

At Visit 1 (Day 1, 2 months of age) the following pre-vaccination procedures will beperformed:

1. informed consent (refer to sections 3.2.1 and 12.2 for further detail)2. demography (refer to section 6.2 for details)

3. prior and concomitant medication and vaccines (refer to section 5.4 for further detail)4. medical history (refer to section 6.2 for details)

5. general physical examination (refer to section 6.2 for details)6. measurement of subject’s height and weight (refer to section 6.2 for details)

7. review of eligibility criteria (refer to sections 4.1 and 4.2 for inclusion and exclusion criteria)

8. enrollment (refer to section 3.2.3)

9. randomization (refer to section 3.2.4)10. prior to vaccination, a blood sample will be drawn for serology testing. Details

regarding the volume of blood and testing to be performed are specified in section 3.5.1

At Visit 2 (Day 61, 4 months of age) and Visit 3 (Day 122, 6 months of age) the following pre-vaccination procedures will be performed:

1. general physical examination (refer to section 6.2 for details)2. review of eligibility criteria (refer to section 4.1 to 4.4 for eligibility criteria and

criteria for delay of vaccination)At Visit 7 (Day 305, 12 months of age) the following pre-vaccination procedures will be performed:

1. general physical examination (refer to section 6.2 for details)

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2. review of eligibility criteria (refer to section 4.1 to 4.4 for eligibility criteria and criteria for delay of vaccination)

3. prior to vaccination, a blood sample will be drawn for serology testing. Details regarding the volume of blood and testing to be performed are specified in section 3.5.1

3.2.5.2 Vaccination Procedures

Vaccination will be performed on Visit 1 (Day 1, 2 months of age), Visit 2 (Day 61, 4 months of age), Visit 3 (Day 122, 6 months of age) and Visit 7 (Day 305, 12 months of age)

At Visit 1 (Day 1), after confirming eligibility and enrolling subject into the study perform vaccination of the subject according to the assigned study vaccine and according to the procedures described in section 5.3. At later clinic visits that involve vaccination, confirm that the subject does not meet any criteria for delaying or cancelling additional study vaccinations, as described in section 4.3 and section 4.4 of the protocol.

3.2.5.3 Post-vaccination Procedures

The following post-vaccination procedures will be performed on Visit 1 (Day 1, 2 months of age), Visit 2 (Day 61, 4 months of age), Visit 3 (Day 122, 6 months of age) and Visit 7(Day 305, 12 months of age):

1. Diary Card TrainingCareful training of the subject’s parent/guardian on how to measure local reactions and body temperature, how to complete and how often to complete the Diary Card is crucial. Training should be directed at the individual(s) who will perform the measurements of reactions and those who will enter the information into the Diary Card. This individual may not be the parent/guardian, but if a person other than the parent/guardian enters information into the Diary Card, this person’s identity must bedocumented in the study file and this person must receive training on the Diary Card. Training of the parent/guardian on how to measure an injection site reaction should be performed while the subject is under observation after vaccination.

Diary Card instruction must include the following:

a. The subject’s parent/guardian must understand that timely completion of the Diary Card on a daily basis is a critical component to study participation. The parent/guardian should also be instructed to write clearly and to complete the diary card in pen. Any corrections to the Diary Card that are performed by the

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person completing the diary card should include a single strikethrough line with a brief explanation for any change. No changes can be made to the Diary Card when it is returned to the clinic.

b. Starting on the day of vaccination, the subject’s parent/guardian will check in the evening for specific types of reactions at the injection site (solicited local adverse events), any specific generalized symptoms (solicited systemic adverse events), body temperature (taken preferably by rectal measurement), any other symptoms or change in the subject’s health status, and any medications taken (excluding vitamins and minerals). These solicited adverse events and body temperature will be recorded in the “six hour” location on the Diary Card.

c. Body temperature measurement is to be performed using the thermometer provided by the site. If the subject feels unusually hot or cold during the day, the subject’s parent/guardian should check body temperature. If the subject has fever, the highest body temperature observed that day should be recorded on the Diary Card. The measurement of solicited local adverse events is to be performed using the ruler provided by the site. The collection of body temperature, solicited local adverse events, solicited systemic adverse events will continue for a total of 7days on the Diary Card. Note: After vaccination with MMR and varicella (at Visit 7) the period for collection of body temperature, medically attended fever, parotid/salivary gland swelling and rash will be extended to 28 days after vaccination. The collection of unsolicited adverse events and medications will continue throughout on the Diary Card up to the evening prior to the next clinic visit.

2. After vaccination, the subject will be observed for at least 30 minutes including observation for unsolicited adverse events, solicited adverse events, and body temperature measurement. Record all safety data collected in the subject’s source documents. Please take the opportunity to remind the subject how to measure solicited reactions and body temperature as part of this observation period.

3. The site should schedule the next study activity, i.e. reminder call with the subject’sparent/guardian.

4. The subject’s parent/guardian will receive a written reminder of the next planned study activity. The parent/guardian will be reminded to complete the Diary Card daily and to contact the site if there are any questions and to contact the site immediately (or as soon as the subject is medically stable) if the subject has a medical condition that leads to a hospitalization or an emergency room visit.

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3.2.5.4 Reminder Telephone Calls

Reminder calls will be performed 2 days and 6 days after each vaccination. Because of the extended period for collection of solicited events after MMR + varicella vaccination, an additional reminder phone call will be performed at 13 days after Visit 7. The purpose of these calls is to remind the subject’s parent/guardian about completion of the Diary Card. It is a conversation that follows the reminder telephone call script provided to the site, and it is not intended to be a call for collection of safety data. If the subject’s parent/guardian wishes to describe safety information, this information should only be collected by a trained healthcare professional at the site, and the safety data described must be written down in source documents. The subject’s parent/guardian should be reminded to write the information down in the diary card and to contact the site via the telephone number provided in the informed consent to discuss medical questions.

3.2.5.5 Clinic Visits After Vaccination

A clinic visit (Visit 4) that does NOT include vaccine administration will be performed on Day 152 (at 7 months of age). At this clinic visit the following procedures will be performed:

1. The Diary Card will be reviewed. Please see section 3.4.1 for additional guidance on diary card review.

2. A blood sample will be drawn for serology testing. Details regarding the volume of blood and testing to be performed are specified in section 3.5.1.

3. A Diary Card will be dispensed for the collection of SAEs, medically attended AEs, AEs leading to premature study withdrawal, any solicited events that persist beyond Day 7 after third vaccination, any medication for treatment of AEs and all vaccinations. Careful instruction of the subject’s parent/guardian on how to fill in the Diary Card will be provided and the importance of the timely completion of the Diary Card will be emphasized.

4. The site should schedule the next clinic visit (safety phone call) with theparent/guardian.

5. The parent/guardian will receive a written reminder of the next planned study activity. The parent/guardian will be reminded to complete the Diary Card daily and to contact the site if there are any questions and to contact the site immediately (or as soon as the subject is medically stable) if the subject has a medical condition that leads to a hospitalization or an emergency room visit.

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3.2.5.6 Safety Calls

Safety phone calls will be performed on Visit 5 (Day 213, 9 months of age) and Visit 6(Day 274, 11 months of age). Safety phone calls are calls made to the subject’s parent/guardian by a trained healthcare provider. These calls will follow a script which will facilitate the collection of relevant safety information. The parent/guardian will be interviewed according to the script, and information relating to unsolicited adverse events(including serious adverse events (SAEs) and AEs leading to study or vaccine withdrawal) and concomitant medications associated with those events. All safety information described by the subject must be written down in a designated location within the source documents and not written on the script used for the telephone call.

The site should schedule the next study activity (next clinic visit or safety phone call)with the parent/guardian. Moreover, the parent/guardian will be reminded to contact the site if there are any questions and to contact the site immediately (or as soon as the subject is medically stable) if the subject has a medical condition that leads to a hospitalization or an emergency room visit.

3.2.5.7 “For cause” Visits

Not applicable

3.2.5.8 Termination Visits

The termination visit (Visit 8) will occur on Day 335 (at 13 months of age). For visit procedures to be performed for a subject whose planned study participation ends prematurely, please see section 3.8.

At the termination visit, the following procedures will be performed:

1. The Diary Card will be reviewed. Please see section 3.4.1 for additional guidance on diary card review;

2. A blood sample will be drawn from for serology testing. Details regarding the volume of blood and testing to be performed are specified in section 3.5.1;

3. Interview of the parent/guardian to collect unsolicited AEs, SAEs and AEs leading to study or vaccine withdrawal;

4. Interview of subject and parent/guardian to collect concomitant medications/ vaccinations;

5. Symptom-directed physical assessment (including measurement of vital signs, body temperature [via rectal route] and a check of general appearance).

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After thanking the parent/guardian for study participation, the site will review the plan of when information relating to the subject’s participation in the study may be available (e.g., study results, treatment assignments). It will also be discussed how information relating to the subject’s participation in the study will be shared with the subject’s healthcare provider, if the parent/guardian chooses to share this information.

The site will complete the termination CRF page and this will mark the completion of the subject’s participation in the study.

3.3 Blinding Procedures

The study is an open-label study. Therefore, no blinding procedures are in place.

3.4 Data Collection

3.4.1 Data Collected From Subjects

All data collected from subjects and provided to the sponsor for analysis must be stripped of any identifiers that reveal the identity of that individual (beyond the use of subject ID, as described in section 3.2.3).

The use of any written or verbal information identifying the subject such as name, initials, photos or testimonials, requires separate and appropriate documented consent from each subject’s parent/guardian.

All subject related data collected during the study will be recorded on eCFRs and Diary Cards.

eCRFs

All data collected from the subject by the investigator at clinical visits according to visit procedures described in section 3.2.5 will be recorded on eCRFs.

Diary Cards

Data collected at home by the subject’s parents/guardians will be recorded on Diary Cards.

The following data will be collected by the subject’s parents/guardians on Diary Cards for 7 days following each vaccination:

- Body temperature

- Medically attended fever

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- Solicited AEs (local and systemic)

- Any AEs- Concomitant medications

- All vaccinations (except the study vaccines)Note: After vaccination with MMR and varicella (at Visit 7) the period for collection of body temperature, medically attended fever and the solicited adverse events parotid/salivary gland swelling and rash will be extended to 28 days after vaccination.

The following data will be collected on Diary Cards from Day 8 after each vaccination until the next clinic visit:

- Serious AEs (SAEs)- Medically attended AEs

- AEs leading to premature withdrawal from the study- Fever and solicited local/systemic AEs persisting beyond Day 7

- All medications for treatment of AEs (with exception of minerals, supplements, vitamins)

- All vaccinations (except the study vaccines)Subsequently, all data collected on Diary Cards by the subject’s parents/guardians will be recorded on eCRFs by the investigator.

Diary Cards will be the only source document allowed for solicited systemic and local adverse events (including body temperature measurements). The following additional rules apply to documentation of safety information collected by Diary Card:

1. No corrections or additions to the Diary Card will be allowed after it is delivered to the site.

2. Any blank or illegible fields on the Diary Card must be described as missing in the CRF.

3. The site must enter all readable entries in the Diary Card into the CRF, including those values that may be biologically implausible (e.g. body temperature: 400°C).

4. Any illegible or implausible data should be reviewed with the parent/guardian. If an underlying solicited or unsolicited adverse event is described. For example, if the subject with a body temperature of 400°C describes that the body temperature was actually 40°C on the day in which body temperature: 400°C was written into the

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Diary Card, this fever of 40°C should be described in the study file and reported as an unsolicited adverse event in the adverse event CRF.

5. Any newly described safety information (including a solicited reaction) must NOT be written into the Diary Card and must be described in the study file as a verbally reported event. Any adverse reaction reported in this fashion must be described as an unsolicited reaction and therefore entered on the adverse event CRF.

3.4.2 Electronic Case Report Forms

In this study, all subject’s data will be entered into eCRFs in a timely fashion by the investigator and/or the investigator’s delegated site staff.

3.5 Laboratory Assessments

3.5.1 Processing, Labeling and Storage of Serum Samples for Serology

In order to provide the necessary serum volume (approximately half of the blood draw volume) for the serology assays, a 5 mL sample of blood will be drawn from subjects at Visit 1 before vaccination, at Visit 4 (Day 152, at 7 months of age), at Visit 7 before vaccination (Day 305, at 12 months of age) and at Visit 8 (335, at 13 months of age). The blood volume will not exceed 5 mL at each time point. Detailed information about the assay and analysis of the serology data is provided in section 6.3.

All samples will be tested blinded. Detailed instructions for blood collection, processing, labeling and storage of samples are included in the Serology Manual.

Samples will be retained in accordance with regulatory guidance for retention of essential study documents as described in section 10.

3.5.2 Pregnancy Testing

Not applicable.

3.5.3 Safety Laboratory Assessments

Not applicable.

3.5.4 Cell Mediated Immunity Assessments

Not applicable.

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3.5.5 Culture/PCR/Genotyping Assessments

Not applicable.

3.6 Stopping/Pausing Guidelines

There are no predetermined stopping rules other than circumstances for which subjects may not be eligible for additional study vaccinations as described in section 4.4 or may be removed from the study according to investigator discretion as described in section 3.7.

3.7 Premature Withdrawal and Early Study Termination

A subject may discontinue study participation at any time prior to the last planned study visit. This is referred to as premature withdrawal from the study (see below for a description of withdrawal from study vaccine for subjects which refers to those subjects who do not receive additional vaccine doses but continue in the study for safety follow-up and/or other procedures). The reasons for premature withdrawal from the study include:

▫ Adverse event

▫ Death▫ Withdrawal of consent

▫ Lost to follow-up▫ Administration reason▫ Protocol deviation

▫ OtherNOTE: Before entering any alternate category as the reason for the subject’s discontinuation from the study, the investigator should make every effort to investigate whether or not safety concerns (adverse event or death) may have been related to the subject’s discontinuation from the study. If a safety concern has been associated with the subject’s discontinuation, this must be described on the Termination CRF page, even if it is not the primary reason for the subject’s discontinuation.

Adverse event as reason for premature study withdrawal

For any subject withdrawing from study participation prior to the planned Termination visit, it is important to determine if an AE was associated with the reason for discontinuing the study. This AE must be identified on the AE CRF page by indicating “Withdrawn from study due to AE”.

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Death as reason for premature study withdrawal

For any subject withdrawn from study participation due to death, this should be noted on the Termination CRF page and the associated SAE that led to the death must be reported.

Withdrawal of consent as reason for premature study withdrawal

The subject’s parent/guardian can withdraw consent for participation in the study at any time without penalty or loss of benefit to which the subject is otherwise entitled. Reason for early termination should be deemed as “withdrawal of consent” if the subject withdraws from participation due to a non-medical reason (i.e., reason other than AE). If the parent/guardian intends to withdraw consent from the study, the investigator should clarify if the subject will withdraw completely from the study or if the subject will continue study participation for safety or a subset of other study procedures. If complete withdrawal from the study by the subject is specified, no further study interventions will be performed with the subject.

The date of termination is the date of the last contact (clinic visit or telephone) in which the subject’s health status was assessed or, in cases where the subject does not agree to any further safety follow-up; it is the date consent is withdrawn.

Lost to follow-up as reason for premature study withdrawal

For subjects who fail to show up for scheduled visits (clinic or safety phone calls ), studystaff are encouraged to make at least three documented attempts to contact the subject by telephone and at least one documented written attempt to contact the subject’sparents/guardians and encourage the completion of study termination procedures. These efforts to contact the subject should be recorded in the source documents. The termination date for the subject to be captured on the Termination CRF page is the date of the last successful visit (clinic or safety phone calls) with the subject.

Administrative reason as reason for premature study withdrawal

For subjects who are withdrawn from the study due to sponsor decision (e.g., meeting prespecified withdrawal criteria or termination of study by the sponsor), this reason should be noted in the Termination CRF page and any ongoing AEs at the time of study withdrawal must be followed until resolution/stabilization.

Protocol deviation as reason for premature study withdrawal

In general, subjects associated with protocol deviations may remain in the study unless continuation in the study jeopardizes the subject’s health, safety, or rights. For subjects who are withdrawn from the study due to receipt of an excluded medication/vaccination

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or due to significant protocol non-compliance, this reason should be noted in the Termination CRF page. Any ongoing AEs at the time of study withdrawal must be followed until resolution/stabilization.

If a subject is withdrawn prematurely from the study for a reason other than those outlined above, this reason must be documented in the Termination CRF page.

Withdrawal of study vaccination

The act of withholding additional study vaccinations is referred to as withdrawal of study vaccination. Subjects may be withdrawn from study vaccination for several reasons including but not limited to: AE related to earlier vaccinations, failure to meet criteria for revaccination (see section 4.4). Subjects who are withdrawn from study vaccination should be encouraged to continue in the study for safety follow-up and other procedures as appropriate until the scheduled termination visit. If the subject is withdrawn from study vaccination(s) due to adverse event, this event must be linked to the withdrawal from vaccination on the AE CRF page.

The sponsor or the investigator (following consultation with the sponsor) has the right to discontinue this study at any time. If the clinical study is prematurely terminated, the investigator is to promptly inform the study subjects and local EC/IRB and should assure appropriate therapy and follow up for the subjects. All procedures and requirements pertaining to the archiving of study documents should be followed. All other study materials (study medication/vaccines, etc.) must be returned to the sponsor.

Withdrawn subjects will not be replaced.

When a subject is withdrawn or withdraws from the study, the procedures described in section 3.8 should be completed if possible.

3.8 Early Termination Visit

When a subject is withdrawn or withdraws from the study, the investigator will notify the sponsor and, when possible, will perform the procedures listed below.

▫ Collect Diary Card▫ Review the subject’s solicited and unsolicited safety data

▫ Perform review of concomitant medications/vaccinations since last visit▫ Collect vital sign measurements, including respiratory rate, blood pressure, pulse rate,

and temperature (rectal)

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▫ Symptom-directed physical assessment (including measurement of vital signs, body temperature [via rectal route] and a check of general appearance)Data from the early termination visit should be recorded on the Study Termination Visit eCRF form.

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4.0 SELECTION OF STUDY POPULATION

4.1 Inclusion Criteria

In order to participate in this study, all subjects must meet ALL of the inclusion criteria described.

Infants eligible to be enrolled into this study are:

1. healthy 2-month old infants (55-89 days, inclusive), who were born after full term pregnancy with an estimated gestational age ≥ 37 weeks and a birth weight ≥ 2.5 kg;

2. for whom a parent/legal guardian has given written informed consent after the nature of the study has been explained;

3. available for all the visits scheduled in the study;4. in good health as determined by medical history, physical examination and clinical

judgment of the investigator.

4.2 Exclusion Criteria

In order to participate in this study, all subjects must meet NONE of the exclusion criteria described below:

1. History of any meningococcal vaccine administration;2. Prior vaccination with any Diphtheria, Tetanus, Pertussis (acellular or whole cell),

Polio (either Inactivated or Oral), Haemophilus influenzae type b (Hib), Pneumococcal, MMR or varicella antigens;

3. Previous ascertained or suspected disease caused by N. meningitidis;

4. Household contact with and/or intimate exposure to an individual with laboratory confirmed N. meningitidis;

5. History of severe allergic reaction after previous vaccinations or hypersensitivity to any vaccine component;

6. Significant acute or chronic infection within the previous 7 days or body temperature 38C within the previous day;

7. Antibiotics within 6 days prior to enrollment;8. Any serious chronic or progressive disease according to the judgment of the

investigator (e.g., neoplasm, insulin dependent diabetes mellitus Type I, cardiac disease, hepatic disease, progressive neurological disease or seizure, either associated with fever or as part of an underlying neurological disorder or syndrome, autoimmune

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disease, HIV infection or AIDS, or blood dyscrasias or diathesis, signs of cardiac or renal failure or severe malnutrition);

9. Known or suspected impairment/alteration of the immune system, immunosuppressive therapy, use of systemic corticosteroids or chronic use of inhaled high-potency corticosteroids since birth;

10. Receipt of blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation;

11. Receipt of, or intent to immunize with any other vaccine(s) (with the exception of rotavirus vaccine,), within 30 days prior and throughout the study period.Furthermore, subjects must have received HepB vaccine preferably at 0, 1 month of age, with the second dose at least 14 days prior to study vaccination. Rotavirus vaccine should be administered at least 14 days before or 14 days after study vaccination;

12. Participation in another clinical trial since birth or planned for during study;13. Family members and household members of research staff;

14. Any condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives.

There may be instances when individuals meet all entry criteria except one that relates to transient clinical circumstances (e.g., body temperature elevation or recent use of excluded medication or vaccine). Under these circumstances, a subject may be considered eligible for study enrollment if the appropriate window for delay has passed, inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be eligible.

4.3 Criteria for Delay of Vaccination and/or Blood Sampling

After enrollment, subjects may encounter clinical circumstances that warrant a delay in subsequent study vaccination. These situations are listed below. In the event that a subject meets a criterion for delay of vaccination, the subject may receive study vaccinesonce the window for delay has passed as long as the subject is otherwise eligible for study participation.

▫ Individuals with significant acute or chronic infection within the previous 7 days orbody temperature ≥38.0°C within the previous day.

▫ Receipt of any antipyretic medication within the previous 6 hours.

▫ Individuals that received any other vaccines (with the exception of HepB androtavirus vaccine), within 30 days prior to enrollment. Individuals that received

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rotavirus vaccine or the second dose of HepB vaccine within 14 days prior to study vaccination.

There are also circumstances under which repeat vaccination is a contraindication in this study. These circumstances include anaphylaxis or severe hypersensitivity reactions following vaccination. If these reactions are to occur, the subject must not receive additional vaccinations but is encouraged to continue in study participation.

There are clinical circumstances that warrant delay of blood collection for immunogenicity assessments in this study. These situations are listed below. In the event that a subject meets a criterion for delay of blood collection, blood collection may proceed once the window for delay has passed.

▫ Subject has received a dose of systemic antibiotics less than 6 days before blood collection.

4.4 Criteria for Repeat Vaccination in the Study

Prior to receipt of additional study vaccination, subjects must be evaluated to confirm that they are eligible for subsequent vaccination. If subjects meet any of the original exclusion criteria or the criteria listed below, they should not receive additional vaccinations.

▫ Subjects who experience any serious adverse event judged to be possibly or probably related to study vaccine or non-study vaccines, including hypersensitivity reactions.

▫ Subjects who develop any new condition which, in the opinion of the investigator, may pose additional risk to the subject if he/she continues to participate in the study.

Subjects who meet any of these criteria must not receive further study vaccinations. However, these subjects should be encouraged to continue study participation, as discussed in sections 3.7 and 3.8.

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5.0 TREATMENT OF SUBJECTS

All vaccines associated with this study are to be stored separately from other vaccines and medications in a secure location under appropriate storage conditions with temperature monitoring. All vaccines associated with this study must be checked for expiration date prior to use. Expired vaccines must not be administered to subjects.

5.1 Study Vaccine(s)

The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be evaluated as part of the study objectives. The study vaccines specific to this study are described below:




▫ GSK Varicella vaccine (Varilrix®)Vaccine compositions are detailed in Table 5.1-1.

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Table 5.1-1: Study Vaccine CompositionsNovartis Meningococcal B Recombinant + OMV vaccine (rMenB+ OMV)active ingredients quantity per 0.5 ml doseN meningitidis 961c purified antigen 50 µgN meningitidis 936-741 purified antigen 50 µgN meningitidis 287-953 purified antigen 50 µgOMV from N meningitidis Strain NZ 98/254 25 gother ingredientsAluminum HydroxideSodium ChlorideSucroseHistidineWater for injectionvaccine presentation pre-filled syringeextractable volume 0.5 mlGSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + HIB®) active ingredients quantity per 0.5 ml doseDiphtheria toxoid1 ≥ 30 IUTetanus toxoid1 ≥ 40 IUPertusis toxoid1 25 µgFilamentous haemagglutinin1 25 µgPertactin 8 µgPoliovirus (inactivated) type 1 (Mahoney strain) 40 D-antigen unitsPoliovirus (inactivated) type 2 (MEF-1 strain) 8-D-anitgen unitsPoliovirus (inactivated) type 3 (Saukett strain) 32-D-anitgen unitsHeamophilus influenzae type B polysaccharide absorbed to tetanus toxoid (approx. 30 µg) carrier protein

10 µg

1adsorbed on aluminium hydroxide (0.5 mg)other ingredientsLactoseSodium Chloride2-phenoxythanolMedium 199 (aminoacids, mineral salts, vitamins)Water for injectionsvaccine presentation vial + pre-filled syringeextractable volume 0.5 ml

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Pfizer 13-valent pneumococcal conjugate vaccine (Prevenar-13®)active ingredients quantity per 0.5 ml dosePneumococcal PS serotype 1* 2.2 µgPneumococcal PS serotype 3* 2.2 µgPneumococcal PS serotype 4* 2.2 µgPneumococcal PS serotype 5* 2.2 µgPneumococcal PS serotype 6A* 2.2 µgPneumococcal PS serotype 6B* 4.4 µgPneumococcal PS serotype 7F* 2.2 µgPneumococcal PS serotype 9V* 2.2 µgPneumococcal PS serotype 14* 2.2 µgPneumococcal PS serotype 18C* 2.2 µgPneumococcal PS serotype 19A* 2.2 µgPneumococcal PS serotype 19F* 2.2 µgPneumococcal PS serotype 23F* 2.2 µg*Conjugated to CRM197 and absorbed on aluminium phosphate (0.125 mg)other ingredientsSodium chlorideSuccine acidPolysorbate 80Water for injectionsvaccine presentation pre-filled syringeextractable volume 0.5 mlGSK Hepatitis B vaccine (Engerix-B®)active ingredients quantity per 0.5 ml doseHepatitis B surface antigen* 10 µgother ingredientsSodium chlorideDisodium Phosphate hydrateSodium Dihydrogen PhosphateWater for injectionsvaccine presentation vialextractable volume 0.5 ml*adsorbed on aluminium hydroxide (0.25 mg)

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GSK Measles, Mumps and Rubella vaccine (Priorix®)active ingredients quantity per 0.5 ml doseLive attenuated measles virus (Schwarz strain) ≥ 103.0 CCID50

Live attenuated mumps virus (RIT 4385 strain) ≥ 103.7 CCID50

Live attenuated rubella virus (Wistar RA 27/3) ≥ 103.0 CCID50

other ingredientsLactoseSorbitolMannitolAminoacidsWater for injectionsvaccine presentation 2 vialsextractable volume 0.5 mlGSK Varicella vaccine (Varilrix®)active ingredients quantity per 0.5 ml doseLive attenuated Varicella virus (OKA strain) ≥ 103.3 PFUOther ingredientsAminoacidsHuman AlbuminNeomycine sulfateLactoseMannitolSorbitolWater for injectionsvaccine presentation 2 vialsextractable volume 0.5 ml

The rMenB+OMV NZ, DTaP-IPV-Hib (Infanrix-IPV + Hib®), 13-valent PCV (Prevenar-13®) and Hepatitis B (Engerix-B®) vaccines should be administered intramuscularly (IM) only.

The MMR (Priorix®) and varicella (Varilrix®) vaccines should be administered subcutaneously (SC) only.

All study vaccines should be protected from light and stored at +2°C to +8 °C.

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5.2 Non-Study Vaccines

Not applicable.

5.3 Vaccines Preparation and Administration

The investigator or designee will be responsible for oversight of the administration of vaccine to subjects enrolled in the study according to the procedures stipulated in this study protocol. All vaccines will be administered only by personnel who are qualified to perform that function under applicable local laws and regulations for the specific study site.

The vaccines must be prepared according to the instructions sheet provided to the investigator. The instruction sheet provides a detailed description of the vaccines preparation and administration and should be placed in the Investigator Site File. The investigator should review these materials prior to study start. Expired vaccines must not be administered.

rMenB+OMV NZ vaccine preparationThe rMenB+OMV NZ vaccine is provided in a pre-filled syringe. The vaccine should be allowed to reach room temperature before administration, according to local vaccination practice. The full content of the pre-filled syringe should be injected to ensure that the administered dose is 0.5 mL. Please refer to the instruction sheet for a detailed description of the vaccines preparation and administration.

Upon storage of the suspension of rMenB+OMV NZ a fine off-white deposit may form. Shake the vaccine well before use to form a homogeneous suspension. The vaccine should be visually inspected for particulate matter and discoloration prior to administration. In the event of any foreign particulate matter and/or variation of physicalaspect being observed, do not administer the vaccine and report the issue as a Pharmaceutical Technical Complaint to NVD. Do not discard the vaccine until authorized by NVD. Any unused medicinal product or waste material should be disposed of in accordance with local requirements once authorized for destruction.

Concomitant routine vaccine preparationThe concomitant routine vaccines used in this study, i.e. GSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + Hib®), Pfizer 13-valent PCV (Prevenar-13®), GSK Hep B vaccine (Engerix-B®), GSK MMR vaccine (Priorix®) and GSK Varicella vaccine (Varilrix®) are all licensed vaccines in Taiwan and must be prepared according to the package insert before use. Expired vaccines must not be administered.

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All vaccines should be given into the anterolateral area of the right or left thigh according to administration routes and locations presented in Table 5.3-1.

Table 5.3-1 Routes and locations for study vaccine administration

Group A (rMenB+OMV NZ concomitant with routine vaccines)Primary schedule (infants) Right thigh

(anterolateral area)Left thigh(anterolateral area)

Visit 1 (2 months of age) IM: rMenB+OMV NZ IM: Prevenar-13® at least 2.5 cm below the injection site of Infanrix-IPV+Hib®

IM: Infanrix-IPV+Hib® at least 2.5 cm above the injection site of Prevnar-13®



Visit 3 (6 months of age) IM: rMenB+OMV NZ at least 2.5 cm below the injection site of Engerix-B®

IM: Prevenar-13® at least 2.5 cm below the injection site of Infanrix-IPV+Hib®

IM: Engerix-B® at least 2.5 cm abovethe injection site of rMenB+OMV NZ


Visit 7 (12 months of age) IM: rMenB+OMV NZ SC: Priorix® at least 2.5 cm below the injection site of Varilrix®

SC: Varilrix® at least 2.5 cm above the injection site of Priorix®

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Group B (routine vaccines only)Primary Series (infants) Right thigh


Visit 1 (2 months of age) IM: Infanrix-IPV+Hib® IM: Prevenar-13®


Visit 3 (6 months of age) IM: Infanrix-IPV+Hib® IM: Prevenar-13® at least 2.5 cm below the injection site of Engerix-B®

IM: Engerix-B® at least 2.5 cm above the injection site of Prevnar-13®

Visit 7 (12 months of age) SC: Varilrix® SC: Priorix®

PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE:

Prior to vaccination, subjects must be determined to be eligible for study vaccination and it must be clinically appropriate in the judgment of the investigator to vaccinate. Eligibility for vaccination prior to first study vaccine administration is determined by evaluating the entry criteria outlined in protocol section 4.1 through 4.2.

Eligibility for subsequent study vaccination is determined by following the criteria outlined in sections 4.3 and 4.4.

Study vaccines should not be administered to individuals with known hypersensitivity to any component of the vaccines.

Standard immunization practices are to be observed and care should be taken to administer the injection intramuscularly. Before administering vaccine, the vaccination site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow the skin to dry. DO NOT inject intravascularly or intragluteally.

As with all injectable vaccines, trained medical personnel and appropriate medical treatment should be readily available in case of anaphylactic reactions following vaccine administration. For example, epinephrine 1:1000, diphenhydramine, and/or other medications for treating anaphylaxis should be available.

5.4 Prior and Concomitant Medications and Vaccines

All medications, vaccines and blood products taken or received by the subject from birth to the start of the study are to be recorded on the Prior and Concomitant Medications eCRF.

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When recording concomitant medications/vaccines, they should be checked against the study entry and continuation criteria in sections 4.1 through 4.4 to ensure that the subject should be enrolled/continue in the study.

Use of the following concomitant medications after enrollment may interfere with the interpretation of the study objectives or indicate an underlying condition resulting in a major protocol violation according to the medical judgment of the Novartis Vaccines and Diagnostics physician.

a. Immunosuppressive therapy and/or use of systemic corticosteroids or chronic use of inhaled high-potency corticosteroids (i.e. impairing the immune system);

b. Blood, blood products or a parenteral immunoglobulin preparation;

The use of antipyretics and/or analgesic medications within 24 hours prior to vaccination must be identified and the reason for their use (prophylaxis versus treatment) must be described in the source documents and Concomitant Medications eCRF.

Any antipyretic medication received within 6 hours prior to vaccination is a reason for delay of the vaccination until time-frame of > 6 hours between vaccination and antipyretic medications is reached (see section 4.3).

Medications taken for prophylaxis are those intended to prevent the onset of symptoms. Medications taken for treatment are intended to reduce or eliminate the presence of symptoms that are present.

5.5 Vaccine Supply, Labeling, Storage, and Tracking

The sponsor will ensure the following:

▫ supply of the study vaccine(s)

▫ appropriate labeling of all study vaccines provided that complies with the legal requirements of each country where the study is to be performed

The investigator must ensure the following:

▫ acknowledge receipt of the study vaccines by a designated staff member at the site, including confirmation that the vaccines:- were received in good condition

- remained within the appropriate temperature range during shipment from the sponsor to the investigator’s designated storage location

- have been confirmed by the sponsor as authorized for use

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▫ proper storage of the study vaccines, including:

- storage in a secure, locked, temperature-controlled location- proper storage according to the instructions specified on the labels

- appropriate record keeping and inventory of the study vaccines, including regular documentation of adequate storage temperature

▫ appropriate use of the study vaccines, including:- use only in accordance with the approved protocol

- proper handling, including confirmation that the vaccine has not expired prior to administration

- appropriate documentation of administration of vaccines to study subjectsincluding:

date, dosage, batch/serial numbers, expiration dates, unique identifying numbers assigned to subjects and study vaccines, and time of vaccine administration. This information will be maintained in an accountability log that will be reviewed by the site monitor.

proper reconciliation of all study and non-study vaccines received from the sponsor. Reconciliation is defined as maintaining records of which and how many vaccines were received, which vaccines (and volume thereof) were administered to subjects, which vaccines were destroyed at the site, and which vaccines were returned to the sponsor, as applicable.

▫ proper adherence to the local institutional policy with respect to destruction of study vaccines.

▫ complete record keeping of vaccine use, wastage, return or destruction, including documentation of:

- copy of the site’s procedure for destruction of hazardous material- number of doses destroyed, date of destruction, destruction code (if available),

method of destruction, and name of individual performing destructionVaccines that have been stored differently from the manufacturer’s indications must notbe used unless the sponsor provides written authorization for use. In the event that the use cannot be authorized, the sponsor will make every effort to replace the vaccine supply. All vaccines used in conjunction with this protocol must be stored separately from normal hospital/practice stocks to prevent unintentional use of study vaccines outside of the clinical trial setting.

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Monitoring of vaccine accountability will be performed by the study monitor during site visits and at the completion of the trial.

At the conclusion of the study, and as appropriate during the course of the study, the investigator must return all unused study vaccines, packaging and supplementary labels to the sponsor.

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6.0 MEASUREMENTS

6.1 Appropriateness of Measurements

The measures of immunogenicity used in this study are standard, i.e., widely used and generally recognized as reliable, accurate, and relevant (able to describe the quality and extent of the immune response).

The measures of safety used in this study are routine clinical procedures. They include a close vigilance for, and stringent reporting of, selected local and systemic adverse events routinely monitored in vaccine clinical trials as indicators of “reactogenicity”.

6.2 Demographics, Medical History and Physical Examination

Prior to study enrollment, demographic data will be collected from the subject, including: gender, date of birth, race, height and weight.

Medical history will also be collected, including but not limited to any medical history that may be relevant to subject eligibility for study participation such as prior vaccinations, concomitant medications, and previous and ongoing illnesses or injuries.

Relevant medical history can also include any medical history that contributes to the understanding of an adverse event that occurs during study participation, if it represents an exacerbation of an underlying disease/preexisting problem.

A general physical examination is to be performed by a qualified health care practitioner and will include the measurement of vital signs (heart rate, blood pressure, body temperature), auscultation of heart and lungs and a medical history-directed exam of other body parts and systems to assess eligibility during Visit 1.“Qualified health care practitioner” refers to any licensed health care professional who is permitted by institutional policy to perform physical examinations and who is identified within the site’s roles and responsibilities log.

At clinic visits after enrollment, subjects will undergo a symptom-directed physical examination. This is a physical examination that will include measurement of vital signs (at a minimum body temperature) and examination of organ systems that are relevant to the investigator based on review of the subject’s reported adverse events, review of systems, concomitant medication use.

All data will be written in the source documents.

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6.3 Immunogenicity Measurements

The assay used in this study to measure immunogenicity is the human serum bactericidal assay (hSBA).

The hSBA is a functional measure of the ability of specific meningococcal serogroup B antibodies, in conjunction with human complement, to kill meningococcal group B indicator strains, and is widely used and generally recognized as the serological correlate of protection.

Blood samples (5 ml) to obtain serum for hSBA will be collected at Visit 1, Visit 4, Visit 7 and Visit 8 (refer to Table 3.1-1 for a summary of the study related events and section 3.2.5 for detailed visit procedures).

SBA against MenB will be determined by performing serum hSBA against a standard panel consisting of three meningococcal group B indicator strains H44/76, 5/99 and NZ98/254. Each of these strains measures bactericidal activity primarily directed against one of the major bactericidal antigens included in the vaccine: strain H44/76 measures SBA against the 741 part of the 936-741 antigen, also known as fHbp variant 1.1; strain 5/99 measures SBA against antigen 961c, also known as NadA; and strain NZ98/254 measures SBA against PorA P1.4, the immunodominant antigen in the OMV NZ vaccine component. In addition, to support results of the SBA against the three indicator strains, SBA will be determined against vaccine antigen 287-953, also known as NHBA, by performing serum hSBA against the recently identified meningococcal group B strainM10713.

The hSBA will be conducted by qualified and certified laboratories.

Additional serologic testing may be performed to further characterize the immune response to rMenB+OMV NZ vaccination (e.g., hSBA and ELISA against other MenB strains/vaccine antigens and non-B N. meningitidis)

Details on all sample handling steps are described in the Clinical Specimen Lab Manualprovided to all study sites.

6.4 Efficacy Measurements

No efficacy measurements will be performed during the study

6.5 Solicited Safety Measurements

Solicited safety measurements are performed to investigate the “reactogenicity” of the study vaccines. The term “reactogenicity” refers to selected signs and symptoms

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(“adverse events”) occurring in the hours and days following a vaccination, to be collected by the subject‘s parent/guardian for six consecutive days, using a pre-defined checklist in a Diary Card (i.e., solicited adverse events). Please see section 3.2.5.3 andsection 8.1 for more detail for capture of solicited safety data.

The following adverse events are included in the Diary Card check list. Each adverse event is to be assessed using the scoring system reported in section 7.4.2.5.2

Solicited local adverse events:

Injection site erythema, induration, tenderness and swelling

Solicited systemic adverse events:

At 2, 4 and 6 months of age:

▫ Change in eating habits, sleepiness, irritability, persistent crying, vomiting, diarrhea and rash.

At 12 months of age (parotid/salivary gland swelling collected as an additional event because of vaccination with MMR + varicella):

▫ Change in eating habits, sleepiness, irritability, persistent crying, vomiting, diarrhea, rash and parotid/salivary gland swelling.

Other solicited data:

▫ Body temperature, use of medication to treat and/or to prevent fever, medically attended fever.

The preferred route of body temperature measurement is the rectal route.

The study staff must review the Diary Card with the subject’s parent/legal guardian at the following clinic visit (see section 3.2.5) and must directly record the solicited local and systemic adverse events, and other solicited reactions on the appropriate Local and Systemic Reactions eCRF. As described in Section 3.4.1, all solicited adverse events that are legible must be recorded verbatim in the eCRFs, even if the values do not appear to be plausible.

If a solicited local or systemic adverse event continues beyond Day 7 (for vaccination Visits 1, 2 and 3) or beyond Day 28 (for vaccination Visit 7) after each vaccination, it will also be recorded as an Adverse Event on the Adverse Events eCRF.

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6.6 Unsolicited Safety Measurements

6.6.1 Adverse Events

An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical investigation in a subject administered a pharmaceutical product at any dose that does not necessarily have to have a causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the investigational product. This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing conditions.

NOTE: Every effort should be made by the investigator to evaluate new safety information reported by a subject (solicited and unsolicited AEs) for an underlying diagnosis and to capture this diagnosis as the event in the AE page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” or “otitis media”).

All AEs will be monitored until resolution or, if the AE becomes chronic, a cause identified. If an AE is unresolved at the conclusion of the study, a clinical assessment will be made by the investigator and medical monitor whether continued follow-up of the AE is warranted.

The severity of events reported on the Adverse Events eCRF will be determined by the investigator as:

Mild: transient with no limitation in normal daily activity.Moderate: some limitation in normal daily activity.Severe: unable to perform normal daily activity.

The relationship of the study treatment to an AE will be determined by the investigator based on the following definitions:

1. Not Related

The AE is not related to an investigational vaccine if there is evidence that clearly indicates an alternative explanation. If the subject has not received the vaccine, the timing of the exposure to the vaccine and the onset of the AE are not reasonably related in time, or other facts, evidence or arguments exist that reasonably suggest an alternative explanation, then the AE is not related.

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2. Possibly Related

The administration of the investigational vaccine and AE are considered reasonably related in time and the AE could be explained by exposure to the investigational vaccine or by other causes.

3. Probably Related

Exposure to the investigational vaccine and AE are reasonably related in time and no alternative explanation has been identified.

The relationship of the study treatment to an unsolicited AE will be determined by the investigator. Solicited AEs will not be evaluated for relationship to study vaccine and severity of solicited AEs is defined as described in section 6.5.

Adverse events will also be evaluated by the investigator for the co-existence of any of the other following conditions:

▫ “Medically attended adverse event”: an adverse event that leads to an unscheduled visit to a healthcare practitioner.

Please note: any solicited adverse event that meets any of the following criteria must also be entered as an adverse event on the Adverse Event eCRF:

▫ Solicited local or systemic adverse event leading to a “medically attended adverse event”.

▫ Solicited local or systemic adverse event leading to the subject withdrawing from the study or the subject being withdrawn from the study by the investigator.

▫ Solicited local or systemic adverse event lasting beyond 7 days’ duration.▫ Solicited local or systemic adverse events that lead to subject withdrawal from study

vaccination.▫ Solicited local or systemic adverse event that otherwise meets the definition of a

serious adverse event (see section 6.6.2).

Kawasaki Disease

Rare (up to 1/1000 people affected) cases of Kawasaki Disease have been detected in previous clinical studies, both in infants receiving rMenB+OMV NZ and in infants notreceiving rMenB+OMV NZ. Kawasaki Disease may include symptoms such as fever that lasts for more than five days, associated with a skin rash on the trunk of the body, and sometimes followed by a peeling of the skin on the hands and fingers, swollen glands in

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the neck, red eyes, lips, throat and tongue. Sometimes it might present with atypical symptoms. Since the prevalence of this disease is higher among the Taiwanese and East-Asian population compared to the foreign populations, investigators are requested to closely monitor subjects for any suspected case of Kawasaki Disease.

6.6.1.1 Adverse Events of Special Interest

Not Applicable.

6.6.2 Serious Adverse Events

A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in one or more of the following:

▫ Death.▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at

immediate risk of death from the event as it occurred); it does not refer to an event which hypothetically might have caused death if it were more severe.

▫ Required or prolonged hospitalization.▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial

disruption of a person’s ability to conduct normal life functions).▫ Congenital anomaly/or birth defect.▫ An important and significant medical event that may not be immediately life

threatening or resulting in death or hospitalization but, based upon appropriate medical judgment, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed above.

Adverse events which do not fall into these categories are defined as non-serious.

It should be noted that a severe adverse event need not be serious in nature and that a serious adverse event need not, by definition, be severe.

Serious adverse events will be captured both on the VSAE form as well as on the AE eCRF. All SAEs will be evaluated by the investigator for relationship of the event to study vaccine. SAEs that are judged to be possibly or probably related to the study vaccine should be reported to the sponsor as related (i.e., suspected) events.

The relationship of the study treatment to an SAE will be determined by the investigator based on the following definitions:

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1. Related/suspected

The SAE is judged by the investigator to be possibly or probably related to the study vaccine on the AE CRF page (see section 6.6.1).

2. Not Related

The SAE is not related if exposure to the study vaccine has not occurred, or the occurrence of the SAE is not reasonably related in time, or the SAE is considered unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or arguments to suggest a causal relationship.

The relationship of the study vaccine to an SAE will be determined by the investigator.

In addition, SAEs will be evaluated by the sponsor or designee for “expectedness.” An unexpected AE is one that is not listed in the current Summary of Product Characteristics or the Investigator’s Brochure or an event that is by nature more specific or more severe than a listed event.

In addition, a pre-existing event or condition that results in hospitalization should be recorded on the Medical History eCRF. If the onset of an event occurred before the subject entered the trial (e.g., any pre-planned hospitalization for conditions like cosmetic treatments or for non-emergency routine visits for a pre-existing condition), the hospitalization would not lead to an AE being classified as serious unless, in the view of the investigator, hospitalization was prolonged as a result of participation in the clinical trial or was necessary due to a worsening of the pre-existing condition.

6.6.3 Methods for Assessing and Recording AEs and SAEs

The period of observation for AEs extends from the time the subject signs informedconsent until he or she completes the specified safety follow-up period (until 13 months of age) or terminates the study early (whichever comes first). AEs occurring after the informed consent form is signed but prior to receiving study vaccine/product will be documented as an adverse event and recorded on the Adverse Events eCRF and within source documents. However, AEs occurring prior to receipt of any study vaccine will be analyzed separately from “treatment emergent” AEs (AEs occurring after administration of the first study vaccine).

All AEs meeting criteria for reporting, regardless of severity, will be monitored by the investigator until resolution or stabilization. All subjects experiencing AEs - whether considered associated with the use of the study vaccine or not - must be monitored until symptoms subside and any abnormal laboratory values have returned to baseline, or until

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there is a satisfactory explanation for the changes observed, or until death, in which case a full pathologist’s report should be supplied, if possible. All findings must be reported on an Adverse Events CRF and on the VSAE form, if necessary, which is part of the Investigator Site File. All findings in subjects experiencing AEs must be reported also inthe subject's medical records.

All SAEs which occur during the course of the trial, whether considered to be associated with the study vaccination or not, must be reported within 24 hours of the site becoming aware of the event by telephone or fax to NVD. Contact details for submitting SAEs to NVD or its designee and instructions for completion of documentation will be provided in a handout located in the Investigator Site File.

All SAEs are also to be documented on the Adverse Events eCRF. Any medication or other therapeutic measures used to treat the AE will be recorded on the appropriate eCRF(s) in addition to the outcome of the AE.

After receipt of the initial report, representatives of NVD will contact the investigator if it is necessary to obtain further information for assessment of the event.

All SAEs must be reported by the investigator to his/her corresponding IRB andapplicable regulatory authorities in accordance with institutional policy/regulatory requirements and adequate documentation of this notification must be provided to the sponsor.

NVD or its designee must also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious and non-serious adverse vaccine reactions (also referred to as “SUSARs”) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other safety signal relating to use of one of the study vaccines is reported to NVD or its designee, the sponsor will communicate the information to the investigator and the investigator will be responsible for submitting this information to the IRB and other relevant authorities.

Post-Study Events

Any AE that occurs outside of the protocol-specified observation period or after the end of the study but considered to be caused by the study vaccine must be reported to NVD. These AEs will be processed by the NVD Pharmacovigilance group. Instructions for how to submit these AEs will be provided in a handout in the Investigator Site File.

6.6.4 Pregnancies

Not applicable.

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6.7 Safety Laboratory Measurements

Not applicable.

6.8 Other Measurements

Not applicable.

6.9 Data Monitoring Committee

No Data Monitoring Committees will be utilized for this study.

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7.0 ENDPOINTS AND STATISTICAL ANALYSES

7.1 Endpoints

7.1.1 Primary Endpoint(s)


7.1.2 Secondary Immunogenicity Endpoints

Key Secondary Immunogenicity Endpoint


Other Secondary Immunogenicity Endpoint

SBA GMTs, GMRs and percentage of subjects with SBA titer 1:5 against the indicator strains H44/76, 5/99, NZ98/254 and strain M10713 at baseline (2 months of age), 1 month after the third vaccination (7 months of age), prior to the booster dose (12 months of age) and 1 month after the booster dose (13 months of age).

7.1.3 Secondary Efficacy Endpoints

Not applicable.

7.1.4 Safety Endpoints

Safety will be measured throughout the entire study period (from Day 1 to Day 335) for each group. Analysis of safety will be presented overall and by injection number.

The measures for assessing safety and tolerability will be performed according to Table 7.1.4-1.

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Table 7.1.4-1: Safety Assessments

30 minutes after each vaccination (Day 1, Day 61, Day 122, Day 305)

1. Immediate reactions:- Signs or symptoms of anaphylaxis- Immediate local and systemic reactions


1. Body Temperature - Daily Body temperature.- Fever (defined as body temperature ≥ 38.0°C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics

2. Solicited Local Adverse Events (injection site erythema, induration, tenderness and swelling).

3. Solicited Systemic Adverse Events (Change in eating habits, sleepiness, irritability, persistent crying, vomiting, diarrhea and rash. In addition to these, parotid/salivary gland swelling** will also be collected after the administration of MMR and Varicella vaccination).


5. All medications (with the exception of minerals, supplements, vitamins , local anesthetic cream and emollients).


From Day 8 until last study visit (Day 335)

1. Serious Adverse Events2. Medically attended Adverse Events3. Adverse Events leading to premature withdrawal from the study4. Fever and solicited local/systemic Adverse Events persisting beyond Day 75. All medications for treatment of Adverse Events recorded in this period

(with the exception of minerals, supplements, vitamins)6. All vaccinations (except the study vaccines)

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Additional assessments for 28 days after MMRV vaccinations

1. Body Temperature- Daily temperature- Fever (defined as temperature ≥38°C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics

2. Solicited reactions for MMR + Varicella:- Parotid/salivary gland swelling**- Rash

*Medically attended fever: any fever for which a medical visit was sought.**As part of the study evaluations for MMR + varicella given at 12 months of age parents should be encouraged to see a doctor if subjects develop parotid/salivary gland swelling and obtain a diagnosis.§Medically attended adverse events: any adverse event requiring a medical visit (medical visit: a visit by a doctor or a nurse entitled to conduct medical visit [according to local regulations]).#Serious Adverse Events are defined in Protocol section 6.6.2.

7.1.5 Other Endpoints

Not applicable.

7.1.6 Exploratory Endpoints

Not applicable.

7.2 Success Criteria

7.2.1 Success Criteria for Primary Objectives

The primary objective of this study is to demonstrate sufficiency of the immune response to rMenB+OMV NZ vaccine when given concomitantly with routine vaccines (DTaP-IPV-Hib, HepB and PCV-13) to healthy infants at 2, 4, 6 months of age at 1 month after the third vaccination (at 7 months of age).

Sufficient immune response at 1 month after the third vaccination is defined as: the lower limit of the two-sided 95% CI for the percentage of subjects with SBA titer ≥ 1:5 (at visit 4, 7 months of age) should be greater or equal to 70%.

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7.2.2 Success Criteria for Key Secondary Immunogenicity Objectives

The key secondary objective is to demonstrate sufficiency of the immune response to a booster dose of rMenB+OMV NZ vaccine when given concomitantly with routine vaccines (i.e., MMR and Varicella) to healthy infants at 12 months of age that were previously primed with 3-doses of rMenB+OMV NZ, 1 month after the booster dose (at 13 months of age)

Similarly to the primary objective, the secondary success criterion is that the lower limit of the two-sided 95% CI for the percentage of subjects with SBA titer ≥ 1:5 at 1 month after the booster dose should be greater or equal to 75%.

All other secondary immunogenicity end-points are descriptive and are not associated to success criteria.

7.2.3 Success Criteria for Secondary Efficacy Objectives

Not applicable.

7.2.4 Success Criteria for Safety Objectives

No successes criteria are defined for safety; all endpoints are presented descriptively.

7.3 Analysis Sets

Demographic data and baseline characteristics will be summarized and presented for the enrolled set.

The primary population for immunogenicity analysis in this study is the Full Analysis Set (FAS) but all analysis will be presented for both FAS and Per Protocol set (PPS).

The FAS, PPS and Safety Set will be defined for each relevant objective or time point/period.

FAS/PPS:

- Day 1 (baseline, 2 months of age), Day 152 (1 month after third dose, 7 months of age), Day 305 (prior to booster dose, 12 months of age) and day 335 (1 month after booster dose, 13 months of age)

Safety set after the first three vaccinations:

- Solicited adverse events: 30 minutes, Day 1-3 (without 30 min), Day 4-7, and Day1-7 (without 30 min) after each vaccination.

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- Unsolicited adverse events: Day 1-7 after vaccination.

- Serious or medical relevant adverse events: Between each vaccination, for all study period.

Safety set after the booster vaccination:

- Solicited adverse events: 30 minutes, Day 1-3 (without 30 min), Day 4-7, and Day 1-7 (without 30 min) after booster vaccination.

- Unsolicited adverse events: Day 1-7 after booster vaccination.

- Serious or medical relevant adverse events (from the day of booster to end of study.

- Solicited systemic reaction for MMR + varicella from Day 1 to Day 7 (without 30 min), from Day 8 to Day 28 and from Day 1 to day 28 (without 30 min) after MMR + varicella vaccination.

7.3.1 All Enrolled Set

All subjects for whom a parent/legal guardian given informed consent and for whom demographic data are collect regardless of the subject’s randomization and treatment status in the trial and received a subject ID.

7.3.2 Exposed Set

All subjects in the Enrolled Population who receive a study vaccination.

7.3.3 Full Analysis Set (FAS) Efficacy/Immunogenicity Set

All subjects in the Enrolled Population who:

▫ received at least one dose of a study vaccination and provided immunogenicity data at relevant time points.

FAS populations will be analyzed “as randomized” (i.e., according to the vaccine a subject was designated to receive, which may be different from the vaccine the subject actually received).

7.3.4 Per Protocol (PP) Population, Efficacy/Immunogenicity Set

All subjects in the FAS Immunogenicity Population who:

▫ Are not excluded due to reasons (see section 7.3.8) defined prior to analysis

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▫ Correctly received the vaccine (i.e., receive the vaccine to which the subject was randomized and received the vaccine at the scheduled time points)

Exclusions will be considered by objective/time point, i.e., sometimes not all data of a subject but only part of the subject's data will be removed from the PPS analysis.

7.3.5 Safety Set

Safety set will be defined by study period (i.e., after each injection) to avoid a bias due to an inflated denominator.

Safety Set (solicited adverse events and other solicited reactions)

All subjects in the Exposed Population who:

▫ Provide post vaccination reactogenicity data

Safety Set (unsolicited adverse events)


▫ Have post-vaccination unsolicited adverse event records

Safety Set (overall)


▫ Have post-vaccination solicited or unsolicited recordsSubjects will be analyzed as "treated" (i.e., according to the vaccine a subject received, rather than the vaccine to which the subject may have been randomized).

7.3.6 Other Analysis Sets

No other analysis sets are defined.

7.3.7 Subgroups

No subgroup analysis is intended for this study

7.3.8 Protocol Deviations

A protocol deviation is any change, divergence, or departure from the study design or procedures of a study protocol. An exclusion refers to a protocol deviation that is used to remove data from an analysis population at the time of analysis. Relevant protocol

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deviations will be defined as exclusionary from the analysis according to protocol objectives and endpoints, which will be specified in the statistical analysis plan.

Any deviation that affects the subject's rights, safety, or well- being and/or the completeness, accuracy and reliability of the study data constitutes a major protocol deviation. Changes or alterations in the conduct of the trial which do not have a major impact on the subject's rights, safety or well-being, or the completeness, accuracy and reliability of the study data are considered minor protocol deviations. Major and minor deviations will be reviewed to determine the final list of deviations that will be used for exclusion from the analysis set(s).

The following deviations are considered major:▫ A subject received incorrect study vaccine or dose of study vaccine.

▫ A subject met withdrawal criteria during the study but was not withdrawn.▫ A subject received an excluded medication or vaccine.

▫ A subject was enrolled but does not meet the protocol's eligibility criteria.▫ A subject with no safety data

▫ Inadvertent loss of samples or data that support the analysis of primary or key objectives

▫ Failure to obtain informed consent prior to initiation of study-related procedures

▫ Falsifying research or medical records.Subjects who terminate study participation prematurely for reasons such as withdrawal of consent, adverse event (including death) or administrative reason do not represent protocol deviations, nor are the missing assessments that should otherwise have been collected for that subject later in the study considered protocol deviations.

Pre-specified reasons for delay or cancellation of study vaccination as reflected in sections 4.3 and 4.4 do not constitute protocol deviations.

All protocol deviations will be classified into major and minor. Major protocol deviations will be summarized by vaccine, center (overall) and grouped into the different categories as defined above. The site monitor will keep the investigator informed of minor and major protocol deviations, so that the investigator can comply with reporting these deviations to the local EC/IRB according to their institutional policy.

Designated staff at the Sponsor will develop a memo that describes the selected deviations that are identified as exclusions from per protocol analysis populations. This memo will be included in the trial master file.

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7.4 Analysis Plan

7.4.1 Analysis of Demographic and Baseline Characteristics

Descriptive statistics (mean, standard deviation, median, minimum and maximum) for age height and weight at enrollment will be calculated by overall and by vaccine group.

Distributions of subjects by sex and race will be summarized overall and by vaccine group.

7.4.2 Analysis of Primary Objectives

7.4.2.1 Statistical Hypotheses for Primary Objectives

For the primary immunogenicity objective we assume that Ykj, k=NZ98/254, H44/76, 5/99, one of the strains; j=1,..,n, are identical and independent Bernoulli distributed random variables: Ykj ~ B(1, πk), with πk representing the unknown proportion of subjects in Group A strain k with a SBA titer ≥ 1:5 one month after the third dose of therMenB+OMV NZ vaccine, and n represents the number of subjects.

The following three primary null hypotheses will be tested:

H0k: πk ≤ 0.70 vs. H1k: πk > 0.70 for k= NZ98/254, H44/76, 5/99

The overall null hypothesis is:

H0: πk ≤ 0.70 vs. H1: πk > 0.70 for k= NZ98/254, H44/76, 5/99

where

As the overall null hypothesis is the union of the three null hypotheses, it will be rejected if all three single hypotheses are rejected, simultaneously, at 1-sided level of 0.025.

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7.4.2.2 Analysis Populations for Primary Objectives

The primary objective will be assessed based on both, the FAS and PPS.

7.4.2.3 Statistical Methods for Primary Objectives

Percentage of subjects in Group A with SBA titer >1:5

For each strains, NZ98/254, H44/76, and 5/99 the percentage of subjects in vaccine group A achieving an SBA titer > 1:5 at 1 month after the third vaccination (Day 152, 7 months of age) will be presented as point estimates together with the two-sided 95% confidence intervals computed using the Clopper-Pearson method (Clopper, 1934).

Handling of missing values for Immunogenicity data

The mechanism of missing immunogenicity values can be reasonably considered asmissing completely at random (MCAR), i.e., not informative. Therefore the immunogenicity analysis will comprise a complete case analysis only without introducingany bias. No imputation methods will be applied.

7.4.2.4 Sample Size and Power Considerations of Primary Objectives

Sample size for this study was calculated under considerations and assumptions based on the antibody response of infants observed in the Novartis Vaccines study V72P13 where infants enrolled received 3 doses of the rMenB+OMV NZ vaccine at 2, 4 and 6 months of age. The percentage of subjects with a SBA titer ≥ 1:5 at 1 month after the third vaccination reported in V72P13 study was 100% (99%-100%) for strain 44/76, 84% (82%-86%) for strain NZ98/254, and 100% (99%-100%) for strain 5/99.

We assume that the infants in this study will have antibody responses similar to those observed in V72P13, with the percentage of subjects with SBA titer ≥ 1:5 ranging from 84% for strain NZ98/254 and 99% for strains 44/76 and 5/99.

The following Table shows the power that the proportion of subjects with SBA titer ≥ 1:5 one month after the third dose of the rMenB+OMV NZ vaccine is > the threshold, π0, assuming that the true proportions are 0.84, 0.99, and 0.99, respectively, for strains NZ98/254, 44/76, 5/99, with evaluable number of subjects (N = 120) and threshold (π0 = 0.70). The exact test of binomial proportions with two-sided alpha of 0.05 was used to calculate the power.

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Table 7.4.2.4-1: Power that the Proportion of Subjects with SBA titer ≥1:5 is greater than 0.70 (threshold π0) for a Given Strain, True Underlying Proportion, and Sample Size

Strain

πk(proportion of


π0(Threshold)

Evaluable Sample Size for

Group APower

NZ98/254 0.84 0.70 120 94%44/76 0.99 0.70 120 99%5/99 0.99 0.70 120 99%

A sample size of 120 evaluable infants was chosen for infants receiving rMenB+OMV NZ together with routine vaccines (Group A). Assume a true proportion of subjects with SBA titer ≥1:5 of 0.84, 0.99 and 0.99 for the NZ98/254, 44.76, and 5/99 strains, respectively, one month after the third injection. With this sample size of 120 evaluable subjects, using an exact test for a single binomial proportion and a 2-sided alpha (Type Ierror) of 0.05, the power to reject the null hypothesis associated with the primary objective and demonstrate sufficiency of response (i.e., > 0.70) is 94%, 99% and 99%, respectively.


Infants randomized to the control arm will receive routine vaccines only. The control arm of this study has been chosen for safety evaluation purpose and to assess the prevalence of bactericidal meningococcal B antibodies over the study period in infants not receiving rMenB+OMV NZ vaccine (negative control). To avoid unnecessary blood draws in infants, a randomization ratio of 2:1 was chosen. Considering a non ‘per protocol rate’ of approximately 20%, a total of 225 infants are request to be enrolled in to the study (150 in rMenB+OMV NZ+ routine vaccination arm and 75 in routine vaccine only arm).

7.4.2.5 Analysis of Safety Objectives

7.4.2.5.1 Analysis of Extent of Exposure

Investigational vaccination group consists of three doses of rMenB+OMV NZ at 2, 4, 6 months of age given concomitantly with routine infant vaccines (DTaP-IPV-Hib, HepB, 13-valent PCV), and a booster dose given at 12 month of age concomitantly with MMR and varicella vaccines.

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Control arm vaccination (Group B) consists of no dose of rMenB+OMV NZ but same routine infant vaccines as in the investigation arm (Group A).

7.4.2.5.2 Analysis of Solicited Local and Systemic Adverse Events and Other Reactions

All solicited local and systemic adverse events will be summarized according to defined severity grading scales.

The pre-defined severity grading scales for solicited local and systemic adverse events are summarized in Table 7.4.2.5.2-1.

Frequencies and percentages of subjects experiencing each solicited adverse event will be presented for each symptom severity. Summary tables showing the occurrence of any local or systemic adverse event overall and at each time point will also be presented.

Post-vaccination solicited adverse events reported from day 1 to day 7 after each vaccination will be summarized for the intervals day 1-3, day 4-7, day 1-7 by maximal severity and by vaccine group, excluding the 30 minute measurement, which will be summarized separately.

Each solicited local and systemic adverse event will also be further summarized as “none” versus “any”.

Implausible measurements (for further definition see analysis plan) will be left out of the analysis.

Use of antipyretics and analgesics will be summarized by frequency, by type of use (prophylactic versus treatment) and percentage of subjects reporting use.

The influence of antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever) will be assessed.

Body temperature will be summarized by 0.5 °C increments from 36.0 °C up to ≥40 °C and will be broken down according to route of measurement.

Medically attended fever will be summarized by number and percentage of subjects.

Post MMR and varicella vaccination (Visit 7, 12 month of age) body temperature,parotid/salivary gland swelling and rash will be collected for 28 days and reported together with all systemic reaction for the first 7 days and presented also from day 8 to day 28, and for day 1 to day 28.

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Glands swelling will be subdivided into parotid swelling, salivary swelling, parotid swelling seen by doctor or salivary swelling seen by doctor and will be summarized by number and percentage of subjects.

Table 7.4.2.5.2-1: Severity grading for solicited local and systemic adverse events

None(Grade 0)

Mild(Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

Injection site Tenderness no tenderness Minor light

reaction to touchCried or protested

to touchCried when injected

limb was moved

Injection site erythema 0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm

Injection site swelling 0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm

Injection site induration 0 - 9 mm 10 - 25 mm 26 - 50 mm > 50 mm

Change in eating habits

No change in eating habits

Eating less than normal for 1 to 2

feedsMissed 1 or 2 feeds Missed more than 2

feeds

Sleepiness No change in alertness

Shows an increased

drowsiness

Sleeps through feeds

Sleeps most of the time and it is hard to

arouse him/her

IrritabilityNo change in

child’s disposition

Requires more cudding and he/she is less playfull than

usual

More difficult to settle Unable to console

Persitent crying No persistent crying

Crying less than one hour

Crying for 1 to < 3 hours

Crying for 3 or more hours

Vomitting No vomitting 1-2 episodes / 24 hours

>2 episodes/24 hours

Requires outpatient hydration

DiarrheaFewer than 2

loose stools/24 hours

2-3 loose stools or < 400 gr/24 hrs

4-5 stools or 400-800 gr/24hrs

6 or more watery stools or >800 gr/24

hrs or requires outpatient IV

hydration

Rash No rashLocalized area of

the skin (1 extremity only)

Moderate area of the skin (2 or more

body regions without whole body

involvement)

Most of the skin

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7.4.2.5.3 Analysis of Spontaneously Reported Adverse Events

All the adverse events occurring during the study, judged either as probably related, possibly related, or not related to vaccination by the investigator, will be recorded.

The original verbatim terms used by investigators to identify adverse events in the CRFs will be mapped to preferred terms using the MedDRA dictionary. The adverse events will then be grouped by MedDRA preferred terms into frequency tables according to system organ class. All reported adverse events, as well as adverse events judged by the investigator as at least possibly related to study vaccine, will be summarized according to system organ class and preferred term within system organ class. These summaries will be presented by vaccination group and by interval of study observation. When an adverse event occurs more than once for a subject, the maximal severity and strongest relationship to the vaccine group will be counted.

Separate summaries will be produced for the following categories

▫ serious adverse events▫ adverse events that are possibly or probably related to vaccine

▫ adverse event leading to withdrawal▫ adverse events leading to a medically attended visit▫ adverse event by data source

Data listings of all adverse events will be provided by subject. In addition, adverse events in the categories above will be provided as listed data.

7.4.2.5.4 Analysis of Safety Laboratory Values

Not applicable.

7.4.3 Analysis of Key Secondary Immunogenicity Objectives

Hypotheses of key Secondary Immunogenicity Objectives

For the key secondary immunogenicity analysis, we assume that Ykj, k=strains NZ98/254, H44/76, 5/99; j=1,..,n, are identical and independent Bernoulli distributed random variables: Yj ~ B(1, πk), with πk representing the unknown proportion of subjects with a SBA titer ≥ 1:5 at 1 month after the booster vaccination and k denotes the three indicator strains NZ98/254, H44/76, and 5/99.

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where

As the overall null hypothesis is the union of the three null hypotheses, it will be rejected if all three single hypotheses are rejected, simultaneously, at 1-sided level 0.025.

The other secondary immunogenicity objectives are intended to be descriptive and no null hypothesis is associated with them.

Analysis Populations for Key Secondary Immunogenicity Objectives

The key secondary objective will be assessed based on both, the FAS and PPS.

Statistical Methods of Key Secondary Immunogenicity Objectives

Analyses of Percentages of subjects with SBA titer >1:5 at 1 month after booster dose

For each meningococcal B strain, H44/76, 5/99, NZ98/254 the percentage of subjects with a SBA titer ≥1:5 will be presented as point estimates along with the associated 95% Clopper-Pearson confidence intervals (CIs) at Day 305 (before booster dose) and at Day 335 (1 month after the booster dose).

Missing values will be left out in the appropriate analyses because they are regarded as non-informative and missing completely at random.

Sample Size and Power Considerations for Key Secondary Immunogenicity Objectives

Similar considerations regarding the primary objectives were done for the key secondaryobjective. In order to avoid adjusting for multiplicity the key secondary objective will be tested only if the primary objective has been successfully demonstrated.

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In V72P13E1 the following data were observed, one month after a booster dose given to infants who received 3 doses of rMenB+OMV NZ at 2, 4 and 6 months of age:

In Strain 44/76, the percentage of subjects with a SBA titer ≥ 1:5 was 100% (99%-100%), in Strain 5/99, it was 100% (99%-100%) and in Strain NZ98/254 it was 95% (93%-97%)

We assume that the infants in this study will have antibody responses similar to those observed in V72P13E1 following the booster injection, with the percentage of subjects with SBA titer ≥ 1:5 ranging from 95% for strain NZ98/254 and 99% for strains 44/76 and 5/99.

The following Table shows the power that the proportion of subjects with SBA titer ≥ 1:5 one month after the booster dose of the rMenB+OMV NZ vaccine is > the threshold, π0, assuming that the true proportions are 0.95, 0.99, and 0.99, respectively, for strains NZ98/254, 44/76, 5/99, with evaluable number of subjects (N = 120) and threshold (π0 = 0.75). The exact test of binomial proportions with two-sided alpha of 0.05 was used to calculate the power.


Strain

πk(proportion of


π0(Threshold)


Group A Power

NZ98/254 0.95 0.75 120 99%44/76 0.99 0.75 120 99%5/99 0.99 0.75 120 99%

A sample size of 120 evaluable infants was chosen for the investigational vaccine (Group A). Assume a true proportion of subjects with SBA titer ≥1:5 of 0.95, 0.99 and 0.99 for the NZ98/254, 44.76, and 5/99 strains, respectively, one month after the booster (fourth)injection. With this sample size of 120 evaluable subjects, using an exact test for a single binomial proportion and a 2-sided alpha (Type I error) of 0.05, the power to reject the null hypothesis associated with the key secondary objective and demonstrate sufficiency of response (i.e., > 0.75) is 99%, 99% and 99%, respectively.

Assuming the results for the three strains are independent, the overall power to demonstrate sufficiency of response after the booster dose is equal to 97%, the product of the 3 individual powers.

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7.4.4 Analysis of Key Secondary Efficacy Objectives

There are no key-secondary efficacy objectives in this study.

7.4.5 Analysis of Key Secondary Other Objectives

There are no key-secondary other objectives in this study.

7.4.6 Analysis of Non-Key Objective

SBA GMTs, GMRs and the percentage of subjects with SBA titer ≥ 1:5 and their associated 95% CIs, median, minimal and maximal values will be determined for each strain (H44/76, 5/99, NZ98/254 and M10713) at baseline (Day 1), at 1 months after the third dose (Day 152), before the booster dose (at Day 305) and at one month after the booster dose (Day 335) both in infants receiving rMenB+OMV NZ with routine vaccines (Group A) and in infants receiving routine vaccines only (Group B). The control arm(infants receiving routine vaccines only) has been included to assess the prevalence of bactericidal meningococcal B antibodies over the study period in infants not receiving rMenB+OMV NZ vaccine (negative control).

The analysis of this Non-Key Secondary objective will be descriptive and will be presented together with N (number of subjects).


7.5 Planned Interim Analysis

An unblinded interim analysis is planned to be performed at 1 month after the 3rd

vaccination when all subjects enrolled have either performed the Study Visit 4 (Day 152, 7 months of age) or were withdrawn from study.

The purpose of this interim analysis is to assess the primary immunogenicity objectiveand collect safety data at 1 month after the third dose and submit a full interim report to the Taiwanese Health Authorities. This analysis will consist of an interim analysis of safety data and a final analysis of immunogenicity data 1 month after the 3rd vaccination to assess the primary objective.

No stopping rules are established for this planned interim analysis as all subjects that did not withdraw their consent or were not withdrawn for any other reason will receive the booster dose at the next visit (i.e., Visit 7, Day 305) and will be followed to the end of the trial (Visit 8, Day 335).

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Because the primary study objective is to demonstrate sufficiency of response of rMenB+OMV NZ after the third vaccination and all enrolled subjects who have immunogenicity data will be included in the interim analysis no alpha correction will be performed for the primary or key secondary analysis which will be conducted both at the one-sided 0.025 significant level.

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27 FEB 17ePublished V72_60 Final CSR

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8.0 SOURCE DOCUMENTATION, STUDY MONITORING, AND AUDITING

In order to ensure consistency across sites, study monitoring and auditing will be standardized and performed in accordance with the sponsor’s or delegated contractresearch organization’s (CRO) standard operating procedures and applicable regulatory requirements (e.g., FDA, EMA, and ICH guidelines).

Prior to enrollment of the first study subject, NVD or delegate will train investigators and/or their study staff on the study protocol, all applicable study procedures, documentation practices (including signing of the source document agreement (SDA, see section 8.1) and all electronic systems. CRFs supplied by the sponsor must be completed for each enrolled subject (see section 7.3.1 for definition of enrolled subject). Documentation of screened but not enrolled subjects must be maintained at the site and made available for review by the site monitor. All data entries as well as study related documents will be checked by the sponsor and/or site monitor. In addition, the investigator and site staff will be made aware of the plans to monitor the data collected at the site.

8.1 Source Documentation

Prior to the start of the study, the site staff participating in the study conduct will be trained on what documents will be required for review as source documentation (i.e., original records, laboratory reports, medical records, subject diaries. The kinds of documents that will serve as source documents will be specified in the SDA. The final SDA will be available prior to first subject, first visit (FSFV).

In addition, source documentation must include all of the following: subject identification (on each page), eligibility and participation, proper informed consent procedures, dates of visits, adherence to protocol procedures, adequate reporting and follow-up of adverse events, documentation of prior/concomitant medication/vaccines, study vaccine receipt/dispensing/return records, study vaccine administration information, any data collected by a telephone conversation with the subject’s parent/guardian and date of completion and reason.

The subject’s parents or legal guardian(s) must also allow access to the subject’s medical records. Parent(s) or legal guardian(s) of each subject, must be informed of this prior to the start of the study and consent for access to medical records may be required in accordance with local regulations.

All safety data reported by subjects must be written down in source documents prior to entry of the data into CRFs. If there are multiple sources of information (e.g., Diary Card, verbal report of the subject, telephone contact details, medical chart) supporting the

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diagnosis of an adverse event, these sources must be identified in the source documents, discrepancies between sources clarified, the ultimate diagnosis must be justified and written in the source documents, and this diagnosis must be captured in the adverse event CRF (AE CRF). The AE CRF must also capture which source(s) of information were used to determine the adverse event (e.g., subject recall, medical chart, Diary Card, and/or other sources).

8.2 Study Monitoring and Source Data Verification

A contract research organization (CRO) may be involved in the monitoring of protocol conduct and data entry. If a CRO is involved in study oversight, the name and address of this CRO will be located in the investigator site file. Prior to enrollment of the first study subject, NVD will develop a Clinical Monitoring Plan to specify how monitoring will be performed for the study.

Study progress will be monitored by NVD or its representative (e.g., a CRO) as frequently as necessary to ensure:

▫ that the rights and well-being of human subjects are protected

▫ the reported trial data are accurate, complete, and verifiable from the source documents and

▫ the conduct of the trial is in compliance with the current approved protocol/amendment(s), GC and applicable regulatory requirements

Contact details for the team involved in study monitoring will be identified in a handout located in the Investigator Site File. Study data recorded on CRFs will be verified bychecking the CRF entries against source documents in order to ensure data completeness and accuracy as required by study protocol. Additional documents such as the investigator site file, pharmacy records, and informed consent documentation must also be available for review if requested. Arrangements for monitoring visits will be made in advance in accordance with the monitoring plan, except in case of emergency. The investigator and/or site staff must make source documents of subjects enrolled in this study available for inspection by NVD or its representative at the time of each monitoring visit. These documents must also be available for inspection, verification and copying, as required by regulations, by officials of the regulatory health authorities (e.g., FDA, EMA and others) and/or ECs/IRBs. The investigator and study site staff must comply with applicable privacy, data protection and medical confidentiality laws for use and disclosure of information related to the study and enrolled subjects.

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9.0 DATA MANAGEMENT

9.1 Data Entry and Management

In this study, all data will be entered onto electronic case report forms (eCRFs) in a timely fashion by the investigator and/or the investigator’s dedicated site staff. Data entered onto eCRFs are stored on a secure website. The data collected on this secure website are assimilated into an EDC system, which is compliant with 21 Part 11 policies of the Code of Federal Regulations. The EDC will be designed and validated by NVD prior to activation for data entry by sites. The investigator must review data entered and electronically sign the eCRFs to verify their accuracy.

Access to the EDC system for data entry or review will require training and distinct individual access code assignments to those site staff members who will be entering study data and those involved in study oversight who may review study data. Data are collected within EDC, to which the sponsor and site monitors have exclusively “read only” access. eCRF data will be reviewed routinely by study personnel from NVD and clinical monitors.

All serology results produced by Clinical Serology, NVD will be entered into the Seroad database by NVD’s Clinical Serology Laboratory, Marburg. All results will be checked in the laboratory for validity and completeness.

9.2 Data Clarification

As part of the conduct of the trial, NVD may have questions about the data entered by the site, referred to as queries. The monitors and the sponsor are the only parties that can generate a query.

All corrections and clarifications will be entered into the EDC and will be identified by the person entering the information, the reason for the change, as well as the time of the changes made. If changes are made to a previously and electronically signed CRF, the investigator must confirm and endorse the changes.

9.3 Data Coding Procedures

Coding of Adverse Events, Medical History, and Prior and Concomitant Medications will be performed using standard dictionaries as described in the Data Management Plan.

9.4 Data Protection

NVD respects the subjects’ rights to privacy and will ensure the confidentiality of their medical information in accordance with all applicable laws and regulations.

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10.0 RECORD RETENTION

Investigators must retain all study records required by NVD and by the applicable regulations in a secure and safe facility. The investigator must consult a NVDrepresentative before disposal of any study records, and must notify the sponsor of any change in the location, disposition, or custody of the study files. Essential documents must be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. “Essential documents” are defined as documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents should be retained for a longer period, however, if required by the applicable regulatory requirements or by an agreement with the sponsor. The Committee for Human Medicinal Products for Human Use (CHMP) requires retention for the maximum period of time permitted by the institution, but not less than 15 years (ICH E6, 4.9.5). It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained (ICH E6, 5.5.12).

These principles of record retention will also be applied to the storage of laboratory samples, provided that the integrity of the stored sample permits testing.

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11.0 USE OF INFORMATION AND PUBLICATION

NVD assures that the key design elements of this protocol will be posted in a publicly accessible database such as clinicaltrials.gov, and in compliance with current regulations.

NVD also assures that key results of this clinical trial will be posted in a publicly accessible database within the required time-frame from the last subject’s last study visit as dictated by applicable regulations.

Further to legislated data disclosure, NVD will ensure that as far as possible results of this study will be published as scientific/clinical papers in high-quality peer-reviewed journals. Preparation of such manuscripts will be made with full collaboration of principal investigators and in accordance with the current guidelines of Good Publication Practice (Graf 2009).

NVD must be notified of any intent to publish data collected from the study and prior approval from NVD must be obtained prior to publication.

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12.0 ETHICS

12.1 Regulatory and Ethical Compliance

This clinical study was designed and shall be implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations, Novartis codes on protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki (European Council 2001, US Code of Federal Regulations, ICH 1997).

12.2 Informed Consent Procedures

Eligible subjects may only be included in the study after providing written informed consent or assent, as described in section 3.2.1. Before the start of the trial, the investigator will have the informed consent and any other materials that will be provided to the subjects reviewed and approved by the IRB/EC. This review and approval will be documented and stored with other study documents. The investigator or designee must fully inform the subject or legal guardian of all pertinent aspects of the trial. A copy of the written informed consent will be given to the subject or the designee. The subject/designee must be allowed ample time to ask about the details of the trial and to make a decision as to whether or not to participate in the study. The subject and/or legal guardian must sign the consent form indicating their agreement to participate in the study before any study-related procedures are conducted. If the subject and/or legal guardian is unable to read and write, a witness must be present during the informed consent discussion and at the time of informed consent signature.

Prior to the start of the study, NVD will provide to investigators a separate document with a proposed informed consent form that complies with the ICH GCP guideline and regulatory requirements and is considered appropriate for this study. Any changes to the proposed consent form suggested by the investigator must be agreed to by NVD before submission to the IRB/EC and a copy of the approved version must be provided to the NVD monitor after IRB/EC approval.

12.3 Responsibilities of the Investigator and IRB/EC

The protocol and the proposed informed consent form must be reviewed and approved by a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH 1997). A signed and dated statement that the protocol and informed consent have been approved by the IRB/EC must be given to NVD before study initiation. Prior to study start and at any time the protocol is amended during study conduct, the investigator is required to sign a protocol signature page confirming his/her agreement to conduct the study in accordance

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with these documents and all of the instructions and procedures found in this protocol and to give access to all relevant data and records to NVD monitors, auditors, Novartis Clinical Quality Assurance representatives, designated agents of NVD, IRBs/ECs, and regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory authority, the investigator must inform NVD immediately that this request has been made.

The investigator also responsible for the following:

▫ maintaining a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties

▫ demonstrating the capability of recruiting the required number of suitable subjects within the recruitment period

▫ demonstrating sufficient time and staffing to properly conduct and complete the study within the agreed trial period

▫ ensuring that all persons assisting with the study are adequately informed about the protocol, the investigational product(s), and their study-related duties and functions

▫ ensuring that appropriately trained health care professionals are responsible for all study-related medical decisions and for ensuring appropriate medical care of subjects experiencing any adverse event related to the study

▫ if permission to do so is given by the subject’s parent/guardian, ensuring that the subject’s primary healthcare provider is informed of the subject’s participation in the study.

The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)). In addition, the investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.

The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:

(a) to the IRB/IEC for review and approval/favourable opinion,

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(b) to the sponsor for agreement and, if required,

(c) to the regulatory authority(ies).

12.4 Protocol Adherence

Investigators will apply due diligence to avoid protocol deviations. Under no circumstances should the investigator contact NVD or its agents, if any, monitoring the trial to request approval of a protocol deviation, as no authorized deviations are permitted. If the investigator feels a change to the protocol would improve the conduct of the study this must be considered a protocol amendment, and unless such an amendment is agreed upon by NVD and approved by the IRB/EC it cannot be implemented. All significantprotocol deviations will be recorded and reported in the Clinical Study Report.

12.5 Protocol Amendments

An amendment is a written description of change(s) to or formal clarification of a study protocol which may impact on the conduct of the clinical study, potential benefit of the clinical study, or may affect subject safety, including changes of study objectives, study design, subject population, sample sizes, study procedures, or significant administrative aspects. An administrative change of a study protocol is a minor correction or clarification that has no significant impact on the way the clinical study is to be conducted and no effect on subject safety (e.g., change of telephone number(s), logistical changes). Protocol amendments must be approved by NVD, Health Authorities where required, and the IRB/EC. In cases when the amendment is required in order to protect the subject safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding the need for formal approval of a protocol amendment, the investigator is expected to take any immediate action required for the safety of any subject included in this study, even if this action represents a deviation from the protocol. In such cases, NVD should be notified of this action, the IRB/EC at the study site, and, if required by local regulations, the relevant health authority should be informed within 10 working days.

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13.0 REFERENCE LIST

Chiou CS, Liao JC, Liao TL, Li CC, et al. (2006) Molecular epidemiology and emergence of worldwide epidemic clones of Neisseria meningitidis in Taiwan. BMC Infect. Dis. 2006; 6: 25

Clopper C and Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 1934 26: 404–413

Code of Federal Regulations (1997): Food and Drug Administration, Department of Health and Human Services: Title 21, Part 11: Electronic Records Electronic Signatures. Federal Register 62: 13464

European Parliament (2001): Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001. Official Journal of the European Communities. L 121/34-44

Girard MP, Preziosi M, Aguado M, Kieny MP et al. A review of vaccine research and development: Meningococcal disease. Vaccine 2006; 24:4692–4700.

Graf C, Battisti WP, Bridges D (2009). Good publication practice for communicating company sponsored medical research: the GPP2 guidelines. BMJ; 339: b4330

ICH (1997) ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6 (R1). Federal Register, 62 (90): 25691-25709

Pizza M, Scarlato V, Masignani V, Giuliani MM, et al. Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 2000; 287: 1816–1820

Rouaud P, Perrocheau A, Taha MK, Sesboué C, Forgues AM, Parent du Châtelet I, Levy-Bruhl D. Prolonged outbreak of B meningococcal disease in the Seine-Maritime department, France, January 2003 to June 2005. Euro Surveill. 2006; 11: 178-81

59th World Medical Association General Assembly (October 2008) Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Seoul, Korea

World Health Organization. Wkly. Epidemiol. Rec., 2002; 77:329–340

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This signatur e certificate is only valid when accompanied by all the pages of the document. /

Novartis

Document Approval Certificate /

The individuals listed have approved this document for implementation using an electronic signature in the Atlas EDMS. /

UserName: Title: Cluster Physician Date: Tuesday, 14 May 2013, 13:14 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


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Novartis Vaccines and Diagnostics Clinical Study Protocol Amendment 111JUL13 Confidential Page 1 of 3

PRO-01 TEMP 08 / Atlas No. 293623Version No. 1 / Version Date: August 20, 2012

CLINICAL STUDY PROTOCOL V72_60

Amendment Number 1



Property ofNovartis Vaccines and Diagnostics

Confidential

May not be used, divulged, published or otherwise disclosed without writtenconsent of Novartis Vaccines and Diagnostics.

The present amendment reflects changes to the protocol since the first version of the protocol.


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DESCRIPTION OF CHANGE(S) AND RATIONALE:

CHANGE 1(Synopsis, Table 4):

Previously read:

The Times and Events Table 4 in the Synopsis previously did not include ‘X’ for‘Diary Card Reviewed’ at visit 7

Now reads:

The Times and Event Table 4 of the Synopsisnow includes ‘X’ for‘Diary Card Reviewed’ at Visit 7

Rationale for Change:

Correction of omission

CHANGE 2(Section 5.1, Table 5.1-1):

Previously read:

In the previous version, the exact presentations of the commercially available routine vaccines were listed, i.e. ‘vial + pre-filled syringe’ for Infanrix-IPV+Hib®, ‘pre-filled syringe’ for Prevenar-13®, ‘vial’ for Engerix-B®, ‘2 vials’ for Priorix® and ‘2 vials’ for Varilrix®

Now reads:

In the amended version the presentations forall commercially available routine vaccines are changed to ‘as commercially available’


The presentations of the MMR (Priorix®) andVaricella (Varilrix®) vaccine were not correctly described. Since commercially available vaccine presentations differ per countryand different presentations are available in a single country, the presentation for each commercially available routinevaccine has been changed into ‘as commercially available’


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CHANGE 3(Section 5.2, Starting Line 1):

Previously read:

Not applicable

Now reads:

After the study, all subjects will be offered to receive the booster dose of Prevenar-13 (at 15 months of age) to complete the recommended dose-schedule of Prevenar-13. The Prevenar-13 booster dose will be reimbursed by NVD.


A fourth dose of Prevenar-13 will be offered to all subjects after the study period to complete the recommended dose schedule. A similar statement is included in the Informed Consent Form, version 2.0.

CHANGE 4(Section 7.1.5, Starting Line 1):

Previously read:

Not applicable

Now reads:

The percentage of subjects with SBA titers ≥ 1:8 at baseline, one month after the third vaccination, at 12 months of age (prior to the booster dose) and at 13 months of age (one month after the booster dose) for each of the three indicator strains (H44/76, 5/99, NZ98/254) and strain M10713.


Added to align with the pivotal study V72P13 and V72P13E1 that are the reference studies for V72_60.


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Novartis



UserName: Title: Cluster Physician Date: Friday, 12 July 2013, 06:26 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


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Novartis Vaccines and Diagnostics Protocol V72_6011 JUL 13 Final Version 2.0 Confidential Page 1 of 93






Confidential

May not be used, divulged, published or otherwise disclosed without writtenconsent of Novartis Vaccines and Diagnostics


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Objectives:





Safety ObjectivesTo assess the safety and tolerability of 3 doses of rMenB+OMV NZ given at 2, 4, 6 months of age, followed by a booster dose at 12 months of age when concomitantly administered with routine vaccines (i.e. combined DTaP-IPV-Hib and PCV-13 at 2, 4, 6 months; HepB at 6 months of age; MMR and varicella at 12 months of age) and of routine vaccines alone in terms of percentages and numbers of subjects with:



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Methodology:



Study procedures








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Name of Sponsor

Novartis Vaccines and Diagnostics

Protocol number:

V72_60



Part of Interim analysis at 7 monthsGroup Subjects(n) 2 months

(Visit 1)4 months(Visit 2)

6 months(Visit 3)

7 months(Visit 4)

9 months(Visit 5)

11 months(Visit 6)

12 months(Visit 7)

13 months(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-HibPCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-HibPCV-13

rMenB+OMV NZ

DTaP-IPV-HibPCV-13

HepB (3rd dose)*

Blood Draw

Safety Call


MMRVaricella

Blood Draw

Blood Draw


Blood Draw

DTaP-IPV-HibPCV-13

DTaP-IPV-HibPCV-13

HepB (3rd dose)*

Blood Draw

Safety Call

Safety Call MMRVaricella

Blood Draw

Blood Draw

*According to the Taiwanese Immunization Program Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively.In addition, BCG vaccine will be administered ≤ 24 hours after birth


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3. All vaccinations




1. Body Temperature- Daily Body Temperature- Fever (fever is defined as body temperature ≥ 38.0 °C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics






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Protocol number:

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1. Serious Adverse Events2. Medically attended Adverse Events3. Adverse Events leading to premature withdrawal from the study4. Fever and Solicited Adverse Events persisting beyond Day 75. All medications for treatment of Adverse Events recorded in this period

(with the exception of minerals, supplements, vitamins, local anesthetic cream and emollients)



1. Body Temperature - Daily temperature- Fever (defined as temperature ≥38°C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics

2. Solicited reactions for MMR + varicella:- Parotid/salivary gland swelling**- Rash



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Protocol number:

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Number of Subjects planned: To obtain 120 evaluable subjects it is estimated that approximately 150 eligible subjects will need to be enrolled in Group A, to allow for a dropout rate of approximately 20%. Taking into account a randomization ratio between group A:B of 2:1, 75 eligible subjects will need to be enrolled in group B.




Vaccines:






▫ GSK Varicella vaccine (Varilrix®)All vaccines are to be administered by intramuscular (IM) injection on pre-specified locations in the anterolateral area of the left and right thigh.


27 FEB 17Confidential ePublished V72_60 Final CSR

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Protocol number:

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Primary


Key Secondary


Other Secondary


Safety EndpointsLocal (i.e., injection site erythema, induration, tenderness and swelling) and systemic (i.e. change in eating habits, sleepiness, irritability, persistent crying, vomiting, diarrhea, rash, fever [temperature ≥ 38.0 °C] and medically attended fever) adverse events will be assessed for 7 days (including the day of vaccination) post each vaccination according to Table 2.





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Protocol number:

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Statistical Analysis of Primary Objectives and Secondary Objectives:The percentage of subjects with SBA titer ≥1:5 will be presented as point estimates along with the associated 95% Clopper-Pearson confidence intervals (CIs) at baseline (2 months of age, Visit 1), 1 month after the third injection (7 months of age, Visit 4), prior to the booster dose (12 months of age, Visit 7) and at 1 month after the booster dose (13 months of age, Visit 8) for the meningococcal B indicatorstrains H44/76, 5/99 and NZ98/254.






Sample Size and Power Considerations:Sample size for this study was calculated under considerations and assumptionsbased on the antibody response of infants observed in the Novartis Vaccines study V72P13 where infants enrolled received 3 doses of the rMenB+OMV NZ vaccine at 2, 4 and 6 months of age. The percentage of subjects with a SBA titer ≥ 1:5 at 1 month after the third vaccination reported in V72P13 study was 100% (99%-100%) for strain 44/76, 84% (82%-86%) for strain NZ98/254, and 100% (99%-100%) for



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Protocol number:

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strain 5/99.




Strain

πk(proportion of


π0(Threshold)


Power

NZ98/254 0.84 0.70 120 94%44/76 0.99 0.70 120 99%5/99 0.99 0.70 120 99%





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Protocol number:

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6SC

7 RC RC RC 8

Months of Age 2 4 6 7 9 11 12 13Study Day 1 3 7 61 63 67 122 124 128 152 213 274 305 307 311 318 335Time Window (min/max)

n/a

0/+2

0/+2

-4/+

7

2 da

ys (0

/+2)

from

Vis

it 2

6 da

ys (0

/+2)

from

Vis

it 2

61 d

ays (

-4/+

7) fr

omV

isit

2

2 da

ys (0

/+2)

from

Vis

it 3

6 da

ys (0

/+2)

from

Vis

it 3

30 d

ays (

-4/+

7) fr

omV

isit

3

61 d

ays (

-7/+

14) f

rom

Vis

it 4

61 d

ays (

-7/+

14) f

rom

Vis

it 5

183

days

(-7/

+14)

from

Vis

it 3

2 da

ys (0

/+2)

from

Vis

it 7

6 da

ys (0

/+2)

from

Vis

it 7

13 d

ays (

0/+2

)fr

om V

isit

7

30 d

ays (

-4/+

7)fr

om V

isit

7

Informed Consent Xa


Medical History Xa


Xa Xa Xa Xa X

Serology Blood Draw(5 ml)c

Xa X Xa X

rMenB + OMV NZ Vaccination(Group A only)

X X X X

Routine Vaccination(Group A and B) X X X X



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6SC

7 RC RC RC 8


X X X X

Diary Card Dispensede X X X X XReminder Phone Call to Complete Diary Cardf

X X X X X X X X X

Telephone Contact for Review of Safety Datag X X

Assess Local/SystemicAdverse eventsh X X X X

Diary Card Reviewedi X X X X XAssess AEs and SAEsj X X X X X XConcomitant Medicationk X X X X X X X

Study Terminationl Xa. Procedure to be performed prior to vaccinationb. Physical examination must be performed by a qualified health professional in accordance with local regulations and licensing requirements designated


more detail.f. Subject’s parents(s)/legal guardian(s) will be reminded at telephone contact visits to complete Diary Cards and return them at the next clinic visit.



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k. Collect concomitant medications and vaccination history according to the study procedures outlined throughout section 3.2.5 and 5.4.l. Any subject who terminates the study during the Post-Vaccination period is recommended to undergo study-related procedures as outline in section 3.8.m. RC = Reminder Call for completion of Diary Card. See section 3.2.5.4 for greater detail.n. SC = Safety Call. See section 3.2.5.6 for greater detail.



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TABLE OF CONTENTS

PROTOCOL SYNOPSIS V72_60 VERSION 2.0............................................................ 2TABLE OF CONTENTS .............................................................................................. 17

LIST OF ABBREVIATIONS........................................................................................ 221.0 BACKGROUND AND RATIONALE............................................................... 24

2.0 OBJECTIVES.................................................................................................... 262.1 Immunogenicity Objective(s) ......................................................................... 26

2.2 Safety Objectives ........................................................................................... 263.0 STUDY DESIGN AND INVESTIGATIONAL PLAN ...................................... 28

3.1 Overview of Study Design ............................................................................. 283.1.1 Study Period........................................................................................... 31

3.2 Study Procedures ........................................................................................... 313.2.1 Informed Consent/Assent ....................................................................... 31

3.2.2 Screening Procedures ............................................................................. 313.2.3 Enrollment ............................................................................................. 32

3.2.4 Randomization ....................................................................................... 323.2.5 Visit Procedures ..................................................................................... 33


3.2.5.2 Vaccination Procedures ...................................................................... 343.2.5.3 Post-vaccination Procedures ............................................................... 34

3.2.5.4 Reminder Telephone Calls.................................................................. 363.2.5.5 Clinic Visits After Vaccination........................................................... 36

3.2.5.6 Safety Calls ........................................................................................ 373.2.5.7 “For cause” Visits............................................................................... 37

3.2.5.8 Termination Visits .............................................................................. 373.3 Blinding Procedures....................................................................................... 38

3.4 Data Collection .............................................................................................. 383.4.1 Data Collected From Subjects ................................................................ 38



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3.5 Laboratory Assessments................................................................................. 403.5.1 Processing, Labeling and Storage of Serum Samples for Serology.......... 40

3.5.2 Pregnancy Testing .................................................................................. 403.5.3 Safety Laboratory Assessments .............................................................. 40

3.5.4 Cell Mediated Immunity Assessments .................................................... 403.5.5 Culture/PCR/Genotyping Assessments ................................................... 41

3.6 Stopping/Pausing Guidelines.......................................................................... 413.7 Premature Withdrawal and Early Study Termination...................................... 41

3.8 Early Termination Visit.................................................................................. 434.0 SELECTION OF STUDY POPULATION......................................................... 45

4.1 Inclusion Criteria ........................................................................................... 454.2 Exclusion Criteria .......................................................................................... 45

4.3 Criteria for Delay of Vaccination and/or Blood Sampling .............................. 464.4 Criteria for Repeat Vaccination in the Study .................................................. 47

5.0 TREATMENT OF SUBJECTS.......................................................................... 485.1 Study Vaccine(s)............................................................................................ 485.2 Non-Study Vaccines ...................................................................................... 52

5.3 Vaccines Preparation and Administration....................................................... 525.4 Prior and Concomitant Medications and Vaccines.......................................... 54

5.5 Vaccine Supply, Labeling, Storage, and Tracking .......................................... 556.0 MEASUREMENTS........................................................................................... 58

6.1 Appropriateness of Measurements.................................................................. 586.2 Demographics, Medical History and Physical Examination............................ 58

6.3 Immunogenicity Measurements...................................................................... 596.4 Efficacy Measurements.................................................................................. 59

6.5 Solicited Safety Measurements ...................................................................... 596.6 Unsolicited Safety Measurements .................................................................. 61

6.6.1 Adverse Events ...................................................................................... 61



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6.6.2 Serious Adverse Events .......................................................................... 636.6.3 Methods for Assessing and Recording AEs and SAEs ............................ 64

6.6.4 Pregnancies ............................................................................................ 656.7 Safety Laboratory Measurements ................................................................... 66

6.8 Other Measurements ...................................................................................... 666.9 Data Monitoring Committee........................................................................... 66

7.0 ENDPOINTS AND STATISTICAL ANALYSES ............................................. 677.1 Endpoints....................................................................................................... 67

7.1.1 Primary Endpoint(s) ............................................................................... 677.1.2 Secondary Immunogenicity Endpoints.................................................... 67

7.1.3 Secondary Efficacy Endpoints................................................................ 677.1.4 Safety Endpoints .................................................................................... 67

7.1.5 Other Endpoints ..................................................................................... 697.1.6 Exploratory Endpoints............................................................................ 69

7.2 Success Criteria ............................................................................................. 707.2.1 Success Criteria for Primary Objectives.................................................. 707.2.2 Success Criteria for Key Secondary Immunogenicity Objectives ............ 71

7.2.3 Success Criteria for Secondary Efficacy Objectives................................ 717.2.4 Success Criteria for Safety Objectives .................................................... 71

7.3 Analysis Sets ................................................................................................. 717.3.1 All Enrolled Set...................................................................................... 72

7.3.2 Exposed Set........................................................................................... 727.3.3 Full Analysis Set (FAS) Efficacy/Immunogenicity Set ........................... 72

7.3.4 Per Protocol (PP) Population, Efficacy/Immunogenicity Set ................... 727.3.5 Safety Set ............................................................................................... 73

7.3.6 Other Analysis Sets ................................................................................ 737.3.7 Subgroups .............................................................................................. 73




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7.4 Analysis Plan ................................................................................................. 75

7.4.1 Analysis of Demographic and Baseline Characteristics........................... 757.4.2 Analysis of Primary Objectives .............................................................. 75

7.4.2.1 Statistical Hypotheses for Primary Objectives ........................................ 757.4.2.2 Analysis Populations for Primary Objectives ...................................... 76

7.4.2.3 Statistical Methods for Primary Objectives ......................................... 767.4.2.4 Sample Size and Power Considerations of Primary Objectives ........... 76

7.4.2.5 Analysis of Safety Objectives ............................................................. 777.4.2.5.1 Analysis of Extent of Exposure .................................................... 77

7.4.2.5.2 Analysis of Solicited Local and Systemic Adverse Events and Other Reactions .................................................................................................... 78

7.4.2.5.3 Analysis of Spontaneously Reported Adverse Events................... 807.4.2.5.4 Analysis of Safety Laboratory Values .......................................... 80

7.4.3 Analysis of Key Secondary Immunogenicity Objectives......................... 807.4.4 Analysis of Key Secondary Efficacy Objectives ..................................... 83

7.4.5 Analysis of Key Secondary Other Objectives ......................................... 837.4.6 Analysis of Non-Key Objective .............................................................. 83


8.0 SOURCE DOCUMENTATION, STUDY MONITORING, AND AUDITING.. 858.1 Source Documentation................................................................................... 85

8.2 Study Monitoring and Source Data Verification............................................. 869.0 DATA MANAGEMENT................................................................................... 87

9.1 Data Entry and Management .......................................................................... 879.2 Data Clarification........................................................................................... 87

9.3 Data Coding Procedures................................................................................. 879.4 Data Protection .............................................................................................. 87

10.0 RECORD RETENTION.................................................................................... 8811.0 USE OF INFORMATION AND PUBLICATION ............................................. 89

12.0 ETHICS............................................................................................................. 90



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12.2 Informed Consent Procedures ........................................................................ 9012.3 Responsibilities of the Investigator and IRB/EC............................................. 90

12.4 Protocol Adherence........................................................................................ 9212.5 Protocol Amendments.................................................................................... 92

13.0 REFERENCE LIST ........................................................................................... 93



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2.0 OBJECTIVES













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Part of Interim analysis at 7 monthsGroup Subjects

(n)2 months(Visit 1)

4 months(Visit 2)

6 months(Visit 3)

7 months(Visit 4)

9 months(Visit 5)

11 months(Visit 6)

12 months(Visit 7)

13 months(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-HibPCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-HibPCV-13

rMenB+OMV NZ

DTaP-IPV-HibPCV-13

HepB (3rd dose)*

Blood Draw


MMRVaricella

Blood Draw

Blood Draw


Blood Draw

DTaP-IPV-HibPCV-13

DTaP-IPV-HibPCV-13

HepB (3rd dose)*

Blood Draw

Safety Call Safety Call MMRVaricella

Blood Draw

Blood Draw




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3.1.1 Study Period












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- General physical examination (refer to section 6.2 for details)- Review of eligibility criteria (refer to sections 4.1 and 4.2 for the complete list)



3.2.3 Enrollment


3.2.4 Randomization

Enrolled subjects will be randomly assigned to study group A or B in a pre-specified ratio of 2:1 and according to web-based randomization. The list of randomization assignments is produced by a validated system used by the NVD Biostatistics and Clinical Data Management (BCDM) department.




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1. informed consent (refer to sections 3.2.1 and 12.2 for further detail)2. demography (refer to section 6.2 for details)

3. prior and concomitant medication and vaccines (refer to section 5.4 for further detail)4. medical history (refer to section 6.2 for details)

5. general physical examination (refer to section 6.2 for details)6. measurement of subject’s height and weight (refer to section 6.2 for details)



9. randomization (refer to section 3.2.4)10. prior to vaccination, a blood sample will be drawn for serology testing. Details

regarding the volume of blood and testing to be performed are specified in section 3.5.1


1. general physical examination (refer to section 6.2 for details)2. review of eligibility criteria (refer to section 4.1 to 4.4 for eligibility criteria and

criteria for delay of vaccination)At Visit 7 (Day 305, 12 months of age) the following pre-vaccination procedures will be performed:




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1. Diary Card TrainingCareful training of the subject’s parent/guardian on how to measure local reactions and body temperature, how to complete and how often to complete the Diary Card is crucial. Training should be directed at the individual(s) who will perform themeasurements of reactions and those who will enter the information into the Diary Card. This individual may not be the parent/guardian, but if a person other than the parent/guardian enters information into the Diary Card, this person’s identity must be documented in the study file and this person must receive training on the Diary Card. Training of the parent/guardian on how to measure an injection site reaction should be performed while the subject is under observation after vaccination.





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c. Body temperature measurement is to be performed using the thermometer provided by the site. If the subject feels unusually hot or cold during the day, the subject’s parent/guardian should check body temperature. If the subject has fever, the highest body temperature observed that day should be recorded on the Diary Card. The measurement of solicited local adverse events is to be performed using the ruler provided by the site. The collection of body temperature, solicited local adverse events, solicited systemic adverse events will continue for a total of 7days on the Diary Card. Note: After vaccination with MMR and varicella (at Visit 7) the period for collection of body temperature, medically attended fever, parotid/salivary gland swelling and rash will be extended to 28 days after vaccination. The collection of unsolicited adverse events and medications will continue throughout on the Diary Card up to the evening prior to the next clinicvisit.






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3. A Diary Card will be dispensed for the collection of SAEs, medically attended AEs, AEs leading to premature study withdrawal, any solicited events that persist beyondDay 7 after third vaccination, any medication for treatment of AEs and all vaccinations. Careful instruction of the subject’s parent/guardian on how to fill in the Diary Card will be provided and the importance of the timely completion of the Diary Card will be emphasized.





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Not applicable











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3.4 Data Collection





eCRFs


Diary Cards



- Body temperature




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- Any AEs- Concomitant medications

- All vaccinations (except the study vaccines)Note: After vaccination with MMR and varicella (at Visit 7) the period for collection of body temperature, medically attended fever and the solicited adverse events parotid/salivary gland swelling and rash will be extended to 28 days after vaccination.


- Serious AEs (SAEs)- Medically attended AEs

- AEs leading to premature withdrawal from the study- Fever and solicited local/systemic AEs persisting beyond Day 7


- All vaccinations (except the study vaccines)Subsequently, all data collected on Diary Cards by the subject’s parents/guardians will be recorded on eCRFs by the investigator.








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Not applicable.


Not applicable.


Not applicable.



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Not applicable.





▫ Adverse event

▫ Death▫ Withdrawal of consent

▫ Lost to follow-up▫ Administration reason▫ Protocol deviation

▫ OtherNOTE: Before entering any alternate category as the reason for the subject’s discontinuation from the study, the investigator should make every effort to investigate whether or not safety concerns (adverse event or death) may have been related to the subject’s discontinuation from the study. If a safety concern has been associated with the subject’s discontinuation, this must be described on the Termination CRF page, even if it is not the primary reason for the subject’s discontinuation.





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▫ Collect Diary Card▫ Review the subject’s solicited and unsolicited safety data

▫ Perform review of concomitant medications/vaccinations since last visit▫ Collect vital sign measurements, including respiratory rate, blood pressure, pulse rate,

and temperature (rectal)



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3. available for all the visits scheduled in the study;4. in good health as determined by medical history, physical examination and clinical

judgment of the investigator.



5. History of any meningococcal vaccine administration;6. Prior vaccination with any Diphtheria, Tetanus, Pertussis (acellular or whole cell),

Polio (either Inactivated or Oral), Haemophilus influenzae type b (Hib), Pneumococcal, MMR or varicella antigens;





11. Antibiotics within 6 days prior to enrollment;12. Any serious chronic or progressive disease according to the judgment of the

investigator (e.g., neoplasm, insulin dependent diabetes mellitus Type I, cardiac disease, hepatic disease, progressive neurological disease or seizure, either associated with fever or as part of an underlying neurological disorder or syndrome, autoimmune



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15. Receipt of, or intent to immunize with any other vaccine(s) (with the exception of rotavirus vaccine,), within 30 days prior and throughout the study period.Furthermore, subjects must have received HepB vaccine preferably at 0, 1 month of age, with the second dose at least 14 days prior to study vaccination. Rotavirus vaccine should be administered at least 14 days before or 14 days after study vaccination;

16. Participation in another clinical trial since birth or planned for during study;17. Family members and household members of research staff;










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rotavirus vaccine or the second dose of HepB vaccine within 14 days prior to study vaccination.











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▫ GSK Varicella vaccine (Varilrix®)Vaccine compositions are detailed in Table 5.1-1



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Table 5.1-1: Study Vaccine CompositionsNovartis Meningococcal B Recombinant + OMV vaccine (rMenB+ OMV)active ingredients quantity per 0.5 ml doseN meningitidis 961c purified antigen 50 µgN meningitidis 936-741 purified antigen 50 µgN meningitidis 287-953 purified antigen 50 µgOMV from N meningitidis Strain NZ 98/254 25 gother ingredientsAluminum HydroxideSodium ChlorideSucroseHistidineWater for injectionvaccine presentation pre-filled syringeextractable volume 0.5 mlGSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + HIB®) active ingredients quantity per 0.5 ml doseDiphtheria toxoid1 ≥ 30 IUTetanus toxoid1 ≥ 40 IUPertusis toxoid1 25 µgFilamentous haemagglutinin1 25 µgPertactin 8 µgPoliovirus (inactivated) type 1 (Mahoney strain) 40 D-antigen unitsPoliovirus (inactivated) type 2 (MEF-1 strain) 8-D-antigen unitsPoliovirus (inactivated) type 3 (Saukett strain) 32-D-antigen unitsHeamophilus influenzae type B polysaccharide absorbed to tetanus toxoid (approx. 30 µg) carrier protein

10 µg

1adsorbed on aluminium hydroxide (0.5 mg)other ingredientsLactoseSodium Chloride2-phenoxythanolMedium 199 (aminoacids, mineral salts, vitamins)Water for injectionsvaccine presentation as commercially availableextractable volume 0.5 ml



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Pfizer 13-valent pneumococcal conjugate vaccine (Prevenar-13®)active ingredients quantity per 0.5 ml dosePneumococcal PS serotype 1* 2.2 µgPneumococcal PS serotype 3* 2.2 µgPneumococcal PS serotype 4* 2.2 µgPneumococcal PS serotype 5* 2.2 µgPneumococcal PS serotype 6A* 2.2 µgPneumococcal PS serotype 6B* 4.4 µgPneumococcal PS serotype 7F* 2.2 µgPneumococcal PS serotype 9V* 2.2 µgPneumococcal PS serotype 14* 2.2 µgPneumococcal PS serotype 18C* 2.2 µgPneumococcal PS serotype 19A* 2.2 µgPneumococcal PS serotype 19F* 2.2 µgPneumococcal PS serotype 23F* 2.2 µg*Conjugated to CRM197 and absorbed on aluminium phosphate (0.125 mg)other ingredientsSodium chlorideSuccine acidPolysorbate 80Water for injectionsvaccine presentation as commercially availableextractable volume 0.5 mlGSK Hepatitis B vaccine (Engerix-B®)active ingredients quantity per 0.5 ml doseHepatitis B surface antigen* 10 µgother ingredientsSodium chlorideDisodium Phosphate hydrateSodium Dihydrogen PhosphateWater for injectionsvaccine presentation as commercially availableextractable volume 0.5 ml*adsorbed on aluminium hydroxide (0.25 mg)



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GSK Measles, Mumps and Rubella vaccine (Priorix®)active ingredients quantity per 0.5 ml doseLive attenuated measles virus (Schwarz strain) ≥ 103.0 CCID50



other ingredientsLactoseSorbitolMannitolAminoacidsWater for injectionsvaccine presentation as commercially availableextractable volume 0.5 mlGSK Varicella vaccine (Varilrix®)active ingredients quantity per 0.5 ml doseLive attenuated Varicella virus (OKA strain) ≥ 103.3 PFUOther ingredientsAminoacidsHuman AlbuminNeomycine sulfateLactoseMannitolSorbitolWater for injectionsvaccine presentation as commercially availableextractable volume 0.5 ml






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rMenB+OMV NZ vaccine preparationThe rMenB+OMV NZ vaccine is provided in a pre-filled syringe. The vaccine should be allowed to reach room temperature before administration, according to local vaccination practice. The full content of the pre-filled syringe should be injected to ensure that the administered dose is 0.5 mL. Please refer to the instruction sheet for a detailed description of the vaccines preparation and administration.


Concomitant routine vaccine preparationThe concomitant routine vaccines used in this study, i.e. GSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + Hib®), Pfizer 13-valent PCV (Prevenar-13®), GSK Hep B vaccine (Engerix-B®), GSK MMR vaccine (Priorix®) and GSK Varicella vaccine



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(Varilrix®) are all licensed vaccines in Taiwan and must be prepared according to the package insert before use. Expired vaccines must not be administered.



Group A (rMenB+OMV NZ concomitant with routine vaccines)Primary schedule (infants) Right thigh














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Group B (routine vaccines only)Primary Series (infants) Right thigh

















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▫ acknowledge receipt of the study vaccines by a designated staff member at the site, including confirmation that the vaccines:- were received in good condition





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- storage in a secure, locked, temperature-controlled location- proper storage according to the instructions specified on the labels


▫ appropriate use of the study vaccines, including:- use only in accordance with the approved protocol


- appropriate documentation of administration of vaccines to study subjects including:





- copy of the site’s procedure for destruction of hazardous material- number of doses destroyed, date of destruction, destruction code (if available),

method of destruction, and name of individual performing destructionVaccines that have been stored differently from the manufacturer’s indications must notbe used unless the sponsor provides written authorization for use. In the event that the use cannot be authorized, the sponsor will make every effort to replace the vaccine supply. All vaccines used in conjunction with this protocol must be stored separately from normal hospital/practice stocks to prevent unintentional use of study vaccines outside of the clinical trial setting.



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6.0 MEASUREMENTS













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Details on all sample handling steps are described in the Clinical Specimen Lab Manual provided to all study sites.







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1. Not Related




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2. Possibly Related


3. Probably Related








▫ Solicited local or systemic adverse event lasting beyond 7 days’ duration.▫ Solicited local or systemic adverse events that lead to subject withdrawal from study

vaccination.▫ Solicited local or systemic adverse event that otherwise meets the definition of a

serious adverse event (see section 6.6.2).

Kawasaki Disease

Rare (up to 1/1000 people affected) cases of Kawasaki Disease have been detected in previous clinical studies, both in infants receiving rMenB+OMV NZ and in infants not receiving rMenB+OMV NZ. Kawasaki Disease may include symptoms such as fever that lasts for more than five days, associated with a skin rash on the trunk of the body, and sometimes followed by a peeling of the skin on the hands and fingers, swollen glands in



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Not Applicable.



▫ Death.▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at

immediate risk of death from the event as it occurred); it does not refer to an event which hypothetically might have caused death if it were more severe.

▫ Required or prolonged hospitalization.▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial

disruption of a person’s ability to conduct normal life functions).▫ Congenital anomaly/or birth defect.▫ An important and significant medical event that may not be immediately life

threatening or resulting in death or hospitalization but, based upon appropriate medical judgment, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed above.







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2. Not Related






The period of observation for AEs extends from the time the subject signs informed consent until he or she completes the specified safety follow-up period (until 13 months of age) or terminates the study early (whichever comes first). AEs occurring after the informed consent form is signed but prior to receiving study vaccine/product will be documented as an adverse event and recorded on the Adverse Events eCRF and within source documents. However, AEs occurring prior to receipt of any study vaccine will be analyzed separately from “treatment emergent” AEs (AEs occurring after administration of the first study vaccine).




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Post-Study Events


6.6.4 Pregnancies

Not applicable.



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Not applicable.


Not applicable.





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7.1 Endpoints









Not applicable.






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1. Immediate reactions:- Signs or symptoms of anaphylaxis- Immediate local and systemic reactions


1. Body Temperature - Daily Body temperature.- Fever (defined as body temperature ≥ 38.0°C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics




5. All medications (with the exception of minerals, supplements, vitamins, local anesthetic cream and emollients).


From Day 8 until last study visit (Day 335).

1. Serious Adverse Events2. Medically attended Adverse Events3. Adverse Events leading to premature withdrawal from the study4. Fever and solicited local/systemic Adverse Events persisting beyond Day 75. All medications for treatment of Adverse Events recorded in this period

(with the exception of minerals, supplements, vitamins)6. All vaccinations (except the study vaccines)



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1. Body Temperature- Daily temperature- Fever (defined as temperature ≥38°C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics

2. Solicited reactions for MMR + Varicella:- Parotid/salivary gland swelling**- Rash





Not applicable.



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Not applicable.



7.3 Analysis Sets




FAS/PPS:






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7.3.2 Exposed Set











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7.3.5 Safety Set










▫ Have post-vaccination solicited or unsolicited recordsSubjects will be analyzed as "treated" (i.e., according to the vaccine a subject received, rather than the vaccine to which the subject may have been randomized).



7.3.7 Subgroups






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The following deviations are considered major:▫ A subject received incorrect study vaccine or dose of study vaccine.

▫ A subject met withdrawal criteria during the study but was not withdrawn.▫ A subject received an excluded medication or vaccine.

▫ A subject was enrolled but does not meet the protocol's eligibility criteria.▫ A subject with no safety data



▫ Falsifying research or medical records.Subjects who terminate study participation prematurely for reasons such as withdrawal of consent, adverse event (including death) or administrative reason do not represent protocol deviations, nor are the missing assessments that should otherwise have been collected for that subject later in the study considered protocol deviations.






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7.4 Analysis Plan











where




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Percentage of subjects in Group A with SBA titer >1:5

For each strains, NZ98/254, H44/76, and 5/99 the percentage of subjects in vaccine group A achieving an SBA titer > 1:5 at 1 month after the third vaccination (Day 152, 7 months of age) will be presented as point estimates together with the two-sided 95% confidence intervals computed using the Clopper-Pearson method (Clopper, 1934).









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Strain

πk(proportion of


π0(Threshold)


Group APower

NZ98/254 0.84 0.70 120 94%44/76 0.99 0.70 120 99%5/99 0.99 0.70 120 99%









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The influence of antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever) will be assessed.






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None(Grade 0)

Mild(Grade 1)

Moderate(Grade 2)

Severe(Grade 3)

Injection site Tenderness no tenderness Minor light



limb was moved

Injection site erythema 0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm

Injection site swelling 0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm

Injection site induration 0 - 9 mm 10 - 25 mm 26 - 50 mm > 50 mm




feedsMissed 1 or 2 feeds Missed more than 2

feeds

Sleepiness No change in alertness

Shows an increased

drowsiness



arouse him/her




usual

More difficult to settle Unable to console

Persitent crying No persistent crying

Crying less than one hour

Crying for 1 to < 3 hours

Crying for 3 or more hours

Vomitting No vomitting 1-2 episodes / 24 hours

>2 episodes/24 hours

Requires outpatient hydration







hydration





involvement)

Most of the skin



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▫ serious adverse events▫ adverse events that are possibly or probably related to vaccine

▫ adverse event leading to withdrawal▫ adverse events leading to a medically attended visit▫ adverse event by data source



Not applicable.






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where












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Table 7.4.3-1: Power that the Proportion of Subjects with SBA titer ≥1:5 is greater than 0.75 (threshold π0) for a Given Strain, True Underlying Proportion, and Sample Size

Strain

πk(proportion of


π0(Threshold)


Group A Power

NZ98/254 0.95 0.75 120 99%44/76 0.99 0.75 120 99%5/99 0.99 0.75 120 99%




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SBA GMTs, GMRs and the percentage of subjects with SBA titer ≥ 1:5 and their associated 95% CIs, median, minimal and maximal values will be determined for each strain (H44/76, 5/99, NZ98/254 and M10713) at baseline (Day 1), at 1 months after the third dose (Day 152), before the booster dose (at Day 305) and at one month after the booster dose (Day 335) both in infants receiving rMenB+OMV NZ with routine vaccines (Group A) and in infants receiving routine vaccines only (Group B). The control arm(infants receiving routine vaccines only) has been included to assess the prevalence of bactericidal meningococcal B antibodies over the study period in infants not receiving rMenB+OMV NZ vaccine (negative control).









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Because the primary study objective is to demonstrate sufficiency of response of rMenB+OMV NZ after the third vaccination and all enrolled subjects who have immunogenicity data will be included in the interim analysis no alpha correction will be performed for the primary or key secondary analysis which will be conducted both at the one-sided 0.025 significant level.


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Contact details for the team involved in study monitoring will be identified in a handout located in the Investigator Site File. Study data recorded on CRFs will be verified by checking the CRF entries against source documents in order to ensure data completeness and accuracy as required by study protocol. Additional documents such as the investigator site file, pharmacy records, and informed consent documentation must also be available for review if requested. Arrangements for monitoring visits will be made in advance in accordance with the monitoring plan, except in case of emergency. The investigator and/or site staff must make source documents of subjects enrolled in this study available for inspection by NVD or its representative at the time of each monitoring visit. These documents must also be available for inspection, verification and copying, as required by regulations, by officials of the regulatory health authorities (e.g., FDA, EMA and others) and/or ECs/IRBs. The investigator and study site staff must comply with applicable privacy, data protection and medical confidentiality laws for use and disclosure of information related to the study and enrolled subjects.


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9.0 DATA MANAGEMENT










9.4 Data Protection



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12.0 ETHICS









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The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephonenumber(s)). In addition, the investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.




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13.0 REFERENCE LIST













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Novartis



UserName: Title: Cluster Physician Date: Friday, 12 July 2013, 06:39 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


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Novartis Vaccines and Diagnostics Clinical Study Protocol V72_60 Amendment 205 NOV 13 Final Version Confidential Page 1 of 6


CLINICAL STUDY PROTOCOL V72_60

Amendment Number 2




Confidential

May not be used, divulged, published or otherwise disclosed without written

consent of Novartis Vaccines and Diagnostics.

The present amendment reflects changes to the protocol since version 2.0 of the

protocol.


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CHANGE 1 (Section 4.2, Exclusion criteria #15):

Previously read:

“Receipt of, or intent to immunize with any other vaccine(s) (with the exception of rotavirus vaccine), within 30 days prior and throughout the study period. Furthermore, subjects must have received HepB vaccine preferably at 0, 1 month of age, with the second dose at least 14 days prior to study vaccination. Rotavirus vaccine should be administered at least 14 days before or 14 days after study vaccination”

Now reads:

“Receipt of, or intent to immunize with any other vaccine(s) (with the exception of rotavirus vaccine, influenza vaccine and second HepB vaccine), within 30 days prior and throughout the study period. Furthermore, subjects must have received HepB vaccine preferably at 0, 1 month of age, with the second dose at least 14 days prior to study vaccination. Rotavirus vaccine and influenza vaccine should be administered at least 14 days before or 14 days after study vaccination”


Investigator feedback: Influenza vaccine should be allowed as it is given to infants ≥ 6 months of age.

TFDA Feedback: The protocol exclusion criteria #15 excludes subjects who received anyother vaccine within 30 days prior to study involvement (except for rotavirus vaccine) and then adds the second hepatitis B vaccine (month one) shall be given 14 days prior to study involvement. Recommendation to revise the exclusion criteria to exempt “rotavirus vaccine and second Hepatitis vaccine”

CHANGE 2 (Section 4.3, Third bullet-point):

Previously read:

“Individuals that received any other vaccines (with the exception of HepB and rotavirus vaccine), within 30 days prior to enrollment. Individuals that received rotavirus vaccine or the second dose of HepB vaccine within 14 days prior to study vaccination”

Now reads:


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“Individuals that received any other vaccines (with the exception of HepB and rotavirus vaccine), within 30 days prior to enrollment. Individuals that received rotavirus vaccine, influenza vaccine or the second dose of HepB vaccine within 14 days prior to study vaccination”


Investigator feedback: Influenza vaccine should be allowed as it is given to infants ≥ 6 months of age

CHANGE 3 (Section 3.2.4, Starting Line 1):

Previously read:

“Enrolled subjects will be randomly assigned to study group A or B in a pre-specified ratio of 2:1 and according to web-based randomization. The list of randomization assignments is produced by a validated system used by the NVD Biostatistics and Clinical Data Management (BCDM) department”

Now reads:

“Enrolled subjects will be randomly assigned to study group A or B in a pre-specified ratio of 2:1 and according to web-based randomization, using a permuted block randomization with Center as stratification factor, to ensure a good balance of subject’s characteristics in each group. The list of randomization assignments is produced by a validated system used by the NVD Biostatistics and Clinical Data Management (BCDM) department”


TFDA Feedback: Recommendation to state the randomization method and stratificationfactors in the protocol.

CHANGE 4 (Section 7.4.2.5.2, Starting Line 16):

Previously read:

“Use of antipyretics and analgesics will be summarized by frequency, by type of use (prophylactic versus treatment) and percentage of subjects reporting use. The influence of


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antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever) will be assessed.”

Now reads:

“Use of antipyretics and analgesics will be summarized by frequency, by type of use (prophylactic versus treatment) and percentage of subjects reporting use. The influence of antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever) will be assessed”


Correction: Influence of antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever) will not be analyzed.

CHANGE 5 (Synopsis, Page 9 ‘Study vaccines used in this study’):

Previously read:

All vaccines are to be administered by intramuscular (IM) injection on pre-specified locations in the anterolateral area of the left and right thigh.

Now reads:

“rMenB+OMV NZ, Infanrix-IPV+Hib®, Prevenar-13® and Engerix-B® All vaccinesare to be administered by intramuscular (IM) injection on pre-specified locations in the anterolateral area of the left and right thigh.

Priorix® and Varilrix® vaccines should be administered subcutaneously (SC) on pre-specified locations in the anterolateral area of the left and right thigh.”


Correction: MMR (Priorix) and varicella (Varilrix) vaccines are administeredsubcutaneously as is correctly described in the Clinical Study Protocol section 5.1.

CHANGE 6 (Synopsis, Page 16 ‘Times & Events Table 4’, footnote h):

Previously read:


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“Beginning in the evening (approximately 6 hours) following study vaccine administration on Day 1, and daily thereafter through Day 8 (or Day 28 for booster dose), solicited local and systemic adverse events including other reactions (i.e. body temperature measurements and use of antipyretics) will be reported daily by the subject’s parents(s)/ legal guardian(s) on a Diary Card.”

Now reads:

“Beginning in the evening (approximately 6 hours) following study vaccine administration on Day 1, and daily thereafter through Day 7 8(or Day 28 for booster dose), solicited local and systemic adverse events including other reactions (i.e. body temperature measurements and use of antipyretics) will be reported daily by the subject’s parents(s)/ legal guardian(s) on a Diary Card.”


Correction: Solicited data are collected through Day 7 not through Day 8

CHANGE 7 (Section 7.4.2.3, Starting Line 1):

Previously read:

“Percentage of subjects in Group A with SBA titer >1:5

For each strains, NZ98/254, H44/76, and 5/99 the percentage of subjects in vaccine group A achieving an SBA titer > 1:5 at 1 month after the third vaccination (Day 152, 7 months of age) will be presented as point estimates together with the two-sided 95% confidence intervals computed using the Clopper-Pearson method (Clopper, 1934).”

Now reads:

“Percentage of subjects in Group A with SBA titer >1:5

For each strains, NZ98/254, H44/76, and 5/99 the percentage of subjects in vaccine group A achieving an SBA titer > 1:5 at 1 month after the third vaccination (Day 152, 7 months of age) will be presented as point estimates together with the two-sided 95% confidence intervals computed using the Clopper-Pearson method (Clopper, 1934).”


Correction: In initial draft version of the Clinical Study Protocol we were planning to not do any blood draw in group B. However, this has been changed while protocol design


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was progressing and now blood is taken from both Group A and Group B at identical time-points. Therefore, it is not necessary to specify Group A in the description ofstatistical methods for primary objective.

CHANGE 8 (Section 7.4.6, Starting Line 1):

Previously read:

SBA GMTs, GMRs and the percentage of subjects with SBA titer ≥ 1:5 and their associated 95% CIs, [median, minimal and maximal values] will be determined for each strain (H44/76, 5/99, NZ98/254 and M10713) at baseline (Day 1), at 1 months after the third dose (Day 152), before the booster dose (at Day 305) and at one month after the booster dose (Day 335) both in infants receiving rMenB+OMV NZ with routine vaccines (Group A) and in infants receiving routine vaccines only (Group B). The control arm (infants receiving routine vaccines only) has been included to assess the prevalence of bactericidal meningococcal B antibodies over the study period in infants not receiving rMenB+OMV NZ vaccine (negative control)”

Now reads:

SBA GMTs, GMRs and median, minimal and maximal values, as well as the percentage of subjects with SBA titer ≥ 1:5 and their associated 95% CIs, median, minimal and maximal values will be determined for each strain (H44/76, 5/99, NZ98/254 and M10713) at baseline (Day 1), at 1 months after the third dose (Day 152), before the booster dose (at Day 305) and at one month after the booster dose (Day 335) both in infants receiving rMenB+OMV NZ with routine vaccines (Group A) and in infants receiving routine vaccines only (Group B). The control arm (infants receiving routine vaccines only) has been included to assess the prevalence of bactericidal meningococcal B antibodies over the study period in infants not receiving rMenB+OMV NZ vaccine (negative control)”


Correction: Previous protocol text suggests we will assess median, minimal and maximal values for % of subjects with SBA titers, which is not the case. The final sentence in the previous text is redundant and it is not necessary for the description of analysis of non-key objectives.


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Novartis



UserName: Title: Cluster Physician Date: Wednesday, 06 November 2013, 08:11 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


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Novartis Vaccines and Diagnostics Protocol V72_6005 NOV 13 Final Version 3.0 Confidential Page 1 of 93






Confidential


consent of Novartis Vaccines and Diagnostics


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Name of Sponsor:Novartis Vaccines and Diagnostics

Protocol number:V72_60




Rationale: N. meningitidis is an important cause of bacterial meningitis and septicemia in infants and young adults. Meningococcal disease can be caused by serogroups A, B, C, W-135 and Y. Currently, no vaccine is available to protect against serogroup B, which accounts for approximately 50% of confirmed meningococcal disease casesreported in Taiwan. Therefore, there exists an urgent need for an effective vaccine that protects against meningococcal disease caused by serogroup B.





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Objectives:





Safety Objectives

To assess the safety and tolerability of 3 doses of rMenB+OMV NZ given at 2, 4, 6 months of age, followed by a booster dose at 12 months of age when concomitantly administered with routine vaccines (i.e. combined DTaP-IPV-Hib and PCV-13 at 2, 4, 6 months; HepB at 6 months of age; MMR and varicella at 12 months of age) and of routine vaccines alone in terms of percentages and numbers of subjects with:



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Methodology:



Study procedures








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Part of Interim analysis at 7 months

Group Subjects(n) 2 months

(Visit 1)

4 months

(Visit 2)

6 months

(Visit 3)

7 months

(Visit 4)

9 months

(Visit 5)

11 months

(Visit 6)

12 months

(Visit 7)

13 months

(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw

Safety Call


MMR

Varicella

Blood Draw

Blood Draw

B 75 DTaP-IPV-Hib

PCV-13

Blood Draw

DTaP-IPV-Hib

PCV-13

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw

Safety Call

Safety Call MMR

Varicella

Blood Draw

Blood Draw

*According to the Taiwanese Immunization Program Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively.

In addition, BCG vaccine will be administered ≤ 24 hours after birth



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3. All vaccinations




1. Body Temperature

- Daily Body Temperature- Fever (fever is defined as body temperature ≥ 38.0 °C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics







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1. Serious Adverse Events

2. Medically attended Adverse Events

3. Adverse Events leading to premature withdrawal from the study

4. Fever and Solicited Adverse Events persisting beyond Day 7

5. All medications for treatment of Adverse Events recorded in this period (with the exception of minerals, supplements, vitamins, local anesthetic cream and emollients)



1. Body Temperature

- Daily temperature- Fever (defined as temperature ≥38°C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics

2. Solicited reactions for MMR + varicella:

- Parotid/salivary gland swelling**- Rash




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Vaccines:




▫ GSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + Hib®)

▫ Pfizer 13-valent pneumococcal conjugate vaccine (Prevenar-13®)

▫ GSK Hepatitis B vaccine (Engerix-B®)

▫ GSK Measles, Mumps and Rubella vaccine (Priorix®)

▫ GSK Varicella vaccine (Varilrix®)

rMenB+OMV NZ, Infanrix-IPV + Hib®, Prevenar-13® and Engerix-B® are to be administered by intramuscular (IM) injection on pre-specified locations in the anterolateral area of the left and right thigh.

Priorix® and Varilrix® should be administered subcutaneously (SC) on pre-specified locations in the anterolateral area of the left and right thigh.




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Primary


Key Secondary


Other Secondary


Safety Endpoints

Local (i.e., injection site erythema, induration, tenderness and swelling) and systemic (i.e. change in eating habits, sleepiness, irritability, persistent crying, vomiting, diarrhea, rash, fever [temperature ≥ 38.0 °C] and medically attended fever) adverse events will be assessed for 7 days (including the day of vaccination) post each vaccination according to Table 2.





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Statistical Analysis of Primary Objectives and Secondary Objectives:

The percentage of subjects with SBA titer ≥1:5 will be presented as point estimates along with the associated 95% Clopper-Pearson confidence intervals (CIs) at baseline (2 months of age, Visit 1), 1 month after the third injection (7 months of age, Visit 4), prior to the booster dose (12 months of age, Visit 7) and at 1 month after the booster dose (13 months of age, Visit 8) for the meningococcal B indicatorstrains H44/76, 5/99 and NZ98/254.






Sample Size and Power Considerations:

Sample size for this study was calculated under considerations and assumptionsbased on the antibody response of infants observed in the Novartis Vaccines study V72P13 where infants enrolled received 3 doses of the rMenB+OMV NZ vaccine at 2, 4 and 6 months of age. The percentage of subjects with a SBA titer ≥ 1:5 at 1 month after the third vaccination reported in V72P13 study was 100% (99%-100%) for strain 44/76, 84% (82%-86%) for strain NZ98/254, and 100% (99%-100%) for



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strain 5/99.




Strain

πk

(proportion of subjects with SBA

titer ≥ 1:5)

π0

(Threshold)


Power

NZ98/254 0.84 0.70 120 94%

44/76 0.99 0.70 120 99%

5/99 0.99 0.70 120 99%





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Study Related Visit#

1 RCm RC 2 RC RC 3 RC RC 4 5

SCn

6

SC

7 RC RC RC 8

Months of Age 2 4 6 7 9 11 12 13

Study Day 1 3 7 61 63 67 122 124 128 152 213 274 305 307 311 318 335

Time Window (min/max)

n/a

0/+

2

0/+

2

-4/+

7

2 d

ays

(0/+

2) f

rom

Vis

it 2

6 d

ays

(0/+

2) f

rom

Vis

it 2

61 d

ays

(-4/

+7)

fro

mV

isit

2

2 d

ays

(0/+

2) f

rom

Vis

it 3

6 d

ays

(0/+

2) f

rom

Vis

it 3

30 d

ays

(-4/

+7)

fro

mV

isit

3

61 d

ays

(-7/

+14

) fr

omV

isit

4

61 d

ays

(-7/

+14

) fr

omV

isit

5

183

day

s (-

7/+

14)

from

Vis

it 3

2 d

ays

(0/+

2)fr

om V

isit

7

6 d

ays

(0/+

2)fr

om V

isit

7

13 d

ays

(0/+

2)fr

om V

isit

7

30 d

ays

(-4/

+7)

from

Vis

it 7

Informed Consent Xa


Medical History Xa


Xa Xa Xa Xa X

Serology Blood Draw

(5 ml)c

Xa X Xa X

rMenB + OMV NZ Vaccination

(Group A only)

X X X X



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SCn

6

SC

7 RC RC RC 8

Routine Vaccination(Group A and B)

X X X X


X X X X

Diary Card Dispensede X X X X X

Reminder Phone Call to Complete Diary Cardf

X X X X X X X X X

Telephone Contact for Review of Safety Datag

X X

Assess Local/SystemicAdverse eventsh

X X X X

Diary Card Reviewedi X X X X X

Assess AEs and SAEsj X X X X X X

Concomitant Medicationk X X X X X X X

Study Terminationl X



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a. Procedure to be performed prior to vaccinationb. Physical examination must be performed by a qualified health professional in accordance with local regulations and licensing requirements designated


more detail.f. Subject’s parents(s)/legal guardian(s) will be reminded at telephone contact visits to complete Diary Cards and return them at the next clinic visit.g. Subject’s parents(s)/legal guardian(s) will be interviewed by site staff using a scripted interview for collection of safety data. These safety data will be

transcribed in source documents by the individuals performing the interviews.h. Beginning in the evening (approximately 6 hours) following study vaccine administration on Day 1, and daily thereafter through Day 7 (or Day 28 for

booster dose), solicited local and systemic adverse events including other reactions (i.e. body temperature measurements and use of antipyretics) will be reported daily by the subject’s parents(s)/ legal guardian(s) on a Diary Card.



k. Collect concomitant medications and vaccination history according to the study procedures outlined throughout sections 3.2.5 and 5.4.l. Any subject who terminates the study during the Post-Vaccination period is recommended to undergo study-related procedures as outline in section 3.8.m. RC = Reminder Call for completion of Diary Card. See section 3.2.5.4 for greater detail.n. SC = Safety Call. See section 3.2.5.6 for greater detail.



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TABLE OF CONTENTS

PROTOCOL SYNOPSIS V72_60 VERSION 3.0............................................................ 2

TABLE OF CONTENTS .............................................................................................. 17

LIST OF ABBREVIATIONS........................................................................................ 22

1.0 BACKGROUND AND RATIONALE............................................................... 24

2.0 OBJECTIVES.................................................................................................... 26

2.1 Immunogenicity Objective(s) ......................................................................... 26

2.2 Safety Objectives ........................................................................................... 26

3.0 STUDY DESIGN AND INVESTIGATIONAL PLAN ...................................... 28

3.1 Overview of Study Design ............................................................................. 28

3.1.1 Study Period........................................................................................... 31

3.2 Study Procedures ........................................................................................... 31

3.2.1 Informed Consent/Assent ....................................................................... 31

3.2.2 Screening Procedures ............................................................................. 31

3.2.3 Enrollment ............................................................................................. 32

3.2.4 Randomization ....................................................................................... 32

3.2.5 Visit Procedures ..................................................................................... 33


3.2.5.2 Vaccination Procedures ...................................................................... 34

3.2.5.3 Post-vaccination Procedures ............................................................... 34

3.2.5.4 Reminder Telephone Calls.................................................................. 36

3.2.5.5 Clinic Visits After Vaccination........................................................... 36

3.2.5.6 Safety Calls ........................................................................................ 37

3.2.5.7 “For cause” Visits............................................................................... 37

3.2.5.8 Termination Visits .............................................................................. 37

3.3 Blinding Procedures....................................................................................... 38

3.4 Data Collection .............................................................................................. 38

3.4.1 Data Collected From Subjects ................................................................ 38



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3.5 Laboratory Assessments................................................................................. 40

3.5.1 Processing, Labeling and Storage of Serum Samples for Serology.......... 40

3.5.2 Pregnancy Testing .................................................................................. 40

3.5.3 Safety Laboratory Assessments .............................................................. 40

3.5.4 Cell Mediated Immunity Assessments .................................................... 40

3.5.5 Culture/PCR/Genotyping Assessments ................................................... 41

3.6 Stopping/Pausing Guidelines.......................................................................... 41

3.7 Premature Withdrawal and Early Study Termination...................................... 41

3.8 Early Termination Visit.................................................................................. 43

4.0 SELECTION OF STUDY POPULATION......................................................... 45

4.1 Inclusion Criteria ........................................................................................... 45

4.2 Exclusion Criteria .......................................................................................... 45

4.3 Criteria for Delay of Vaccination and/or Blood Sampling .............................. 46

4.4 Criteria for Repeat Vaccination in the Study .................................................. 47

5.0 TREATMENT OF SUBJECTS.......................................................................... 48

5.1 Study Vaccine(s)............................................................................................ 48

5.2 Non-Study Vaccines ...................................................................................... 52

5.3 Vaccines Preparation and Administration....................................................... 52

5.4 Prior and Concomitant Medications and Vaccines.......................................... 54

5.5 Vaccine Supply, Labeling, Storage, and Tracking .......................................... 55

6.0 MEASUREMENTS........................................................................................... 58

6.1 Appropriateness of Measurements.................................................................. 58

6.2 Demographics, Medical History and Physical Examination............................ 58

6.3 Immunogenicity Measurements...................................................................... 59

6.4 Efficacy Measurements.................................................................................. 59

6.5 Solicited Safety Measurements ...................................................................... 59

6.6 Unsolicited Safety Measurements .................................................................. 61

6.6.1 Adverse Events ...................................................................................... 61



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6.6.2 Serious Adverse Events .......................................................................... 63

6.6.3 Methods for Assessing and Recording AEs and SAEs ............................ 64

6.6.4 Pregnancies ............................................................................................ 65

6.7 Safety Laboratory Measurements ................................................................... 66

6.8 Other Measurements ...................................................................................... 66

6.9 Data Monitoring Committee........................................................................... 66

7.0 ENDPOINTS AND STATISTICAL ANALYSES ............................................. 67

7.1 Endpoints....................................................................................................... 67

7.1.1 Primary Endpoint(s) ............................................................................... 67

7.1.2 Secondary Immunogenicity Endpoints.................................................... 67

7.1.3 Secondary Efficacy Endpoints................................................................ 67

7.1.4 Safety Endpoints .................................................................................... 67

7.1.5 Other Endpoints ..................................................................................... 69

7.1.6 Exploratory Endpoints............................................................................ 69

7.2 Success Criteria ............................................................................................. 70

7.2.1 Success Criteria for Primary Objectives.................................................. 70

7.2.2 Success Criteria for Key Secondary Immunogenicity Objectives ............ 71

7.2.3 Success Criteria for Secondary Efficacy Objectives................................ 71

7.2.4 Success Criteria for Safety Objectives .................................................... 71

7.3 Analysis Sets ................................................................................................. 71

7.3.1 All Enrolled Set...................................................................................... 72

7.3.2 Exposed Set........................................................................................... 72

7.3.3 Full Analysis Set (FAS) Efficacy/Immunogenicity Set ........................... 72

7.3.4 Per Protocol (PP) Population, Efficacy/Immunogenicity Set ................... 72

7.3.5 Safety Set ............................................................................................... 73

7.3.6 Other Analysis Sets ................................................................................ 73

7.3.7 Subgroups .............................................................................................. 73




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7.4 Analysis Plan ................................................................................................. 75

7.4.1 Analysis of Demographic and Baseline Characteristics........................... 75

7.4.2 Analysis of Primary Objectives .............................................................. 75

7.4.2.1 Statistical Hypotheses for Primary Objectives ........................................ 75

7.4.2.2 Analysis Populations for Primary Objectives ...................................... 76

7.4.2.3 Statistical Methods for Primary Objectives ......................................... 76

7.4.2.4 Sample Size and Power Considerations of Primary Objectives ........... 76

7.4.2.5 Analysis of Safety Objectives ............................................................. 77

7.4.2.5.1 Analysis of Extent of Exposure .................................................... 77

7.4.2.5.2 Analysis of Solicited Local and Systemic Adverse Events and Other Reactions 78

7.4.2.5.3 Analysis of Spontaneously Reported Adverse Events................... 80

7.4.2.5.4 Analysis of Safety Laboratory Values .......................................... 80

7.4.3 Analysis of Key Secondary Immunogenicity Objectives......................... 80

7.4.4 Analysis of Key Secondary Efficacy Objectives ..................................... 83

7.4.5 Analysis of Key Secondary Other Objectives ......................................... 83

7.4.6 Analysis of Non-Key Objective .............................................................. 83


8.0 SOURCE DOCUMENTATION, STUDY MONITORING, AND AUDITING.. 85

8.1 Source Documentation................................................................................... 85

8.2 Study Monitoring and Source Data Verification............................................. 86

9.0 DATA MANAGEMENT................................................................................... 87

9.1 Data Entry and Management .......................................................................... 87

9.2 Data Clarification........................................................................................... 87

9.3 Data Coding Procedures................................................................................. 87

9.4 Data Protection .............................................................................................. 87

10.0 RECORD RETENTION.................................................................................... 88

11.0 USE OF INFORMATION AND PUBLICATION ............................................. 89

12.0 ETHICS............................................................................................................. 90



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12.2 Informed Consent Procedures ........................................................................ 90

12.3 Responsibilities of the Investigator and IRB/EC............................................. 90

12.4 Protocol Adherence........................................................................................ 92

12.5 Protocol Amendments.................................................................................... 92

13.0 REFERENCE LIST ........................................................................................... 93



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2.0 OBJECTIVES













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Group Subjects

(n)

2 months

(Visit 1)

4 months

(Visit 2)

6 months

(Visit 3)

7 months

(Visit 4)

9 months

(Visit 5)

11 months

(Visit 6)

12 months

(Visit 7)

13 months

(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw


MMR

Varicella

Blood Draw

Blood Draw

B 75 DTaP-IPV-Hib

PCV-13

Blood Draw

DTaP-IPV-Hib

PCV-13

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw

Safety Call Safety Call MMR

Varicella

Blood Draw

Blood Draw




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3.1.1 Study Period












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- General physical examination (refer to section 6.2 for details)

- Review of eligibility criteria (refer to sections 4.1 and 4.2 for the complete list)



3.2.3 Enrollment


3.2.4 Randomization

Enrolled subjects will be randomly assigned to study group A or B in a pre-specified ratio of 2:1 and according to web-based randomization, using a permuted block randomization with Center as stratification factor, to ensure a good balance of subject’s characteristics in each group. The list of randomization assignments is produced by a validated system used by the NVD Biostatistics and Clinical Data Management (BCDM) department.




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1. informed consent (refer to sections 3.2.1 and 12.2 for further detail)

2. demography (refer to section 6.2 for details)

3. prior and concomitant medication and vaccines (refer to section 5.4 for further detail)

4. medical history (refer to section 6.2 for details)


6. measurement of subject’s height and weight (refer to section 6.2 for details)



9. randomization (refer to section 3.2.4)





At Visit 7 (Day 305, 12 months of age) the following pre-vaccination procedures will be performed:




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1. Diary Card Training

Careful training of the subject’s parent/guardian on how to measure local reactions and body temperature, how to complete and how often to complete the Diary Card is crucial. Training should be directed at the individual(s) who will perform the measurements of reactions and those who will enter the information into the Diary Card. This individual may not be the parent/guardian, but if a person other than the parent/guardian enters information into the Diary Card, this person’s identity must be documented in the study file and this person must receive training on the Diary Card. Training of the parent/guardian on how to measure an injection site reaction should be performed while the subject is under observation after vaccination.





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Not applicable











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3.4 Data Collection





eCRFs


Diary Cards



- Body temperature




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- Any AEs

- Concomitant medications

- All vaccinations (except the study vaccines)

Note: After vaccination with MMR and varicella (at Visit 7) the period for collection of body temperature, medically attended fever and the solicited adverse events parotid/salivary gland swelling and rash will be extended to 28 days after vaccination.


- Serious AEs (SAEs)

- Medically attended AEs

- AEs leading to premature withdrawal from the study

- Fever and solicited local/systemic AEs persisting beyond Day 7



Subsequently, all data collected on Diary Cards by the subject’s parents/guardians will be recorded on eCRFs by the investigator.





4. Any illegible or implausible data should be reviewed with the parent/guardian. If an underlying solicited or unsolicited adverse event is described. For example, if thesubject with a body temperature of 400°C describes that the body temperature was actually 40°C on the day in which body temperature: 400°C was written into the



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Not applicable.


Not applicable.


Not applicable.



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Not applicable.





▫ Adverse event

▫ Death

▫ Withdrawal of consent

▫ Lost to follow-up

▫ Administration reason

▫ Protocol deviation

▫ Other

NOTE: Before entering any alternate category as the reason for the subject’s discontinuation from the study, the investigator should make every effort to investigate whether or not safety concerns (adverse event or death) may have been related to the subject’s discontinuation from the study. If a safety concern has been associated with the subject’s discontinuation, this must be described on the Termination CRF page, even if it is not the primary reason for the subject’s discontinuation.





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▫ Collect Diary Card

▫ Review the subject’s solicited and unsolicited safety data

▫ Perform review of concomitant medications/vaccinations since last visit

▫ Collect vital sign measurements, including respiratory rate, blood pressure, pulse rate, and temperature (rectal)



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3. available for all the visits scheduled in the study;

4. in good health as determined by medical history, physical examination and clinical judgment of the investigator.



5. History of any meningococcal vaccine administration;

6. Prior vaccination with any Diphtheria, Tetanus, Pertussis (acellular or whole cell), Polio (either Inactivated or Oral), Haemophilus influenzae type b (Hib), Pneumococcal, MMR or varicella antigens;





11. Antibiotics within 6 days prior to enrollment;

12. Any serious chronic or progressive disease according to the judgment of the investigator (e.g., neoplasm, insulin dependent diabetes mellitus Type I, cardiac disease, hepatic disease, progressive neurological disease or seizure, either associated with fever or as part of an underlying neurological disorder or syndrome, autoimmune



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15. Receipt of, or intent to immunize with any other vaccine(s) (with the exception of rotavirus vaccine, influenza vaccine and second HepB vaccine), within 30 days prior and throughout the study period. Furthermore, subjects must have received HepB vaccine preferably at 0, 1 month of age, with the second dose at least 14 days prior to study vaccination. Rotavirus vaccine and influenza vaccine should be administered at least 14 days before or 14 days after study vaccination;

16. Participation in another clinical trial since birth or planned for during study;

17. Family members and household members of research staff;










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rotavirus vaccine, influenza vaccine or the second dose of HepB vaccine within 14 days prior to study vaccination.











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Vaccine compositions are detailed in Table 5.1-1



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Table 5.1-1: Study Vaccine Compositions

Novartis Meningococcal B Recombinant + OMV vaccine (rMenB+ OMV)

active ingredients quantity per 0.5 ml dose

N meningitidis 961c purified antigen 50 µg

N meningitidis 936-741 purified antigen 50 µg


OMV from N meningitidis Strain NZ 98/254 25 g

other ingredients

Aluminum Hydroxide

Sodium Chloride

Sucrose

Histidine

Water for injection

vaccine presentation pre-filled syringe

extractable volume 0.5 ml

GSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + HIB®)


Diphtheria toxoid1 ≥ 30 IU

Tetanus toxoid1 ≥ 40 IU

Pertusis toxoid1 25 µg

Filamentous haemagglutinin1 25 µg

Pertactin 8 µg

Poliovirus (inactivated) type 1 (Mahoney strain) 40 D-antigen units

Poliovirus (inactivated) type 2 (MEF-1 strain) 8-D-antigen units

Poliovirus (inactivated) type 3 (Saukett strain) 32-D-antigen units

Heamophilus influenzae type B polysaccharide absorbed to tetanus toxoid (approx. 30 µg) carrier protein

10 µg

1adsorbed on aluminium hydroxide (0.5 mg)

other ingredients

Lactose

Sodium Chloride

2-phenoxythanol

Medium 199 (aminoacids, mineral salts, vitamins)

Water for injections

vaccine presentation as commercially available




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Pfizer 13-valent pneumococcal conjugate vaccine (Prevenar-13®)


Pneumococcal PS serotype 1* 2.2 µg




Pneumococcal PS serotype 6A* 2.2 µg

Pneumococcal PS serotype 6B* 4.4 µg

Pneumococcal PS serotype 7F* 2.2 µg

Pneumococcal PS serotype 9V* 2.2 µg


Pneumococcal PS serotype 18C* 2.2 µg




*Conjugated to CRM197 and absorbed on aluminium phosphate (0.125 mg)

other ingredients

Sodium chloride

Succine acid

Polysorbate 80




GSK Hepatitis B vaccine (Engerix-B®)


Hepatitis B surface antigen* 10 µg

other ingredients

Sodium chloride

Disodium Phosphate hydrate

Sodium Dihydrogen Phosphate




*adsorbed on aluminium hydroxide (0.25 mg)



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GSK Measles, Mumps and Rubella vaccine (Priorix®)


Live attenuated measles virus (Schwarz strain) ≥ 103.0 CCID50



other ingredients

Lactose

Sorbitol

Mannitol

Aminoacids




GSK Varicella vaccine (Varilrix®)


Live attenuated Varicella virus (OKA strain) ≥ 103.3 PFU

Other ingredients

Aminoacids

Human Albumin

Neomycine sulfate

Lactose

Mannitol

Sorbitol









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rMenB+OMV NZ vaccine preparation

The rMenB+OMV NZ vaccine is provided in a pre-filled syringe. The vaccine should be allowed to reach room temperature before administration, according to local vaccination practice. The full content of the pre-filled syringe should be injected to ensure that the administered dose is 0.5 mL. Please refer to the instruction sheet for a detailed description of the vaccines preparation and administration.


Concomitant routine vaccine preparation

The concomitant routine vaccines used in this study, i.e. GSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + Hib®), Pfizer 13-valent PCV (Prevenar-13®), GSK Hep B vaccine (Engerix-B®), GSK MMR vaccine (Priorix®) and GSK Varicella vaccine



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Group A (rMenB+OMV NZ concomitant with routine vaccines)

Primary schedule (infants) Right thigh

(anterolateral area)

Left thigh














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Group B (routine vaccines only)

Primary Series (infants) Right thigh


Left thigh

















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▫ acknowledge receipt of the study vaccines by a designated staff member at the site, including confirmation that the vaccines:

- were received in good condition





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- storage in a secure, locked, temperature-controlled location

- proper storage according to the instructions specified on the labels


▫ appropriate use of the study vaccines, including:

- use only in accordance with the approved protocol







- copy of the site’s procedure for destruction of hazardous material

- number of doses destroyed, date of destruction, destruction code (if available), method of destruction, and name of individual performing destruction

Vaccines that have been stored differently from the manufacturer’s indications must notbe used unless the sponsor provides written authorization for use. In the event that the use cannot be authorized, the sponsor will make every effort to replace the vaccine supply. All vaccines used in conjunction with this protocol must be stored separately from normal hospital/practice stocks to prevent unintentional use of study vaccines outside of the clinical trial setting.



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6.0 MEASUREMENTS













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1. Not Related




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2. Possibly Related


3. Probably Related








▫ Solicited local or systemic adverse event lasting beyond 7 days’ duration.

▫ Solicited local or systemic adverse events that lead to subject withdrawal from study vaccination.

▫ Solicited local or systemic adverse event that otherwise meets the definition of a serious adverse event (see section 6.6.2).

Kawasaki Disease




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Not Applicable.



▫ Death.

▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate risk of death from the event as it occurred); it does not refer to an event which hypothetically might have caused death if it were more severe.

▫ Required or prolonged hospitalization.

▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial disruption of a person’s ability to conduct normal life functions).

▫ Congenital anomaly/or birth defect.

▫ An important and significant medical event that may not be immediately life threatening or resulting in death or hospitalization but, based upon appropriate medical judgment, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed above.







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2. Not Related






The period of observation for AEs extends from the time the subject signs informed consent until he or she completes the specified safety follow-up period (until 13 months of age) or terminates the study early (whichever comes first). AEs occurring after the informed consent form is signed but prior to receiving study vaccine/product will be documented as an adverse event and recorded on the Adverse Events eCRF and within source documents. However, AEs occurring prior to receipt of any study vaccine will be analyzed separately from “treatment emergent” AEs (AEs occurring after administration of the first study vaccine).




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Post-Study Events


6.6.4 Pregnancies

Not applicable.



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Not applicable.


Not applicable.





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7.1 Endpoints









Not applicable.






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1. Immediate reactions:



1. Body Temperature

- Daily Body temperature.- Fever (defined as body temperature ≥ 38.0°C)- Medically attended fever*- Prophylactic/therapeutic use of antipyretics- Name of antipyretics










4. Fever and solicited local/systemic Adverse Events persisting beyond Day 7

5. All medications for treatment of Adverse Events recorded in this period(with the exception of minerals, supplements, vitamins)




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1. Body Temperature


2. Solicited reactions for MMR + Varicella:






Not applicable.



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Not applicable.



7.3 Analysis Sets




FAS/PPS:






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7.3.2 Exposed Set











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7.3.5 Safety Set










▫ Have post-vaccination solicited or unsolicited records

Subjects will be analyzed as "treated" (i.e., according to the vaccine a subject received, rather than the vaccine to which the subject may have been randomized).



7.3.7 Subgroups






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The following deviations are considered major:

▫ A subject received incorrect study vaccine or dose of study vaccine.

▫ A subject met withdrawal criteria during the study but was not withdrawn.

▫ A subject received an excluded medication or vaccine.

▫ A subject was enrolled but does not meet the protocol's eligibility criteria.

▫ A subject with no safety data



▫ Falsifying research or medical records.

Subjects who terminate study participation prematurely for reasons such as withdrawal of consent, adverse event (including death) or administrative reason do not represent protocol deviations, nor are the missing assessments that should otherwise have been collected for that subject later in the study considered protocol deviations.






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7.4 Analysis Plan











where




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Percentage of subjects with SBA titer >1:5

For each strain, NZ98/254, H44/76, and 5/99 the percentage of subjects achieving an SBA titer > 1:5 at 1 month after the third vaccination (Day 152, 7 months of age) will be presented as point estimates together with the two-sided 95% confidence intervals computed using the Clopper-Pearson method (Clopper, 1934).









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Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Group APower

NZ98/254 0.84 0.70 120 94%

44/76 0.99 0.70 120 99%

5/99 0.99 0.70 120 99%









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None(Grade 0)

Mild

(Grade 1)

Moderate

(Grade 2)

Severe

(Grade 3)

Injection site Tenderness

no tendernessMinor light



limb was moved

Injection site erythema

0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm

Injection site swelling

0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm

Injection site induration

0 - 9 mm 10 - 25 mm 26 - 50 mm > 50 mm




feedsMissed 1 or 2 feeds

Missed more than 2 feeds

SleepinessNo change in

alertness

Shows an increased

drowsiness



arouse him/her




usual

More difficult to settle

Unable to console

Persitent cryingNo persistent

cryingCrying less than

one hourCrying for 1 to < 3

hoursCrying for 3 or more

hours

Vomitting No vomitting1-2 episodes / 24

hours>2 episodes/24

hoursRequires outpatient

hydration







hydration





involvement)

Most of the skin



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▫ serious adverse events

▫ adverse events that are possibly or probably related to vaccine

▫ adverse event leading to withdrawal

▫ adverse events leading to a medically attended visit

▫ adverse event by data source



Not applicable.





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where












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Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Group APower

NZ98/254 0.95 0.75 120 99%

44/76 0.99 0.75 120 99%

5/99 0.99 0.75 120 99%




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SBA GMTs, GMRs and median, minimal and maximal values, as well as the percentage of subjects with SBA titer ≥ 1:5 and associated 95% CIs, will be determined for each strain (H44/76, 5/99, NZ98/254 and M10713) at baseline (Day 1), at 1 months after the third dose (Day 152), before the booster dose (at Day 305) and at one month after the booster dose (Day 335) both in infants receiving rMenB+OMV NZ with routine vaccines (Group A) and in infants receiving routine vaccines only (Group B).








Because the primary study objective is to demonstrate sufficiency of response of rMenB+OMV NZ after the third vaccination and all enrolled subjects who have immunogenicity data will be included in the interim analysis no alpha correction will be


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performed for the primary or key secondary analysis which will be conducted both at the one-sided 0.025 significant level.


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Contact details for the team involved in study monitoring will be identified in a handout located in the Investigator Site File. Study data recorded on CRFs will be verified by checking the CRF entries against source documents in order to ensure data completeness and accuracy as required by study protocol. Additional documents such as the investigator site file, pharmacy records, and informed consent documentation must also be available for review if requested. Arrangements for monitoring visits will be made in advance in accordance with the monitoring plan, except in case of emergency. The investigator and/or site staff must make source documents of subjects enrolled in this study available for inspection by NVD or its representative at the time of each monitoring visit. These documents must also be available for inspection, verification and copying, as required by regulations, by officials of the regulatory health authorities (e.g., FDA, EMA and others) and/or ECs/IRBs. The investigator and study site staff must comply with applicable privacy, data protection and medical confidentiality laws for use and disclosure of information related to the study and enrolled subjects.


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9.0 DATA MANAGEMENT










9.4 Data Protection



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12.0 ETHICS









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13.0 REFERENCE LIST













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Novartis



UserName: Title: Cluster Physician Date: Wednesday, 06 November 2013, 08:12 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


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PPD

PPD

PPD

PPD

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Novartis Pharma Services AG Clinical Study Protocol V72_60 Amendment # 308JUL14 Confidential Page 1 of 7

PRO-01 TEMP 08 / Atlas No. 293623Version No. 2 / Version Date: May 5, 2014

CLINICAL STUDY PROTOCOL AMENDMENT

Study Number: V72_60

Protocol Title: Protocol Title: A Phase 3, Open Label, Randomized, Controlled, Multi-Center Study to Evaluate the Safety and Immunogenicity of Novartis

Meningococcal B Recombinant Vaccine When Administered concomitantly with Routine Vaccines to Healthy Infants in Taiwan.

Amendment Number 3

Revised Protocol version 4.0 issued on 08 JUL 14

The present amendment reflects changes to the Revised Protocol version 3.0 issued

on 05 NOV 13

Property of Novartis Pharma Services AG

Confidential


consent of Novartis Pharma Services AG


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CHANGE 1 (Cover Page, Header, throughout all the Protocol text):

Previously read:

Novartis Vaccines and Diagnostics (NVD).

NVD.

Now reads:

Header: Novartis Pharma Services AG (NPhS AG)

Sponsor name: Novartis Pharma Services AG (NPhS AG)

Name of the entity which developed and received marketing authorization for Bexsero: Novartis Vaccines.

Throughout the body of the Protocol, the abbreviation NVD was substituted with ‘the Sponsor’ or ‘Novartis’.


Change of the legal entity responsible for the trial to Novartis Pharma Services AG. The acceptable generic naming is also ‘Novartis’. In some cases, e.g. supply of clinical study vaccines, it is necessary to emphasize that the responsibility is on the Sponsor of the study, so ‘the Sponsor’ is used in the text.

CHANGE 2 (Page 40 Section 3.5.1 Processing, Labeling and Storage of Serum Samples for Serology, Paragraph # 2):

Previously read:


Now reads:

All samples will be tested blinded. Detailed instructions for blood collection, processing, labeling and storage of samples are included in the Clinical Specimen Lab Manual.


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The Manual’s title was changed, so the reference in the Protocol should be updated.

CHANGE 3 (Page # 44, newly added Section 3.9 End of Study):

Previously read:

N/A

Now reads:

’’3.9 End of Study

Most clinical trials intended to support the efficacy/immunogenicity and safety of an Investigational Product proceed to full completion of planned sample size accrual.

A subject is considered to have completed the study when he/she has: (1) received all intended doses of study vaccine(s); (2) completed 30 days of safety follow-up after the last dose of vaccine; and (3) approximately 5 mL of blood drawn after the last dose of vaccine.

Evaluation of the primary and/or secondary immunogenicity/efficacy objectives requires the testing of biological samples from the study subjects, which can only be completed after all samples are collected. The last samples for the analysis of the primary and/or secondary objectives will be taken at visit 8. For the purpose of this protocol, end of study is defined as the completion of the testing of such biological samples, to be achieved no later than 8 months after collection of the last biological sample (last visit of the last enrolled subject).’’


Section 3.9 “End of Study” has been included to clarify that after Last Subject Last Visit (LSLV) results of laboratory testing of biological samples (serum) are required to perform analysis of the key secondary objective. For this purpose, End of Study is defined as the completion of the testing of the serum samples.

CHANGE 4 (Page # 46, Section 4.2 Exclusion Criteria, criterion # 11):

Previously read:


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Receipt of, or intent to immunize with any other vaccine(s) (with the exception of rotavirus vaccine, influenza vaccine and second HepB vaccine), within 30 days prior and throughout the study period. Furthermore, subjects must have received HepB vaccine preferably at 0, 1 month of age, with the second dose at least 14 days prior to study vaccination. Rotavirus vaccine and influenza vaccine should be administered at least 14 days before or 14 days after study vaccination.

Now reads:

Receipt of, or intent to immunize with any other vaccine(s) (with the exception of rotavirus vaccine, influenza vaccine and second HepB vaccine), within 30 days prior and throughout the study period. Furthermore, subjects must have received HepB vaccine preferably at 0, 1 month of age, with the second dose at least 14 days prior to study vaccination. Influenza vaccine should be administered at least 14 days before or 14 days after study vaccination; Rotavirus vaccine may be administered during the study as per local practice.


Suggested by investigator so that subjects do not have to make extra clinic visits.

CHANGE 5 (Page # 46 , Section 4.3 Criteria for Delay of Vaccination and/or Blood Sampling, bullet point # 3):

Previously read:

Individuals that received any other vaccines (with the exception of HepB and rotavirus vaccine), within 30 days prior to enrollment. Individuals that received rotavirus vaccine, influenza vaccine or the second dose of HepB vaccine within 14 days prior to study vaccination.

Now reads:

Individuals that received any other vaccines within 30 days prior to enrollment. Individuals that received influenza vaccine or the second dose of HepB vaccine within 14 days prior to study vaccination (Rotavirus vaccine may be administered during the study as per local practice).


Suggested by investigator so that subjects do not have to make extra clinic visits.


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CHANGE 6 (Page # 64, Section 6.6.3 Methods for Assessing and Recording AEs andSAEs, Paragraph Post-Study Events, Paragraph “Post-Study Events”):

Previously read:

Post-Study Events


Now reads:

Post-Study Events

Any suspected SAE that occurs outside of the protocol-specified observation period but considered to be caused by the study vaccine must be reported to Novartis or its designee. These SAEs will be processed by Novartis or its designee as during the course of the study, until 30 days after the protocol specified follow up period. Instructions and contact details for collecting and reporting these suspected SAEs will be provided to the investigator.


Alignment with the new protocol template. The post study AE language removed in favor of the collection of Post Study SAEs.

CHANGE 7 (Page # 64, Section 6.6.3 Methods for Assessing and Recording AEs and SAEs, Paragraph Post-Study Events, Paragraph # 1):

Previously read:

The period of observation for AEs extends from the time the subject signs informed consent until he or she completes the specified safety follow-up period (until 13 months of age) or terminates the study early (whichever comes first).

Now reads:

The period of observation for AEs extends from the time the subject signs informed consent until he or she completes the specified safety follow-up period (until visit 8, at 13 months of age) or terminates the study early (whichever comes first).


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To additionally specify until which visit does the period of observation for AEs extend.

CHANGE 8 (Page # 43, Section 3.8 Early Termination Visit):

Previously read:

Collect vital sign measurements, including respiratory rate, blood pressure, pulse rate, and temperature (rectal)

Now reads:

Collect vital sign measurements, including respiratory rate, pulse rate, and temperature (rectal)


“Blood pressure” has been deleted because it is not a routine practice in Taiwan to measure blood pressure of young children.

CHANGE 9 (Page # 58, Section 6.2 Demographics, Medical History and Physical Examination, Paragraph #4):

Previously read:


Now reads:

A general physical examination is to be performed by a qualified health care practitioner and will include the measurement of vital signs (heart rate, body temperature), auscultation of heart and lungs and a medical history-directed exam of other body parts and systems to assess eligibility during Visit 1.“Qualified health care practitioner” refers


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to any licensed health care professional who is permitted by institutional policy to perform physical examinations and who is identified within the site’s roles and responsibilities log.


“Blood pressure” has been deleted because it is not a routine practice in Taiwan to measure blood pressure of young children.


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Novartis



UserName: Title: Cluster Physician Date: Wednesday, 30 July 2014, 15:21 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


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PPD

PPD

PPD

PPD

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Novartis Pharma Services AG Protocol V72_6008 JUL 14 Final Version 4.0 Confidential Page 1 of 92






Confidential




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Name of Sponsor:Novartis Pharma Services AG


Health authority trial registration number(s):1026003925




Novartis Vaccines (NVx) has developed a Meningococcal B Recombinant Vaccine (rMenB+OMV NZ; Bexsero). Data provided from clinical studies conducted with rMenB+OMV NZ confirm that the vaccine has a similar safety profile to other licensed pediatric vaccines and is able to elicit a robust immune response against the selected meningococcal B strains. On 14th of January 2013, NVx received EU marketing authorisation for Bexsero for use in individuals from 2 months of age and older.


The aim of the proposed study is to assess the safety and immunogenicity of a 3-dose schedule (at 2, 4, 6 months) of rMenB+OMV NZ followed by a booster at 12 months when concomitantly administered with routine vaccines (i.e. combined DTaP-IPV-Hib and 13-valent PCV at 2, 4, 6 months; HepB at 6 months of age; MMR and varicella at 12 months of age) in healthy infants in Taiwan.


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Objectives:





Safety Objectives




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Methodology:



Study procedures








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(Visit 1)

4 months

(Visit 2)

6 months

(Visit 3)

7 months

(Visit 4)

9 months

(Visit 5)

11 months

(Visit 6)

12 months

(Visit 7)

13 months

(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw

Safety Call


MMR

Varicella

Blood Draw

Blood Draw

B 75 DTaP-IPV-Hib

PCV-13

Blood Draw

DTaP-IPV-Hib

PCV-13

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw

Safety Call

Safety Call MMR

Varicella

Blood Draw

Blood Draw

*According to the Taiwanese Immunization Program Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively.In

addition, BCG vaccine will be administered ≤ 24 hours after birth



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Novartis Pharma Services AG Protocol V72_6008JUL14 Final Version 4.0 Confidential Page 7 of 92










3. All vaccinations




1. Body Temperature








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1. Body Temperature







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Number of Subjects planned: To obtain 120 evaluable subjects it is estimated thatapproximately 150 eligible subjects will need to be enrolled in Group A, to allow for a dropout rate of approximately 20%. Taking into account a randomization ratio between group A:B of 2:1, 75 eligible subjects will need to be enrolled in group B.




Vaccines:

The Sponsor will supply all required study vaccines to subjects.













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Primary


Key Secondary


Other Secondary


Safety Endpoints



After the administration of MMR and varicella vaccines (with and without rMenB+OMV NZ) at 12 months of age, rash, parotid/salivary gland swelling, fever [temperature ≥ 38.0°C], medically attended fever and use of antipyretic medication will be assessed for a prolonged period up to day 28 following MMR and varicella vaccination.



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The percentage of subjects with SBA titer ≥1:5 will be presented as point estimates along with the associated 95% Clopper-Pearson confidence intervals (CIs) at baseline (2 months of age, Visit 1), 1 month after the third injection (7 months of age, Visit 4), prior to the booster dose (12 months of age, Visit 7) and at 1 month after the booster dose (13 months of age, Visit 8) for the meningococcal B indicator strains H44/76, 5/99 and NZ98/254.







Sample size for this study was calculated under considerations and assumptions based on the antibody response of infants observed in the Novartis Vaccines study V72P13 where infants enrolled received 3 doses of the rMenB+OMV NZ vaccine at 2, 4 and 6 months of age. The percentage of subjects with a SBA titer ≥ 1:5 at 1 month after the third vaccination reported in V72P13 study was 100% (99%-100%) for strain 44/76, 84% (82%-86%) for strain NZ98/254, and 100% (99%-100%) for



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strain 5/99.




Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Power

NZ98/254 0.84 0.70 120 94%

44/76 0.99 0.70 120 99%

5/99 0.99 0.70 120 99%





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Interim Analysis: An interim analysis for the primary immunogenicity and safety endpoint will be done after all subjects completed the Study Visit 4, one month after the third vaccination (at 7 months of age). Further details regarding the interim analysis are contained in Protocol section 7.5.




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SCn

6

SC

7 RC RC RC 8

Months of Age 2 4 6 7 9 11 12 13

Study Day 1 3 7 61 63 67 122 124 128 152 213 274 305 307 311 318 335


n/a

0/+

2

0/+

2

-4/+

7

2 d

ays

(0/+

2) f

rom

Vis

it 2

6 d

ays

(0/+

2) f

rom

Vis

it 2

61 d

ays

(-4/

+7)

fro

mV

isit

2

2 d

ays

(0/+

2) f

rom

Vis

it 3

6 d

ays

(0/+

2) f

rom

Vis

it 3

30 d

ays

(-4/

+7)

fro

mV

isit

3

61 d

ays

(-7/

+14

) fr

omV

isit

4

61 d

ays

(-7/

+14

) fr

omV

isit

5

183

day

s (-

7/+

14)

from

Vis

it 3

2 d

ays

(0/+

2)fr

om V

isit

7

6 d

ays

(0/+

2)fr

om V

isit

7

13 d

ays

(0/+

2)fr

om V

isit

7

30 d

ays

(-4/

+7)

from

Vis

it 7

Informed Consent Xa


Medical History Xa


Xa Xa Xa Xa X

Serology Blood Draw

(5 ml)c

Xa X Xa X


(Group A only)

X X X X



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SCn

6

SC

7 RC RC RC 8


X X X X


X X X X



X X X X X X X X X


X X


X X X X







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TABLE OF CONTENTS





2.0 OBJECTIVES.................................................................................................... 26





3.1.1 Study Period........................................................................................... 31




3.2.3 Enrollment ............................................................................................. 32

3.2.4 Randomization ....................................................................................... 32







3.2.5.6 Safety Calls ........................................................................................ 37

3.2.5.7 “For cause” Visits............................................................................... 37



3.4 Data Collection .............................................................................................. 38





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3.9 End of Study.................................................................................................. 44







5.1 Study Vaccine(s)............................................................................................ 48





6.0 MEASUREMENTS........................................................................................... 58







6.6.1 Adverse Events ...................................................................................... 61



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6.6.4 Pregnancies ............................................................................................ 66





7.1 Endpoints....................................................................................................... 67





7.1.5 Other Endpoints ..................................................................................... 69







7.3 Analysis Sets ................................................................................................. 70

7.3.1 All Enrolled Set...................................................................................... 71

7.3.2 Exposed Set........................................................................................... 71



7.3.5 Safety Set ............................................................................................... 72


7.3.7 Subgroups .............................................................................................. 72




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7.4 Analysis Plan ................................................................................................. 74




















9.0 DATA MANAGEMENT................................................................................... 86




9.4 Data Protection .............................................................................................. 86



12.0 ETHICS............................................................................................................. 89



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13.0 REFERENCE LIST ........................................................................................... 92



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Requirements for Registration of Pharmaceuticals for Human UseID Identification (Subject ID)IM IntramuscularIPV Inactivated Polio VirusIRB Institutional Review BoardLSLV Last Subject Last VisitMedDRA Medical Dictionary for Regulatory ActivitiesMMR Measles, Mumps, Rubella NVx Novartis Vaccines NZ New ZealandOMV Outer Membrane VesiclesPCV Pneumococcal Conjugate VirusPPS Per Protocol Set



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Since the 1960s, vaccines consisting of purified polysaccharide antigens have been developed against four (A, C, Y, and W-135) of the five pathogenic serogroups. The use of capsular polysaccharide as the basis of a vaccine for prevention of meningococcal B diseases has proven problematic. The meningococcal B capsular polysaccharide is identical to a widely distributed human carbohydrate (α[2→8] N-acetyl neuraminic acid or polysialic acid), which, being a self-antigen, is poorly immunogenic in humans. The recent sequencing of the meningococcal B genome provided a unique opportunity to discover and test gene products that have been left undetected by conventional biochemical and microbiological approaches (Pizza et al. Science 2000). Making use of a novel genome mining approach based on the meningococcal B sequence information, Novartis Vaccines (NVx) has developed a Meningococcal B Recombinant Vaccine (rMenB+OMV NZ). Data provided from clinical studies conducted with rMenB+OMV NZ confirm that the vaccine has a similar safety profile to other licensed pediatric vaccines and is able to elicit a robust immune response against selected meningococcal B strains. On 14th of January 2013, Novartis Vaccines received EU marketing authorisation for Bexsero for use in individuals from 2 months of age and older.



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A comprehensive review of rMenB+OMV NZ is contained in the Investigator’s Brochure (IB) supplied by Novartis; this document should be reviewed prior to initiating the study.







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2.0 OBJECTIVES







To assess bactericidal antibodies against meningococcal B in healthy infants receiving rMenB+OMV NZ concomitantly with routine vaccines (Group A) or routine vaccines alone (Group B) at 2, 4, 6 and 12 months of age, as measured by SBA geometric mean titers (GMTs), and geometric mean ratios between post and pre-vaccination (baseline) titers (GMRs) and percentage of subjects with SBA titer ≥ 1:5 against indicator strains H44/76, 5/99, NZ98/254 and strain M10713 at baseline (2 months of age), 1 month after the third vaccination (7 months of age), prior to the booster dose (12 months of age) and at 1 month after the booster dose (13 months of age).






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Parotid/salivary gland swelling will be collected for an extended period of 28 days after MMR and varicella).





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This is a Phase 3, open-label, randomized, controlled, multi-center study to evaluate the safety and immunogenicity of Novartis rMenB+OMV NZ vaccine when administered concomitantly with routine vaccines to healthy infants in Taiwan. The rMenB+OMV NZ vaccine will be administered in a 3 dose schedule (at 2, 4 and 6 months of age), followed by a booster at 12 months age. Concomitantly, infants will receive routine vaccines, i.e.diphtheria (D), tetanus (T), acellular pertussis (aP), poliovirus types 1, 2, 3 (IPV), Hepatitis B (HepB), Haemophilus influenzae type b (Hib), 13-valent pneumococcal conjugate vaccine (PCV-13), measles, mumps, rubella (MMR) and varicella. For safety comparison and to assess the prevalence of bactericidal meningococcal B antibodies over the study period in infants not receiving rMenB+OMV NZ vaccine infants will receive routine vaccines alone as a control. The results of this study are intended to support licensure of rMenB+OMV NZ in Taiwan.


At the enrollment visit (Visit 1), the investigator, or a person designated by the investigator, should fully inform the subject’s parent(s) or guardian(s) of all pertinent aspects of the trial and the subject’s parent(s)/legal guardian’s written informed consent will be obtained. After obtaining written informed consent from the subject’s parents/legal guardians, a physical examination will be performed and medical history obtained. A brief physical assessment will be performed prior to each subsequent injection.






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Group Subjects

(n)

2 months

(Visit 1)

4 months

(Visit 2)

6 months

(Visit 3)

7 months

(Visit 4)

9 months

(Visit 5)

11 months

(Visit 6)

12 months

(Visit 7)

13 months

(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw


MMR

Varicella

Blood Draw

Blood Draw

B 75 DTaP-IPV-Hib

PCV-13

Blood Draw

DTaP-IPV-Hib

PCV-13

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw


Varicella

Blood Draw

Blood Draw




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3.1.1 Study Period












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3.2.3 Enrollment


3.2.4 Randomization

Enrolled subjects will be randomly assigned to study group A or B in a pre-specified ratio of 2:1 and according to web-based randomization, using a permuted block randomization with Center as stratification factor, to ensure a good balance of subject’s characteristics in each group. The list of randomization assignments is produced by a validated system used by the Novartis Biostatistics and Clinical Data Management (BCDM) department.

If for any reason, after signing the informed consent form (ICF), the subject (who has passed screening) fails to be randomized, the reason for not being randomized should be recorded in source documents as specified in the source data agreement. The information on these subjects, who are randomization failures, should be kept distinct in the source documentation from screen failures, which are described in section 3.2.2.



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7. review of eligibility criteria (refer to sections 4.1 and 4.2 for inclusion and exclusioncriteria)











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The following post-vaccination procedures will be performed on Visit 1 (Day 1, 2 months of age), Visit 2 (Day 61, 4 months of age), Visit 3 (Day 122, 6 months of age) and Visit 7 (Day 305, 12 months of age):







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Safety phone calls will be performed on Visit 5 (Day 213, 9 months of age) and Visit 6(Day 274, 11 months of age). Safety phone calls are calls made to the subject’s parent/guardian by a trained healthcare provider. These calls will follow a script which will facilitate the collection of relevant safety information. The parent/guardian will beinterviewed according to the script, and information relating to unsolicited adverse events(including serious adverse events (SAEs) and AEs leading to study or vaccine withdrawal) and concomitant medications associated with those events. All safety information described by the subject must be written down in a designated location within the source documents and not written on the script used for the telephone call.



Not applicable











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The study is an open-label study. Therefore, no blinding procedures are in place

3.4 Data Collection





eCRFs


Diary Cards



- Body temperature




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- Any AEs



















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Not applicable.


Not applicable.


Not applicable.



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Not applicable.





▫ Adverse event

▫ Death





▫ Other






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For subjects who fail to show up for scheduled visits (clinic or safety phone calls), study staff are encouraged to make at least three documented attempts to contact the subject by telephone and at least one documented written attempt to contact the subject’sparents/guardians and encourage the completion of study termination procedures. These efforts to contact the subject should be recorded in the source documents. The termination date for the subject to be captured on the Termination CRF page is the date of the last successful visit (clinic or safety phone calls) with the subject.







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▫ Collect vital sign measurements, including respiratory rate, pulse rate, andtemperature (rectal)



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▫ Symptom-directed physical assessment (including measurement of vital signs, body temperature [via rectal route] and a check of general appearance) data from the early termination visit should be recorded on the Study Termination Visit eCRF form.

3.9 End of Study



Evaluation of the primary and/or secondary immunogenicity/efficacy objectives requires the testing of biological samples from the study subjects, which can only be completed after all samples are collected. The last samples for the analysis of the primary and/or secondary objectives will be taken at visit 8. For the purpose of this protocol, end of study is defined as the completion of the testing of such biological samples, to be achieved no later than 8 months after collection of the last biological sample (last visit of the last enrolled subject).



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11. Receipt of, or intent to immunize with any other vaccine(s) (with the exception of rotavirus vaccine, influenza vaccine and second HepB vaccine), within 30 days prior and throughout the study period. Furthermore, subjects must have received HepB vaccine preferably at 0, 1 month of age, with the second dose at least 14 days prior to study vaccination. Influenza vaccine should be administered at least 14 days before or14 days after study vaccination; Rotavirus vaccine may be administered during the study as per local practice.









▫ Individuals that received any other vaccines within 30 days prior to enrollment. Individuals that received influenza vaccine or the second dose of HepB vaccine within



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14 days prior to study vaccination (Rotavirus vaccine may be administered during the study as per local practice).











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other ingredients

Aluminum Hydroxide

Sodium Chloride

Sucrose

Histidine

Water for injection









Pertactin 8 µg





10 µg


other ingredients

Lactose

Sodium Chloride

2-phenoxythanol







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other ingredients

Sodium chloride

Succine acid

Polysorbate 80







other ingredients

Sodium chloride









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other ingredients

Lactose

Sorbitol

Mannitol

Aminoacids







Other ingredients

Aminoacids

Human Albumin

Neomycine sulfate

Lactose

Mannitol

Sorbitol









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After the study, all subjects will be offered to receive the booster dose of Prevenar-13 (at 15 months of age) to complete the recommended dose-schedule of Prevenar-13. The Prevenar-13 booster dose will be reimbursed by the Sponsor.






Upon storage of the suspension of rMenB+OMV NZ a fine off-white deposit may form. Shake the vaccine well before use to form a homogeneous suspension. The vaccine should be visually inspected for particulate matter and discoloration prior to administration. In the event of any foreign particulate matter and/or variation of physical aspect being observed, do not administer the vaccine and report the issue as a Pharmaceutical Technical Complaint to Novartis. Do not discard the vaccine until authorized by Novartis. Any unused medicinal product or waste material should be disposed of in accordance with local requirements once authorized for destruction.





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Left thigh














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Left thigh

















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Use of the following concomitant medications after enrollment may interfere with the interpretation of the study objectives or indicate an underlying condition resulting in a major protocol violation according to the medical judgment of the Novartis Vaccines physician.



The use of antipyretics and/or analgesic medications within 24 hours prior to vaccination must be identified and the reason for their use (prophylaxis versus treatment) must bedescribed in the source documents and Concomitant Medications eCRF.














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6.0 MEASUREMENTS








A general physical examination is to be performed by a qualified health care practitioner and will include the measurement of vital signs (heart rate, body temperature), auscultation of heart and lungs and a medical history-directed exam of other body parts and systems to assess eligibility during Visit 1.“Qualified health care practitioner” refers to any licensed health care professional who is permitted by institutional policy to perform physical examinations and who is identified within the site’s roles and responsibilities log.





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1. Not Related




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2. Possibly Related


3. Probably Related











Kawasaki Disease




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Not Applicable.



▫ Death.












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2. Not Related






The period of observation for AEs extends from the time the subject signs informed consent until he or she completes the specified safety follow-up period (until visit 8, at 13 months of age) or terminates the study early (whichever comes first). AEs occurring after the informed consent form is signed but prior to receiving study vaccine/product will be documented as an adverse event and recorded on the Adverse Events eCRF and within source documents. However, AEs occurring prior to receipt of any study vaccine will be analyzed separately from “treatment emergent” AEs (AEs occurring after administration of the first study vaccine).




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there is a satisfactory explanation for the changes observed, or until death, in which case a full pathologist’s report should be supplied, if possible. All findings must be reported on an Adverse Events CRF and on the VSAE form, if necessary, which is part of the Investigator Site File. All findings in subjects experiencing AEs must be reported also in the subject's medical records.

All SAEs which occur during the course of the trial, whether considered to be associated with the study vaccination or not, must be reported within 24 hours of the site becoming aware of the event by telephone or fax to Novartis. Contact details for submitting SAEs to Novartis or its designee and instructions for completion of documentation will be provided in a handout located in the Investigator Site File.


After receipt of the initial report, representatives of Novartis will contact the investigator if it is necessary to obtain further information for assessment of the event.


Novartis or its designee must also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious and non-serious adverse vaccine reactions (also referred to as “SUSARs”) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other safety signal relating to use of one of the study vaccines is reported to Novartis or its designee, the sponsor will communicate the information to the investigator and the investigator will be responsible for submitting this information to the IRB and other relevant authorities.

Post-Study Events




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6.6.4 Pregnancies

Not applicable.


Not applicable.


Not applicable.





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7.1 Endpoints









Not applicable.






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1. Body Temperature
















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1. Body Temperature








Not applicable.







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Not applicable.



7.3 Analysis Sets




FAS/PPS:






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7.3.2 Exposed Set











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7.3.5 Safety Set














7.3.7 Subgroups






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7.4 Analysis Plan











where




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Percentage of subjects with SBA titer >1:5

For each strain, NZ98/254, H44/76, and 5/99 the percentage of subjects achieving an SBA titer > 1:5 at 1 month after the third vaccination (Day 152, 7 months of age) will be presented as point estimates together with the two-sided 95% confidence intervals computed using the Clopper-Pearson method (Clopper, 1934).


The mechanism of missing immunogenicity values can be reasonably considered as missing completely at random (MCAR), i.e., not informative. Therefore the immunogenicity analysis will comprise a complete case analysis only without introducingany bias. No imputation methods will be applied.







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Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Group APower

NZ98/254 0.84 0.70 120 94%

44/76 0.99 0.70 120 99%

5/99 0.99 0.70 120 99%









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None(Grade 0)

Mild

(Grade 1)

Moderate

(Grade 2)

Severe

(Grade 3)





limb was moved


0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm


0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm


0 - 9 mm 10 - 25 mm 26 - 50 mm > 50 mm







alertness

Shows an increased

drowsiness



arouse him/her




usual


Unable to console





hours


hours>2 episodes/24


hydration







hydration





involvement)

Most of the skin


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Not applicable.





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where












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Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Group APower

NZ98/254 0.95 0.75 120 99%

44/76 0.99 0.75 120 99%

5/99 0.99 0.75 120 99%




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Prior to enrollment of the first study subject, Novartis or delegate will train investigators and/or their study staff on the study protocol, all applicable study procedures, documentation practices (including signing of the source document agreement (SDA, see section 8.1) and all electronic systems. CRFs supplied by the sponsor must be completed for each enrolled subject (see section 7.3.1 for definition of enrolled subject). Documentation of screened but not enrolled subjects must be maintained at the site and made available for review by the site monitor. All data entries as well as study related documents will be checked by the sponsor and/or site monitor. In addition, the investigator and site staff will be made aware of the plans to monitor the data collected at the site.







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A contract research organization (CRO) may be involved in the monitoring of protocol conduct and data entry. If a CRO is involved in study oversight, the name and address of this CRO will be located in the investigator site file. Prior to enrollment of the first study subject, Novartis will develop a Clinical Monitoring Plan to specify how monitoring will be performed for the study.

Study progress will be monitored by Novartis or its representative (e.g., a CRO) as frequently as necessary to ensure:




Contact details for the team involved in study monitoring will be identified in a handout located in the Investigator Site File. Study data recorded on CRFs will be verified by checking the CRF entries against source documents in order to ensure data completeness and accuracy as required by study protocol. Additional documents such as the investigator site file, pharmacy records, and informed consent documentation must also be available for review if requested. Arrangements for monitoring visits will be made in advance in accordance with the monitoring plan, except in case of emergency. The investigator and/or site staff must make source documents of subjects enrolled in this study available for inspection by Novartis or its representative at the time of each monitoring visit. These documents must also be available for inspection, verification and copying, as required by regulations, by officials of the regulatory health authorities (e.g., FDA, EMA and others) and/or ECs/IRBs. The investigator and study site staff must comply with applicable privacy, data protection and medical confidentiality laws for use and disclosure of information related to the study and enrolled subjects.


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9.0 DATA MANAGEMENT


In this study, all data will be entered onto electronic case report forms (eCRFs) in a timely fashion by the investigator and/or the investigator’s dedicated site staff. Data entered onto eCRFs are stored on a secure website. The data collected on this secure website are assimilated into an EDC system, which is compliant with 21 Part 11 policies of the Code of Federal Regulations. The EDC will be designed and validated by the Sponsor prior to activation for data entry by sites. The investigator must review data entered and electronically sign the eCRFs to verify their accuracy.

Access to the EDC system for data entry or review will require training and distinct individual access code assignments to those site staff members who will be entering study data and those involved in study oversight who may review study data. Data are collected within EDC, to which the sponsor and site monitors have exclusively “read only” access. eCRF data will be reviewed routinely by study personnel from the Sponsor and clinical monitors.

All serology results produced by Clinical Serology, Novartis will be entered into the Seroad database by Novartis Clinical Serology Laboratory, Marburg. All results will be checked in the laboratory for validity and completeness.


As part of the conduct of the trial, the Sponsor may have questions about the data entered by the site, referred to as queries. The monitors and the Sponsor are the only parties that can generate a query.




9.4 Data Protection

The Sponsor respects the subjects’ rights to privacy and will ensure the confidentiality of their medical information in accordance with all applicable laws and regulations.


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Investigators must retain all study records required by Novartis and by the applicable regulations in a secure and safe facility. The investigator must consult a Novartis representative before disposal of any study records, and must notify the Sponsor of any change in the location, disposition, or custody of the study files. Essential documents must be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. “Essential documents” are defined as documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents should be retained for a longer period, however, if required by the applicable regulatory requirements or by an agreement with the sponsor. The Committee for Human Medicinal Products for Human Use (CHMP) requires retention for the maximum period of time permitted by the institution, but not less than 15 years (ICH E6, 4.9.5). It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained (ICH E6, 5.5.12).



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Novartis assures that the key design elements of this protocol will be posted in a publicly accessible database such as clinicaltrials.gov, and in compliance with current regulations.

Novartis also assures that key results of this clinical trial will be posted in a publicly accessible database within the required time-frame from the last subject’s last study visit as dictated by applicable regulations.

Further to legislated data disclosure, Novartis will ensure that as far as possible results of this study will be published as scientific/clinical papers in high-quality peer-reviewed journals. Preparation of such manuscripts will be made with full collaboration of principal investigators and in accordance with the current guidelines of Good Publication Practice (Graf 2009).

Novartis must be notified of any intent to publish data collected from the study and prior approval from Novartis must be obtained prior to publication.


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12.0 ETHICS





Prior to the start of the study, Novartis will provide to investigators a separate document with a proposed informed consent form that complies with the ICH GCP guideline and regulatory requirements and is considered appropriate for this study. Any changes to the proposed consent form suggested by the investigator must be agreed to by Novartis before submission to the IRB/EC and a copy of the approved version must be provided to the Novartis monitor after IRB/EC approval.


The protocol and the proposed informed consent form must be reviewed and approved by a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH 1997). A signed and dated statement that the protocol and informed consent have been approved by the IRB/EC must be given to Novartis before study initiation. Prior to study start and at any time the protocol is amended during study conduct, the investigator is required to sign a protocol signature page confirming his/her agreement to conduct the study in accordance


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with these documents and all of the instructions and procedures found in this protocol and to give access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, designated agents of Novartis, IRBs/ECs, and regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory authority, the investigator must inform Novartis immediately that this request has been made.












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Investigators will apply due diligence to avoid protocol deviations. Under no circumstances should the investigator contact the Sponsor or its agents, if any, monitoring the trial to request approval of a protocol deviation, as no authorized deviations are permitted. If the investigator feels a change to the protocol would improve the conduct of the study this must be considered a protocol amendment, and unless such an amendment is agreed upon by Novartis and approved by the IRB/EC it cannot be implemented. All significant protocol deviations will be recorded and reported in the Clinical Study Report.


An amendment is a written description of change(s) to or formal clarification of a study protocol which may impact on the conduct of the clinical study, potential benefit of the clinical study, or may affect subject safety, including changes of study objectives, study design, subject population, sample sizes, study procedures, or significant administrative aspects. An administrative change of a study protocol is a minor correction or clarification that has no significant impact on the way the clinical study is to be conducted and no effect on subject safety (e.g., change of telephone number(s), logistical changes). Protocol amendments must be approved by Novartis, Health Authorities where required, and the IRB/EC. In cases when the amendment is required in order to protect the subject safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding the need for formal approval of a protocol amendment, the investigator is expected to take any immediate action required for the safety of any subject included in this study, even if this action represents a deviation from the protocol. In such cases, Novartis should be notified of this action, the IRB/EC at the study site, and, if required by local regulations, the relevant health authority should be informed within 10 working days.


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13.0 REFERENCE LIST













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Novartis



UserName: Title: Cluster Physician Date: Wednesday, 06 August 2014, 13:32 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


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Novartis Pharma Services AG Clinical Study Protocol V72_60 Amendment #414OCT14 Confidential Page 1 of 5




Protocol Title:



Amendment Number 4

Revised Protocol version 5.0 issued on 14OCT14


on 08JUL14


Confidential




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CHANGE 1 (Page # 47, Section 4.2 Exclusion Criteria, Point # 11):

Previously read:

11. Receipt of, or intent to immunize with any other vaccine(s) (with the exception of rotavirus vaccine, influenza vaccine and second HepB vaccine), within 30 days prior and throughout the study period. Furthermore, subjects must have received HepB vaccine preferably at 0, 1 month of age, with the second dose at least 14 days prior to study vaccination. Influenza vaccine should be administered at least 14 days before or 14 days after study vaccination; Rotavirus vaccine may be administered during the study as per local practice.

Now reads:

11. Receipt of, or intent to immunize with any other vaccine(s) (with the exception of rotavirus vaccine, influenza vaccine and second HepB vaccine), within 28 days prior and throughout the study period. Furthermore, subjects must have received HepB vaccine preferably at 0, 1 month of age, with the second dose at least 14 days prior to study vaccination. Influenza vaccine should be administered at least 14 days before or 14 days after study vaccination; Rotavirus vaccine may be administered during the study as per local practice.


The BCG standard vaccination is now often given on the 1st month of life instead of at birth, because most Taiwanese parents now consent to having SCID (Severe CombinedImmunodeficiency) test and Newborn screening with results due after a month. The subsequent immunization visit is scheduled by the Physicians 1 month/ 4 weeks later, which per local practice is calculated as 28 days rather than 30 days. The protocol is amended to allow for inclusion of those subjects for which 1 month was calculated as 28 days.

CHANGE 2 (Page # 48, Section 4.3 Criteria for Delay of Vaccination and/or Blood Sampling, Bullet point # 3):

Previously read:



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Now reads:

▫ Individuals that received any other vaccines within 28 days prior to enrollment. Individuals that received influenza vaccine or the second dose of HepB vaccine within 14 days prior to study vaccination (Rotavirus vaccine may be administered during the study as per local practice).


The BCG standard vaccination is now often given on the 1st month of life instead of at birth. The subsequent visit is scheduled by the Physicians 1 month/ 4 weeks later, which per local practice is calculated as 28 days rather than 30 days. The protocol is amended to allow for inclusion of those subjects for which 1 month was calculated as 28 days.

CHANGE 3 (Page # 6, Protocol Synopsis: Section Study Procedures, Footnote to Table 1: Randomization groups and visits schedule)

and

CHANGE 4 (Page # 30, Section 3.1 Overview of Study Design, Footnote to Table 3.1-1: Summary of study related events):

Previously read:

According to the Taiwanese Immunization Program Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively. In addition, BCG vaccine will be administered ≤ 24 hours after birth.

Now reads:

*According to the Taiwanese Immunization Program for Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively. In addition, BCG vaccine will be administered ≤ 24 hours after birth or at 1 month of age, as per current local practice.


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The BCG standard vaccination is now often given on the 1st month of life instead of at birth, because most Taiwanese parents now consent to having SCID (Severe Combined Immunodeficiency) test and Newborn screening with results due after a month.

CHANGE 5 (Page # 32, Section 3.2.3 Enrollment):

Previously read:

After an individual is determined to be eligible for study participation, the subject will be enrolled in the electronic data capture (EDC) system; using the screening number assigned by the EDC System and then randomized. At randomization, the subject will automatically be assigned a unique Subject ID. The Subject ID consists of a 5 digit number resulting from the combination of the site number, the subject’s order of randomization at the site.

Now reads:

After an individual is determined to be eligible for study participation, the subject will be enrolled in the electronic data capture (EDC) system; using the screening number assigned by the Investigator and then randomized. At randomization, the subject will automatically be assigned a unique Subject ID. The Subject ID consists of a 5 digit number resulting from the combination of the site number, the subject’s order of randomization at the site.


The correct information is that the screening number currently is assigned by theInvestigator, not by the EDC system.

CHANGE 6 (Page # 80, Section 7.4.2.3 Statistical Methods for Primary Objectives, Percentage of subjects with SBA titer ≥ 1:5):

Previously read:

Percentage of subjects with SBA titer > 1:5

For each strain, NZ98/254, H44/76, and 5/99 the percentage of subjects achieving an SBA titer > 1:5 at 1 month after the third vaccination (Day 152, 7 months of age) will be


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presented as point estimates together with the two-sided 95% confidence intervals computed using the Clopper-Pearson method (Clopper, 1934).

Now reads:

Percentage of subjects with SBA titer ≥ 1:5

For each strain, NZ98/254, H44/76, and 5/99 the percentage of subjects achieving an SBA titer ≥ 1:5 at 1 month after the third vaccination (Day 152, 7 months of age) will be presented as point estimates together with the two-sided 95% confidence intervals computed using the Clopper-Pearson method (Clopper, 1934).


Correction of a typo (the correct value is “SBA titer ≥ 1:5”, not “SBA titer > 1:5”).

CHANGE 7 (Page # 87, Section 7.4.3 Analysis of Key Secondary Immunogenicity Objectives, Paragraph Statistical Methods of Key Secondary Immunogenicity Objectives):

Previously read:


Now reads:

Analyses of Percentages of subjects with SBA titer ≥1:5 at 1 month after booster dose


Correction of a typo (the correct value is “SBA titer ≥ 1:5”, not “SBA titer > 1:5”).


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Novartis



UserName: Title: Head, Geographic Expansion & Established Vaccines Cluster Date: Wednesday, 15 October 2014, 12:04 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


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Novartis Pharma Services AG Protocol V72_6014 OCT 14 Final Version 5.0 Confidential Page 1 of 92






Confidential




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Objectives:





Safety Objectives




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Methodology:



Study procedures








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(Visit 1)

4 months

(Visit 2)

6 months

(Visit 3)

7 months

(Visit 4)

9 months

(Visit 5)

11 months

(Visit 6)

12 months

(Visit 7)

13 months

(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw

Safety Call


MMR

Varicella

Blood Draw

Blood Draw

B 75 DTaP-IPV-Hib

PCV-13

Blood Draw

DTaP-IPV-Hib

PCV-13

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw

Safety Call

Safety Call MMR

Varicella

Blood Draw

Blood Draw

*According to the Taiwanese Immunization Program for Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively. In

addition, BCG vaccine will be administered ≤ 24 hours after birth or at 1 month of age, as per current local practice.



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3. All vaccinations




1. Body Temperature








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1. Body Temperature







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Vaccines:














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Primary


Key Secondary


Other Secondary


Safety Endpoints






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Sample size for this study was calculated under considerations and assumptions based on the antibody response of infants observed in the Novartis Vaccines study V72P13 where infants enrolled received 3 doses of the rMenB+OMV NZ vaccine at 2, 4 and 6 months of age. The percentage of subjects with a SBA titer ≥ 1:5 at 1 month after the third vaccination reported in V72P13 study was 100% (99%-100%) for strain 44/76, 84% (82%-86%) for strain NZ98/254, and 100% (99%-100%) for



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strain 5/99.




Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Power

NZ98/254 0.84 0.70 120 94%

44/76 0.99 0.70 120 99%

5/99 0.99 0.70 120 99%





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Interim Analysis: An interim analysis for the primary immunogenicity and safety endpoint will be done after all subjects completed the Study Visit 4, one month after the third vaccination (at 7 months of age). Further details regarding the interim analysis are contained in Protocol section 7.5.




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SCn

6

SC

7 RC RC RC 8

Months of Age 2 4 6 7 9 11 12 13

Study Day 1 3 7 61 63 67 122 124 128 152 213 274 305 307 311 318 335


n/a

0/+

2

0/+

2

-4/+

7

2 d

ays

(0/+

2) f

rom

Vis

it 2

6 d

ays

(0/+

2) f

rom

Vis

it 2

61 d

ays

(-4/

+7)

fro

mV

isit

2

2 d

ays

(0/+

2) f

rom

Vis

it 3

6 d

ays

(0/+

2) f

rom

Vis

it 3

30 d

ays

(-4/

+7)

fro

mV

isit

3

61 d

ays

(-7/

+14

) fr

omV

isit

4

61 d

ays

(-7/

+14

) fr

omV

isit

5

183

day

s (-

7/+

14)

from

Vis

it 3

2 d

ays

(0/+

2)fr

om V

isit

7

6 d

ays

(0/+

2)fr

om V

isit

7

13 d

ays

(0/+

2)fr

om V

isit

7

30 d

ays

(-4/

+7)

from

Vis

it 7

Informed Consent Xa


Medical History Xa


Xa Xa Xa Xa X

Serology Blood Draw

(5 ml)c

Xa X Xa X


(Group A only)

X X X X



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SCn

6

SC

7 RC RC RC 8


X X X X


X X X X



X X X X X X X X X


X X


X X X X







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TABLE OF CONTENTS





2.0 OBJECTIVES.................................................................................................... 26





3.1.1 Study Period........................................................................................... 31




3.2.3 Enrollment ............................................................................................. 32

3.2.4 Randomization ....................................................................................... 32







3.2.5.6 Safety Calls ........................................................................................ 37

3.2.5.7 “For cause” Visits............................................................................... 37



3.4 Data Collection .............................................................................................. 38





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3.9 End of Study.................................................................................................. 44







5.1 Study Vaccine(s)............................................................................................ 48





6.0 MEASUREMENTS........................................................................................... 58







6.6.1 Adverse Events ...................................................................................... 61



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6.6.4 Pregnancies ............................................................................................ 66





7.1 Endpoints....................................................................................................... 67





7.1.5 Other Endpoints ..................................................................................... 69







7.3 Analysis Sets ................................................................................................. 70

7.3.1 All Enrolled Set...................................................................................... 71

7.3.2 Exposed Set........................................................................................... 71



7.3.5 Safety Set ............................................................................................... 72


7.3.7 Subgroups .............................................................................................. 72




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7.4 Analysis Plan ................................................................................................. 74




















9.0 DATA MANAGEMENT................................................................................... 86




9.4 Data Protection .............................................................................................. 86



12.0 ETHICS............................................................................................................. 89



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13.0 REFERENCE LIST ........................................................................................... 92



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Requirements for Registration of Pharmaceuticals for Human UseID Identification (Subject ID)IM IntramuscularIPV Inactivated Polio VirusIRB Institutional Review BoardLSLV Last Subject Last VisitMedDRA Medical Dictionary for Regulatory ActivitiesMMR Measles, Mumps, Rubella NVx Novartis Vaccines NZ New ZealandOMV Outer Membrane VesiclesPCV Pneumococcal Conjugate VirusPPS Per Protocol Set



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Since the 1960s, vaccines consisting of purified polysaccharide antigens have been developed against four (A, C, Y, and W-135) of the five pathogenic serogroups. The use of capsular polysaccharide as the basis of a vaccine for prevention of meningococcal B diseases has proven problematic. The meningococcal B capsular polysaccharide is identical to a widely distributed human carbohydrate (α[2→8] N-acetyl neuraminic acid or polysialic acid), which, being a self-antigen, is poorly immunogenic in humans. The recent sequencing of the meningococcal B genome provided a unique opportunity to discover and test gene products that have been left undetected by conventional biochemical and microbiological approaches (Pizza et al. Science 2000). Making use of a novel genome mining approach based on the meningococcal B sequence information, Novartis Vaccines (NVx) has developed a Meningococcal B Recombinant Vaccine (rMenB+OMV NZ). Data provided from clinical studies conducted with rMenB+OMV NZ confirm that the vaccine has a similar safety profile to other licensed pediatric vaccines and is able to elicit a robust immune response against selected meningococcal B strains. On 14th of January 2013, Novartis Vaccines received EU marketing authorisation for Bexsero for use in individuals from 2 months of age and older.



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2.0 OBJECTIVES













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Group Subjects

(n)

2 months

(Visit 1)

4 months

(Visit 2)

6 months

(Visit 3)

7 months

(Visit 4)

9 months

(Visit 5)

11 months

(Visit 6)

12 months

(Visit 7)

13 months

(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw


MMR

Varicella

Blood Draw

Blood Draw

B 75 DTaP-IPV-Hib

PCV-13

Blood Draw

DTaP-IPV-Hib

PCV-13

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw


Varicella

Blood Draw

Blood Draw

*According to the Taiwanese Immunization Program for Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively.In addition, BCG vaccine will be administered ≤ 24 hours after birth or at 1 month of age, as per current local practice.



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3.1.1 Study Period












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3.2.3 Enrollment

After an individual is determined to be eligible for study participation, the subject will be enrolled in the electronic data capture (EDC) system; using the screening number assigned by the Investigator and then randomized. At randomization, the subject will automatically be assigned a unique Subject ID. The Subject ID consists of a 5 digit number resulting from the combination of the site number, the subject’s order of randomization at the site.

3.2.4 Randomization





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Not applicable











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3.4 Data Collection





eCRFs


Diary Cards



- Body temperature




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- Any AEs



















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Not applicable.


Not applicable.


Not applicable.



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Not applicable.





▫ Adverse event

▫ Death





▫ Other






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▫ Collect vital sign measurements, including respiratory rate, pulse rate, and temperature (rectal)



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3.9 End of Study






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other ingredients

Aluminum Hydroxide

Sodium Chloride

Sucrose

Histidine

Water for injection









Pertactin 8 µg





10 µg


other ingredients

Lactose

Sodium Chloride

2-phenoxythanol







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other ingredients

Sodium chloride

Succine acid

Polysorbate 80







other ingredients

Sodium chloride









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other ingredients

Lactose

Sorbitol

Mannitol

Aminoacids







Other ingredients

Aminoacids

Human Albumin

Neomycine sulfate

Lactose

Mannitol

Sorbitol









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Upon storage of the suspension of rMenB+OMV NZ a fine off-white deposit may form. Shake the vaccine well before use to form a homogeneous suspension. The vaccine should be visually inspected for particulate matter and discoloration prior to administration. In the event of any foreign particulate matter and/or variation of physical aspect being observed, do not administer the vaccine and report the issue as aPharmaceutical Technical Complaint to Novartis. Do not discard the vaccine until authorized by Novartis. Any unused medicinal product or waste material should be disposed of in accordance with local requirements once authorized for destruction.





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Left thigh














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Left thigh

















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6.0 MEASUREMENTS













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1. Not Related




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2. Possibly Related


3. Probably Related











Kawasaki Disease




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Not Applicable.



▫ Death.








Serious adverse events will be captured both on the VSAE form as well as on the AEeCRF. All SAEs will be evaluated by the investigator for relationship of the event to study vaccine. SAEs that are judged to be possibly or probably related to the study vaccine should be reported to the sponsor as related (i.e., suspected) events.




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2. Not Related










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there is a satisfactory explanation for the changes observed, or until death, in which case a full pathologist’s report should be supplied, if possible. All findings must be reported on an Adverse Events CRF and on the VSAE form, if necessary, which is part of the Investigator Site File. All findings in subjects experiencing AEs must be reported also in the subject's medical records.






Post-Study Events




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6.6.4 Pregnancies

Not applicable.


Not applicable.


Not applicable.





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7.1 Endpoints









Not applicable.






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1. Body Temperature
















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1. Body Temperature








Not applicable.







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Not applicable.



7.3 Analysis Sets




FAS/PPS:






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7.3.2 Exposed Set











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7.3.5 Safety Set














7.3.7 Subgroups






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7.4 Analysis Plan











where




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Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Group APower

NZ98/254 0.84 0.70 120 94%

44/76 0.99 0.70 120 99%

5/99 0.99 0.70 120 99%









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None(Grade 0)

Mild

(Grade 1)

Moderate

(Grade 2)

Severe

(Grade 3)





limb was moved


0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm


0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm


0 - 9 mm 10 - 25 mm 26 - 50 mm > 50 mm







alertness

Shows an increased

drowsiness



arouse him/her




usual


Unable to console





hours


hours>2 episodes/24


hydration







hydration





involvement)

Most of the skin


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Not applicable.





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where












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Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Group APower

NZ98/254 0.95 0.75 120 99%

44/76 0.99 0.75 120 99%

5/99 0.99 0.75 120 99%




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9.0 DATA MANAGEMENT










9.4 Data Protection



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12.0 ETHICS







The protocol and the proposed informed consent form must be reviewed and approved by a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH 1997). A signed and dated statement that the protocol and informed consent have been approved by the IRB/EC must be given to Novartis before study initiation. Prior to study start and at any time the protocol is amended during study conduct, the investigator is required to sign a protocol signature page confirming his/her agreement to conduct the study in accordance


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with these documents and all of the instructions and procedures found in this protocol and to give access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, designated agents of Novartis, IRBs/ECs, and regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory authority, the investigator must inform Novartis immediately that this request has been made.












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13.0 REFERENCE LIST













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Novartis



UserName: Title: Head, Geographic Expansion & Established Vaccines Cluster Date: Wednesday, 15 October 2014, 12:05 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


Page 1513 of 3966

PPD

PPD

PPD

PPD

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Novartis Pharma Services AG Clinical Study Protocol V72_60 Amendment 515DEC15 Confidential Page 1 of 3




Protocol Title: A Phase 3, Open Label, Randomized, Controlled, Multi-Center Study to Evaluate the Safety and Immunogenicity of Novartis Meningococcal B

Recombinant Vaccine When Administered concomitantly with Routine Vaccines to Healthy Infants in Taiwan.

Amendment Number 5

Revised Protocol version 6.0 issued on 15DEC15


on 14OCT14

Property of Novartis Vaccines

Confidential


consent of Novartis Vaccines


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CHANGE 1 (Page 13, Synopsis)

Previously read:

An interim analysis for the primary immunogenicity and safety endpoint will be done after all subjects completed the Study Visit 4, one month after the third vaccination (at 7 months of age). Further details regarding the interim analysis are contained in Protocol section 7.5.

Now reads:

No interim analysis will be conducted for this study.


Interim analysis was initially planned to be conducted after all the subjects completed Visit 4 (i.e., 1 month after 3rd vaccination) to facilitate a rolling submission for marketing authorization of Bexsero in Taiwan. However, now the sponsor strategy is to file for marketing authorization of Bexsero after final CSR is available (i.e., after all subjects complete Visit 8 one month after booster dose).

CHANGE 2 (Page 82, Section7.5 Planned Interim Analysis):

Previously read:



The purpose of this interim analysis is to assess the primary immunogenicity objective and collect safety data at 1 month after the third dose and submit a full interim report to the Taiwanese Health Authorities. This analysis will consist of an interim analysis of safety data and a final analysis of immunogenicity data 1 month after the 3rd vaccination to assess the primary objective.


Because the primary study objective is to demonstrate sufficiency of response of rMenB+OMV NZ after the third vaccination and all enrolled subjects who have


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immunogenicity data will be included in the interim analysis no alpha correction will be performed for the primary or key secondary analysis which will be conducted both at the one-sided 0.025 significant level.

Now reads:



Interim analysis was initially planned to be conducted after all the subjects completed Visit 4 (i.e., 1 month after 3rd vaccination) to facilitate a rolling submission for marketing authorization of Bexsero in Taiwan. However, now the sponsor strategy is to file for marketing authorization of Bexsero after final CSR is available (i.e., after all subjects complete Visit 8 one month after booster dose).


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Novartis



UserName: Title: Cluster Physician Date: Thursday, 17 December 2015, 12:04 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


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Novartis Pharma Services AG Protocol V72_6015 DEC 15 Final Version 6.0 Confidential Page 1 of 91






Confidential




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Objectives:





Safety Objectives




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Methodology:



Study procedures









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(Visit 1)

4 months

(Visit 2)

6 months

(Visit 3)

7 months

(Visit 4)

9 months

(Visit 5)

11 months

(Visit 6)

12 months

(Visit 7)

13 months

(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw

Safety Call


MMR

Varicella

Blood Draw

Blood Draw

B 75 DTaP-IPV-Hib

PCV-13

Blood Draw

DTaP-IPV-Hib

PCV-13

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw

Safety Call

Safety Call MMR

Varicella

Blood Draw

Blood Draw

*According to the Taiwanese Immunization Program for Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively. In addition, BCG vaccine will be administered ≤ 24 hours after birth or at 1 month of age, as per current local practice.



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3. All vaccinations




1. Body Temperature








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1. Body Temperature




*Medically attended fever: any fever for which a medical visit was sought.

** As part of the study evaluations for MMR + varicella given at 12 months of age parents should be encouraged to see a doctor if subjects develop parotid/salivary gland swelling and obtain a diagnosis.§Medically attended adverse events: any adverse event requiring a medical visit (medical visit: a visit by a doctor or a nurse entitled to conduct medical visit [according to local regulations]).#Serious Adverse Events are defined in Protocol Section 6.6.2.



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Vaccines:



Novartis meningococcal Recombinant B with Outer Membrane Vesicles Vaccine (rMenB+OMV NZ)

GSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + Hib®)










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Primary


Key Secondary


Other Secondary


Safety Endpoints







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We assume that the infants in this study will have antibody responses similar to those observed in V72P13, with the percentage of subjects with SBA titer ≥ 1:5



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ranging from 84% for strain NZ98/254 and 99% for strains 44/76 and 5/99.



Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Power

NZ98/254 0.84 0.70 120 94%

44/76 0.99 0.70 120 99%

5/99 0.99 0.70 120 99%



Infants randomized to the control arm will receive routine vaccines only. The control arm of this study has been chosen for safety evaluation purpose and to assess the prevalence of bactericidal meningococcal B antibodies over the study period in infants not receiving rMenB+OMV NZ vaccine. To avoid unnecessary



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blood draws in infants, a randomization ratio of 2:1 was chosen.



Interim Analysis: No interim analysis will be conducted for this study.




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SCn

6

SC

7 RC RC RC 8

Months of Age 2 4 6 7 9 11 12 13

Study Day 1 3 7 61 63 67 122 124 128 152 213 274 305 307 311 318 335


n/a

0/+

2

0/+

2

-4/+

7

2 d

ays

(0/+

2) f

rom

Vis

it 2

6 d

ays

(0/+

2) f

rom

Vis

it 2

61 d

ays

(-4/

+7)

fro

mV

isit

2

2 d

ays

(0/+

2) f

rom

Vis

it 3

6 d

ays

(0/+

2) f

rom

Vis

it 3

30 d

ays

(-4/

+7)

fro

mV

isit

3

61 d

ays

(-7/

+14

) fr

omV

isit

4

61 d

ays

(-7/

+14

) fr

omV

isit

5

183

day

s (-

7/+

14)

from

Vis

it 3

2 d

ays

(0/+

2)fr

om V

isit

7

6 d

ays

(0/+

2)fr

om V

isit

7

13 d

ays

(0/+

2)fr

om V

isit

7

30 d

ays

(-4/

+7)

from

Vis

it 7

Informed Consent Xa


Medical History Xa


Xa Xa Xa Xa X

Serology Blood Draw

(5 ml)c

Xa X Xa X


(Group A only)

X X X X


X X X X



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SCn

6

SC

7 RC RC RC 8


X X X X



X X X X X X X X X


X X


X X X X







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a. Procedure to be performed prior to vaccination

b. Physical examination must be performed by a qualified health professional in accordance with local regulations and licensing requirements designatedwithin the Site Responsibility Delegation Log. See section 6.2 for components of physical examination by visit.

c. Maximal blood drawn refers to volume drawn at each specified visit. See section 3.5.1 for greater detail regarding blood sampling volumes.

d. A 30 minutes post injection hypersensitivity reactions measurement will be performed under site staff supervision during each vaccination visit.

e. Subjects/subject’s legal guardians will receive instruction on Diary Card completion. A Diary Card will be dispensed at this visit. See section 3.2.5.3 for more detail.

f. Subject’s parents(s)/legal guardian(s) will be reminded at telephone contact visits to complete Diary Cards and return them at the next clinic visit.





k. Collect concomitant medications and vaccination history according to the study procedures outlined throughout sections 3.2.5 and 5.4.

l. Any subject who terminates the study during the Post-Vaccination period is recommended to undergo study-related procedures as outline in section 3.8.

m. RC = Reminder Call for completion of Diary Card. See section 3.2.5.4 for greater detail.

n. SC = Safety Call. See section 3.2.5.6 for greater detail.



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TABLE OF CONTENTS




1.0 BACKGROUND AND RATIONALE ................................................................. 24

2.0 OBJECTIVES ...................................................................................................... 26

2.1 Immunogenicity Objective(s)........................................................................... 26

2.2 Safety Objectives ............................................................................................. 26

3.0 STUDY DESIGN AND INVESTIGATIONAL PLAN......................................... 28

3.1 Overview of Study Design ............................................................................... 28

3.1.1 Study Period ............................................................................................. 31

3.2 Study Procedures ............................................................................................. 31

3.2.1 Informed Consent/Assent .......................................................................... 31

3.2.2 Screening Procedures................................................................................ 31

3.2.3 Enrollment ................................................................................................ 32

3.2.4 Randomization.......................................................................................... 32

3.2.5 Visit Procedures........................................................................................ 33

3.2.5.1 Pre-vaccination Procedures ................................................................ 33

3.2.5.2 Vaccination Procedures...................................................................... 34

3.2.5.3 Post-vaccination Procedures............................................................... 34

3.2.5.4 Reminder Telephone Calls ................................................................. 36


3.2.5.6 Safety Calls........................................................................................ 37

3.2.5.7 “For cause” Visits .............................................................................. 37

3.2.5.8 Termination Visits.............................................................................. 37

3.3 Blinding Procedures......................................................................................... 38

3.4 Data Collection................................................................................................ 38

3.4.1 Data Collected From Subjects ................................................................... 38

3.4.2 Electronic Case Report Forms................................................................... 40



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3.5 Laboratory Assessments .................................................................................. 40

3.5.1 Processing, Labeling and Storage of Serum Samples for Serology ............ 40

3.5.2 Pregnancy Testing..................................................................................... 40

3.5.3 Safety Laboratory Assessments................................................................. 40

3.5.4 Cell Mediated Immunity Assessments....................................................... 40

3.5.5 Culture/PCR/Genotyping Assessments...................................................... 41

3.6 Stopping/Pausing Guidelines ........................................................................... 41

3.7 Premature Withdrawal and Early Study Termination........................................ 41

3.8 Early Termination Visit ................................................................................... 43

3.9 End of Study.................................................................................................... 44

4.0 SELECTION OF STUDY POPULATION........................................................... 45

4.1 Inclusion Criteria ............................................................................................. 45

4.2 Exclusion Criteria ............................................................................................ 45

4.3 Criteria for Delay of Vaccination and/or Blood Sampling ................................ 46

4.4 Criteria for Repeat Vaccination in the Study .................................................... 47

5.0 TREATMENT OF SUBJECTS ............................................................................ 48

5.1 Study Vaccine(s).............................................................................................. 48

5.2 Non-Study Vaccines ........................................................................................ 52

5.3 Vaccines Preparation and Administration......................................................... 52

5.4 Prior and Concomitant Medications and Vaccines............................................ 54

5.5 Vaccine Supply, Labeling, Storage, and Tracking ............................................ 55

6.0 MEASUREMENTS ............................................................................................. 58

6.1 Appropriateness of Measurements ................................................................... 58

6.2 Demographics, Medical History and Physical Examination.............................. 58

6.3 Immunogenicity Measurements ....................................................................... 59

6.4 Efficacy Measurements.................................................................................... 59

6.5 Solicited Safety Measurements ........................................................................ 59

6.6 Unsolicited Safety Measurements .................................................................... 61

6.6.1 Adverse Events ......................................................................................... 61

6.6.1.1 Adverse Events of Special Interest ..................................................... 63



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6.6.2 Serious Adverse Events............................................................................. 63

6.6.3 Methods for Assessing and Recording AEs and SAEs............................... 64

6.6.4 Pregnancies............................................................................................... 66

6.7 Safety Laboratory Measurements..................................................................... 66

6.8 Other Measurements ........................................................................................ 66

6.9 Data Monitoring Committee ............................................................................ 66

7.0 ENDPOINTS AND STATISTICAL ANALYSES................................................ 67

7.1 Endpoints......................................................................................................... 67

7.1.1 Primary Endpoint(s).................................................................................. 67

7.1.2 Secondary Immunogenicity Endpoints ...................................................... 67

7.1.3 Secondary Efficacy Endpoints................................................................... 67

7.1.4 Safety Endpoints....................................................................................... 67

7.1.5 Other Endpoints ........................................................................................ 69

7.1.6 Exploratory Endpoints .............................................................................. 69

7.2 Success Criteria ............................................................................................... 69

7.2.1 Success Criteria for Primary Objectives .................................................... 69

7.2.2 Success Criteria for Key Secondary Immunogenicity Objectives............... 70

7.2.3 Success Criteria for Secondary Efficacy Objectives .................................. 70

7.2.4 Success Criteria for Safety Objectives....................................................... 70

7.3 Analysis Sets ................................................................................................... 70

7.3.1 All Enrolled Set ........................................................................................ 71

7.3.2 Exposed Set ............................................................................................. 71

7.3.3 Full Analysis Set (FAS) Efficacy/Immunogenicity Set.............................. 71

7.3.4 Per Protocol (PP) Population, Efficacy/Immunogenicity Set ..................... 71

7.3.5 Safety Set.................................................................................................. 72

7.3.6 Other Analysis Sets................................................................................... 72

7.3.7 Subgroups................................................................................................. 72

7.3.8 Protocol Deviations................................................................................... 72

7.4 Analysis Plan................................................................................................... 74

7.4.1 Analysis of Demographic and Baseline Characteristics ............................. 74



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7.4.2 Analysis of Primary Objectives ................................................................. 74

7.4.2.1 Statistical Hypotheses for Primary Objectives ...................................... 74

7.4.2.2 Analysis Populations for Primary Objectives...................................... 75

7.4.2.3 Statistical Methods for Primary Objectives......................................... 75


7.4.2.5 Analysis of Safety Objectives............................................................. 76

7.4.2.5.1 Analysis of Extent of Exposure ................................................... 76

7.4.2.5.2 Analysis of Solicited Local and Systemic Adverse Events and Other Reactions........................................................................... 77

7.4.2.5.3 Analysis of Spontaneously Reported Adverse Events .................. 79

7.4.2.5.4 Analysis of Safety Laboratory Values.......................................... 79

7.4.3 Analysis of Key Secondary Immunogenicity Objectives ........................... 79

7.4.4 Analysis of Key Secondary Efficacy Objectives........................................ 82

7.4.5 Analysis of Key Secondary Other Objectives ............................................ 82

7.4.6 Analysis of Non-Key Objective................................................................. 82

7.5 Planned Interim Analysis ................................................................................. 82

8.0 SOURCE DOCUMENTATION, STUDY MONITORING, AND AUDITING .... 83

8.1 Source Documentation..................................................................................... 83

8.2 Study Monitoring and Source Data Verification............................................... 84

9.0 DATA MANAGEMENT ..................................................................................... 85

9.1 Data Entry and Management ............................................................................ 85

9.2 Data Clarification ............................................................................................ 85

9.3 Data Coding Procedures................................................................................... 85

9.4 Data Protection ................................................................................................ 85

10.0 RECORD RETENTION....................................................................................... 86

11.0 USE OF INFORMATION AND PUBLICATION................................................ 87

12.0 ETHICS ............................................................................................................... 88

12.1 Regulatory and Ethical Compliance ................................................................. 88

12.2 Informed Consent Procedures .......................................................................... 88

12.3 Responsibilities of the Investigator and IRB/EC............................................... 88



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12.4 Protocol Adherence.......................................................................................... 90

12.5 Protocol Amendments...................................................................................... 90

13.0 REFERENCE LIST.............................................................................................. 91



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Requirements for Registration of Pharmaceuticals for Human UseID Identification (Subject ID)IM IntramuscularIPV Inactivated Polio VirusIRB Institutional Review BoardLSLV Last Subject Last VisitMedDRA Medical Dictionary for Regulatory ActivitiesMMR Measles, Mumps, Rubella NVx Novartis Vaccines NZ New ZealandOMV Outer Membrane VesiclesPCV Pneumococcal Conjugate VirusPPS Per Protocol SetSAE Serious Adverse Event



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SBA Serum Bactericidal Activity SC SubcutaneouslySDA Source Data AgreementSUSAR Serious Unexpected Suspected Adverse ReactionSOP Standard Operating ProcedureVSAE Vaccine Serious Adverse EventWHO World Health Organization



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Since the 1960s, vaccines consisting of purified polysaccharide antigens have been developed against four (A, C, Y, and W-135) of the five pathogenic serogroups. The use of capsular polysaccharide as the basis of a vaccine for prevention of meningococcal B diseases has proven problematic. The meningococcal B capsular polysaccharide is identical to a widely distributed human carbohydrate (α[2→8] N-acetyl neuraminic acid or polysialic acid), which, being a self-antigen, is poorly immunogenic in humans. The recent sequencing of the meningococcal B genome provided a unique opportunity to discover and test gene products that have been left undetected by conventional biochemical and microbiological approaches (Pizza et al. Science 2000). Making use of a novel genome mining approach based on the meningococcal B sequence information,Novartis Vaccines (NVx) has developed a Meningococcal B Recombinant Vaccine (rMenB+OMV NZ). Data provided from clinical studies conducted with rMenB+OMV NZ confirm that the vaccine has a similar safety profile to other licensed pediatric vaccines and is able to elicit a robust immune response against selected meningococcal B strains. On 14th of January 2013, Novartis Vaccines received EU marketing authorisation for Bexsero for use in individuals from 2 months of age and older.



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2.0 OBJECTIVES










- Solicited local and systemic adverse events reported from Day 1 (day ofvaccination) through Day 7 after each vaccination. (Fever, Rash and



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Subjects that have been enrolled in this study will receive the study vaccines in an open-label fashion, i.e. the subject’s parent(s)/legal guardian(s) and study staff will not be blinded for the group to which the subject is assigned. Subjects randomized to Group Awill receive 4 vaccinations of rMenB+OMV NZ concomitantly with routine vaccines according to the Taiwanese immunization program at 2, 4, 6 and 12 months of age.



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Subjects assigned to the control group (Group B) will receive routine vaccines alone at 2, 4, 6 and 12 months of age. All vaccines will be administered to the subjects by designated nurse(s) or physician(s).



Immediate local and systemic adverse events or signs/symptoms of anaphylaxis will be collected for 30 minutes after each vaccination by study personnel.

Body temperature, fever (body temperature ≥ 38.0 °C), medically attended fever, solicited local and systemic adverse events, any adverse events and any medication taken by the subject will be collected for 7 days (extended to 28 days after MMR + varicella vaccination) after each vaccination using a Diary Card.

All serious adverse events, medically attended adverse events, adverse events leading to premature withdrawal from the study, all solicited adverse events and fever persisting beyond Day 7 and any medication for treatment of adverse events will be collected throughout the entire study using Diary Cards.

Safety Phone calls will be performed when subjects are approximately 9 and 11 months of age to collect information relating to unsolicited adverse events and concomitant medications associated with those events.





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Group Subjects

(n)

2 months

(Visit 1)

4 months

(Visit 2)

6 months

(Visit 3)

7 months

(Visit 4)

9 months

(Visit 5)

11 months

(Visit 6)

12 months

(Visit 7)

13 months

(Visit 8)

A 150 rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

Blood Draw

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

rMenB+OMV NZ

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw


MMR

Varicella

Blood Draw

Blood Draw

B 75 DTaP-IPV-Hib

PCV-13

Blood Draw

DTaP-IPV-Hib

PCV-13

DTaP-IPV-Hib

PCV-13

HepB (3rd dose)*

Blood Draw


Varicella

Blood Draw

Blood Draw

*According to the Taiwanese Immunization Program for Infants the 1st and 2nd dose of HepB will be administered at 0 and 1 months of age, respectively.

In addition, BCG vaccine will be administered ≤ 24 hours after birth or at 1 month of age, as per current local practice.



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3.1.1 Study Period












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3.2.3 Enrollment

After an individual is determined to be eligible for study participation, the subject will be enrolled in the electronic data capture (EDC) system; using the screening number assigned by the Investigator and then randomized. At randomization, the subject will automatically be assigned a unique Subject ID. The Subject ID consists of a 5 digit number resulting from the combination of the site number, the subject’s order ofrandomization at the site.

3.2.4 Randomization





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Is randomized but does not receive any study vaccine.

Has consent for participation in the study but who is withdrawn for reasons other than an adverse event.





















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a. The subject’s parent/guardian must understand that timely completion of the Diary Card on a daily basis is a critical component to study participation. The parent/guardian should also be instructed to write clearly and to complete the diary card in pen. Any corrections to the Diary Card that are performed by the person completing the diary card should include a single strikethrough line with a brief



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explanation for any change. No changes can be made to the Diary Card when it is returned to the clinic.


c. Body temperature measurement is to be performed using the thermometer provided by the site. If the subject feels unusually hot or cold during the day, the subject’s parent/guardian should check body temperature. If the subject has fever, the highest body temperature observed that day should be recorded on the Diary Card. The measurement of solicited local adverse events is to be performed using the ruler provided by the site. The collection of body temperature, solicited local adverse events, solicited systemic adverse events will continue for a total of 7 days on the Diary Card. Note: After vaccination with MMR and varicella (at Visit 7) the period for collection of body temperature, medically attended fever, parotid/salivary gland swelling and rash will be extended to 28 days after vaccination. The collection of unsolicited adverse events and medications will continue throughout on the Diary Card up to the evening prior to the next clinic visit.






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Not applicable











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3.4 Data Collection





eCRFs


Diary Cards



- Body temperature




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- Any AEs
















4. Any illegible or implausible data should be reviewed with the parent/guardian. If an underlying solicited or unsolicited adverse event is described. For example, if the subject with a body temperature of 400°C describes that the body temperature was actually 40°C on the day in which body temperature: 400°C was written into the Diary Card, this fever of 40°C should be described in the study file and reported as an unsolicited adverse event in the adverse event CRF.



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Not applicable.


Not applicable.


Not applicable.



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Not applicable.





Adverse event

Death

Withdrawal of consent

Lost to follow-up

Administration reason

Protocol deviation

Other






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Collect Diary Card

Review the subject’s solicited and unsolicited safety data

Perform review of concomitant medications/vaccinations since last visit

Collect vital sign measurements, including respiratory rate, pulse rate, and temperature (rectal)



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3.9 End of Study






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8. Any serious chronic or progressive disease according to the judgment of the investigator (e.g., neoplasm, insulin dependent diabetes mellitus Type I, cardiac disease, hepatic disease, progressive neurological disease or seizure, either associatedwith fever or as part of an underlying neurological disorder or syndrome, autoimmune



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Individuals with significant acute or chronic infection within the previous 7 days orbody temperature ≥38.0°C within the previous day.

Receipt of any antipyretic medication within the previous 6 hours.

Individuals that received any other vaccines within 28 days prior to enrollment. Individuals that received influenza vaccine or the second dose of HepB vaccine within



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Subject has received a dose of systemic antibiotics less than 6 days before blood collection.



Subjects who experience any serious adverse event judged to be possibly or probably related to study vaccine or non-study vaccines, including hypersensitivity reactions.

Subjects who develop any new condition which, in the opinion of the investigator, may pose additional risk to the subject if he/she continues to participate in the study.




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Novartis meningococcal Recombinant B with Outer Membrane Vesicles Vaccine (rMenB+OMV NZ)

GSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + Hib®)








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other ingredients

Aluminum Hydroxide

Sodium Chloride

Sucrose

Histidine

Water for injection









Pertactin 8 µg





10 µg


other ingredients

Lactose

Sodium Chloride

2-phenoxythanol







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other ingredients

Sodium chloride

Succine acid

Polysorbate 80







other ingredients

Sodium chloride









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other ingredients

Lactose

Sorbitol

Mannitol

Aminoacids







Other ingredients

Aminoacids

Human Albumin

Neomycine sulfate

Lactose

Mannitol

Sorbitol









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Upon storage of the suspension of rMenB+OMV NZ a fine off-white deposit may form. Shake the vaccine well before use to form a homogeneous suspension. The vaccine should be visually inspected for particulate matter and discoloration prior to administration. In the event of any foreign particulate matter and/or variation of physical aspect being observed, do not administer the vaccine and report the issue as aPharmaceutical Technical Complaint to Novartis. Do not discard the vaccine until authorized by Novartis. Any unused medicinal product or waste material should be disposed of in accordance with local requirements once authorized for destruction.


The concomitant routine vaccines used in this study, i.e. GSK 5-in-1 DTaP-IPV-Hib vaccine (Infanrix-IPV + Hib®), Pfizer 13-valent PCV (Prevenar-13®), GSK Hep B vaccine (Engerix-B®), GSK MMR vaccine (Priorix®) and GSK Varicella vaccine (Varilrix®) are all licensed vaccines in Taiwan and must be prepared according to the package insert before use. Expired vaccines must not be administered.



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Left thigh














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Left thigh

















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supply of the study vaccine(s)

appropriate labeling of all study vaccines provided that complies with the legal requirements of each country where the study is to be performed


acknowledge receipt of the study vaccines by a designated staff member at the site, including confirmation that the vaccines:






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proper storage of the study vaccines, including:




appropriate use of the study vaccines, including:






proper adherence to the local institutional policy with respect to destruction of study vaccines.

complete record keeping of vaccine use, wastage, return or destruction, including documentation of:






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6.0 MEASUREMENTS













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Solicited safety measurements are performed to investigate the “reactogenicity” of the study vaccines. The term “reactogenicity” refers to selected signs and symptoms (“adverse events”) occurring in the hours and days following a vaccination, to be



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collected by the subject‘s parent/guardian for six consecutive days, using a pre-defined checklist in a Diary Card (i.e., solicited adverse events). Please see section 3.2.5.3 andsection 8.1 for more detail for capture of solicited safety data.






Change in eating habits, sleepiness, irritability, persistent crying, vomiting, diarrhea and rash.


Change in eating habits, sleepiness, irritability, persistent crying, vomiting, diarrhea, rash and parotid/salivary gland swelling.


Body temperature, use of medication to treat and/or to prevent fever, medically attended fever.






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1. Not Related




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2. Possibly Related


3. Probably Related




“Medically attended adverse event”: an adverse event that leads to an unscheduled visit to a healthcare practitioner.


Solicited local or systemic adverse event leading to a “medically attended adverse event”.

Solicited local or systemic adverse event leading to the subject withdrawing from the study or the subject being withdrawn from the study by the investigator.

Solicited local or systemic adverse event lasting beyond 7 days’ duration.

Solicited local or systemic adverse events that lead to subject withdrawal from study vaccination.

Solicited local or systemic adverse event that otherwise meets the definition of a serious adverse event (see section 6.6.2).

Kawasaki Disease

Rare (up to 1/1000 people affected) cases of Kawasaki Disease have been detected in previous clinical studies, both in infants receiving rMenB+OMV NZ and in infants not receiving rMenB+OMV NZ. Kawasaki Disease may include symptoms such as fever that lasts for more than five days, associated with a skin rash on the trunk of the body, and sometimes followed by a peeling of the skin on the hands and fingers, swollen glands in the neck, red eyes, lips, throat and tongue. Sometimes it might present with atypical



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symptoms. Since the prevalence of this disease is higher among the Taiwanese and East-Asian population compared to the foreign populations, investigators are requested to closely monitor subjects for any suspected case of Kawasaki Disease.


Not Applicable.



Death.

Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate risk of death from the event as it occurred); it does not refer to an event which hypothetically might have caused death if it were more severe.

Required or prolonged hospitalization.

Persistent or significant disability/incapacity (i.e., the event causes a substantial disruption of a person’s ability to conduct normal life functions).

Congenital anomaly/or birth defect.

An important and significant medical event that may not be immediately life threatening or resulting in death or hospitalization but, based upon appropriate medical judgment, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed above.



Serious adverse events will be captured both on the VSAE form as well as on the AEeCRF. All SAEs will be evaluated by the investigator for relationship of the event to study vaccine. SAEs that are judged to be possibly or probably related to the study vaccine should be reported to the sponsor as related (i.e., suspected) events.




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2. Not Related







All AEs meeting criteria for reporting, regardless of severity, will be monitored by the investigator until resolution or stabilization. All subjects experiencing AEs - whether considered associated with the use of the study vaccine or not - must be monitored until symptoms subside and any abnormal laboratory values have returned to baseline, or until there is a satisfactory explanation for the changes observed, or until death, in which case a



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full pathologist’s report should be supplied, if possible. All findings must be reported on an Adverse Events CRF and on the VSAE form, if necessary, which is part of the Investigator Site File. All findings in subjects experiencing AEs must be reported also in the subject's medical records.






Post-Study Events




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6.6.4 Pregnancies

Not applicable.


Not applicable.


Not applicable.





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7.1 Endpoints









Not applicable.






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1. Body Temperature
















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1. Body Temperature




*Medically attended fever: any fever for which a medical visit was sought.

**As part of the study evaluations for MMR + varicella given at 12 months of age parents should be encouraged to see a doctor if subjects develop parotid/salivary gland swelling and obtain a diagnosis.§Medically attended adverse events: any adverse event requiring a medical visit (medical visit: a visit by a doctor or a nurse entitled to conduct medical visit [according to local regulations]).#Serious Adverse Events are defined in Protocol section 6.6.2.




Not applicable.







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Not applicable.



7.3 Analysis Sets




FAS/PPS:






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7.3.2 Exposed Set




received at least one dose of a study vaccination and provided immunogenicity data at relevant time points.




Are not excluded due to reasons (see section 7.3.8) defined prior to analysis



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Correctly received the vaccine (i.e., receive the vaccine to which the subject was randomized and received the vaccine at the scheduled time points)


7.3.5 Safety Set




Provide post vaccination reactogenicity data



Have post-vaccination unsolicited adverse event records



Have post-vaccination solicited or unsolicited records




7.3.7 Subgroups






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A subject received incorrect study vaccine or dose of study vaccine.

A subject met withdrawal criteria during the study but was not withdrawn.

A subject received an excluded medication or vaccine.

A subject was enrolled but does not meet the protocol's eligibility criteria.

A subject with no safety data

Inadvertent loss of samples or data that support the analysis of primary or key objectives

Failure to obtain informed consent prior to initiation of study-related procedures

Falsifying research or medical records.







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7.4 Analysis Plan











where




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Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Group APower

NZ98/254 0.84 0.70 120 94%

44/76 0.99 0.70 120 99%

5/99 0.99 0.70 120 99%









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Page 1594 of 3966

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None(Grade 0)

Mild

(Grade 1)

Moderate

(Grade 2)

Severe

(Grade 3)





limb was moved


0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm


0 - 9 mm 10 - 25 mm 26 - 50 mm >50 mm


0 - 9 mm 10 - 25 mm 26 - 50 mm > 50 mm







alertness

Shows an increased

drowsiness



arouse him/her




usual


Unable to console





hours


hours>2 episodes/24


hydration







hydration





involvement)

Most of the skin


Page 1595 of 3966

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serious adverse events

adverse events that are possibly or probably related to vaccine

adverse event leading to withdrawal

adverse events leading to a medically attended visit

adverse event by data source



Not applicable.





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where












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Strain

πk


titer ≥ 1:5)

π0

(Threshold)


Group APower

NZ98/254 0.95 0.75 120 99%

44/76 0.99 0.75 120 99%

5/99 0.99 0.75 120 99%




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All safety data reported by subjects must be written down in source documents prior to entry of the data into CRFs. If there are multiple sources of information (e.g., Diary Card, verbal report of the subject, telephone contact details, medical chart) supporting the diagnosis of an adverse event, these sources must be identified in the source documents,


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discrepancies between sources clarified, the ultimate diagnosis must be justified and written in the source documents, and this diagnosis must be captured in the adverse event CRF (AE CRF). The AE CRF must also capture which source(s) of information were used to determine the adverse event (e.g., subject recall, medical chart, Diary Card, and/or other sources).




that the rights and well-being of human subjects are protected

the reported trial data are accurate, complete, and verifiable from the source documents and

the conduct of the trial is in compliance with the current approved protocol/amendment(s), GC and applicable regulatory requirements



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9.0 DATA MANAGEMENT










9.4 Data Protection



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12.0 ETHICS







The protocol and the proposed informed consent form must be reviewed and approved by a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH 1997). A signed and dated statement that the protocol and informed consent have been approved by the IRB/EC must be given to Novartis before study initiation. Prior to study start and at any time the protocol is amended during study conduct, the investigator is required to sign a protocol signature page confirming his/her agreement to conduct the study in accordance with these documents and all of the instructions and procedures found in this protocol and


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to give access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, designated agents of Novartis, IRBs/ECs, and regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory authority, the investigator must inform Novartis immediately that this request has been made.


maintaining a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties

demonstrating the capability of recruiting the required number of suitable subjects within the recruitment period

demonstrating sufficient time and staffing to properly conduct and complete the study within the agreed trial period

ensuring that all persons assisting with the study are adequately informed about the protocol, the investigational product(s), and their study-related duties and functions

ensuring that appropriately trained health care professionals are responsible for all study-related medical decisions and for ensuring appropriate medical care of subjects experiencing any adverse event related to the study

if permission to do so is given by the subject’s parent/guardian, ensuring that the subject’s primary healthcare provider is informed of the subject’s participation in the study.






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13.0 REFERENCE LIST













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Novartis



UserName: Title: Cluster Physician Date: Thursday, 17 December 2015, 12:06 GMT Meaning: As an approver, I agree with the content and format of this document. ================================================


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PPD

PPD

PPD

PPD

16.1.2 Sample case report form


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16.1.1 protocol and protocol amendments · property of novartis vaccines and diagnostics...

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