finom-rokotetutkimuksen tulosten esitys fda:n asiantuntijakokouksessa

FinOM Efficacy Trial of 7-Valent

Pneumococcal Conjugate Vaccine

Terhi Kilpi

National Public Health Institute (KTL)

Finland

2

FinOM Study Group

• Principal investigator

• Study coordination

• Bacteriology

• Immunology

• Otorhinolaryngology

• Biostatistics

• Data management

• Virology

• Study clinic personnel

• Senior adviser

• Juhani Eskola, Terhi Kilpi

• Arto Palmu , Kari S Lankinen

• Elja Herva, Maija Leinonen

• Helena Käyhty, Heidi Åhman

• Pekka Karma

• Jukka Jokinen, Mika Lahdenkari,

Jouko Verho

• Jaason Haapakoski, Esa

Ruokokoski, Marko Grönholm

• Tapani Hovi

• Wilhelm Bredenberg, Heljä

Savolainen, Ritva Syrjänen

• P Helena Mäkelä

FinOM Vaccine Trial

3

FinOM Vaccine Trial

• evaluated efficacy of two 7-valent pneumococcal (Pnc)

conjugate vaccines for prevention of AOM due to

vaccine serotypes in children less than 2 years of age

• clinical phase from December 1995 to March 1999

• 2 497 children enrolled (55 % of the birth cohort) in

Tampere area

4

Study design

• All children were randomized to receive PncCRM

(Prevnar®, Prevenar®), PncOMPC, or control (HBV)

vaccine at 2, 4, 6, and 12 mo

• Follow-up from 2 to 24 mo at the study clinic

• All respiratory infections requiring medical attention

were evaluated and treated at the study clinic

FinOM Vaccine Trial

5

Definition of AOM

• Symptoms

– At least one of the following: fever, earache, irritability,

diarrhea, vomiting, acute otorrhea not caused by otitis

externa, or other symptoms of respiratory infection

• Signs

– A visually abnormal tympanic membrane (in regard of color,

position and/or mobility) suggesting middle ear effusion

FinOM Studies

6

Acute Otitis Media (AOM)

• Myringotomy with aspiration performed in AOM with

effusion

• Middle ear fluid (MEF) sample for bacterial culture,

pneumococcal serotyping and pneumolysin PCR

• AOM episode defined to start at diagnosis and to last

for 30 days

FinOM Studies

7

Efficacy of PncCRM against AOM

• Primary

– All AOM episodes due to vaccine serotypes

• Secondary

– First and subsequent AOM episodes due to vaccine serotypes

• Other

– All Pnc AOM episodes

– All AOM episodes

– Recurrent AOM

FinOM Vaccine Trial

8

Efficacy of PncCRM against AOM

• Post Hoc

– AOM episodes due to vaccine related serotypes (6A, 9N, 18B, 19A,

23A)

– AOM episodes due to serotypes unrelated to vaccine types

– AOM episodes due to individual serotypes

FinOM Vaccine Trial

9

Disposition of subjects

PncCRM Control Total

Enrolled 831 831 1662

Excluded from PP analysis 20 10 30

Early temination of PP f-up 25 27 52

Withdrawn permanently 33 32 65

Completed as PP 786 794 1580

Completed ITT follow-up 798 799 1597

FinOM Vaccine Trial

10

All AOM episodes due to vaccine serotypes FinOM Vaccine Trial

PncCRM Control Total

Number of episodes 107 250 357

Rate/person-year 0.09 0.21

Primary analysis

Vaccine efficacy: 57% (95% CI: 44% to 67%)

Per protocol follow-up from 6.5 to 24 months of age

11

First and subsequent AOM episodes due

to vaccine serotypes

PncCRM HBVVaccine efficacy

%95 %

lower CL95 %

upper CL

First

N 89 177

Rate* 0.08 0.17

52 39 63

Subsequent

N 18 73

Rate* 0.25 0.47

45 5 69

FinOM Vaccine Trial

Per protocol follow-up

Secondary analysis

*Per person-year

12

Summary of efficacy results

EpisodesEndpoint


%95 %

lower CL95 %

upper CL

AOM due to vaccineserotypes

107 250 57 44 64

Pneumococcal AOM(culture+)

271 414 34 21 45

Pneumococcal AOM(culture and/or PCR+)

548 687 20 7 31

Any AOM 1251 1345 6 -4 16

Recurrent AOM 123 149 16 -6 35

FinOM Vaccine Trial


Acute Otitis Media

13

Summary of efficacy results

EpisodesEndpoint


%95 %

lower CL95 %

upper CL

AOM due to vaccineserotypes

135 292 54 41 64


322 467 32 19 42

Pneumococcal AOM(culture and/or PCR+)

642 775 18 5 29

Any AOM 1474 1532 4 -7 14

Recurrent AOM 158 174 9 -12 27

FinOM Vaccine Trial

Intention to treat follow-up from 2 to 24 months of age

Acute Otitis Media

14

Pneumococcal AOM episodes

EpisodesEndpoint


%

95 %lowerCL

95 %upper CL


271 414 34 21 45

Pneumococcal AOM(culture+ and/or PCR+)

548 687 20 7 31

Pneumococcal AOM(culture– and PCR+)

310 326 4 -15 19

FinOM Vaccine Trial


Acute Otitis Media

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PCR counts* in MEF of

Pnc Ply PCR positive AOM

0

100000

200000

300000

400000

500000

600000

PncCRM HBV PncCRM HBV

PCR counts

Pnc culture negative Pnc culture positive

* GM (95% CI)

FinOM Vaccine Trial

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Individual vaccine serotypes

EpisodesSerotype


%95 %

lower CL95 %

upper CL

23F 33 82 59 35 75

19F 43 58 25 -14 51

6B 9 56 84 62 93

14 8 26 69 20 88

18C 7 17 58 -4 83

9V 5 11 54 -48 86

4 2 4 49 -176 91

FinOM Vaccine Trial


Acute Otitis Media

17

Vaccine, vaccine-related and other serotypes

EpisodesSerotypes

PncCRM HBV

Vaccine efficacy%

95 %lower CL

95 %upper CL

Vaccine 107 250 57 44 67

Vaccine-related 41 84 51 27 67

Other 125 95 -33 -80 1

Pnc AOM(culture+)

271 414 34 21 45

FinOM Vaccine Trial


Acute Otitis Media

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Vaccine-related serotypes

EpisodesSerotype

PncCRM HBV

Vaccine efficacy%

95 %lower CL

95 %upper CL

6B 9 56 84 62 93

6A 19 45 57 24 76

19F 43 58 25 -14 51

19A 17 26 34 -26 65

FinOM Vaccine Trial


Acute Otitis Media

19

PncCRM

• is efficacious against

– culture-confirmed, vaccine serotype specific AOM

(VE: 57%)

– culture-confirmed AOM due to vaccine-related

serotypes (VE: 51%)

– culture-confirmed pneumococcal AOM (VE: 34%)

FinOM Vaccine Trial Conclusions

Extended follow-up

FinOM Vaccine Trial

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Objectives

• To assess long-term effects of PncCRM on

– pneumococcal carriage

– antibody persistence

– surgery due to OM in the routine practice after

the Vaccine Trial

FinOM Follow-up Study

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Methods

• Single follow-up visit at the age of 4 to 5 years in spring

2001

• Collection of data

– Parental interview

– Pneumatic otoscopy

– Medical records

– Nasopharyngeal, blood and saliva samples


23

Inclusion criteria

PncCRM Control Total %

Enrolled in the FinOMVaccine Trial

831 831 1662 100

Completed ITT follow-up 798 799 1597 96

Still living in the area 746 744 1490 90

Informed consent for the Follow-up Study

403 353 756 45


24

0 10 20 30 40 50 60

1597

Study flow

Start of long-term follow-up

Children, N

FinOM Vaccine Trial and Follow-up Study

65 dropped out

during the trial

1662

756

1490

107 moved out of

Tampere Area

Age, months

Fully evaluated children

= Analysis population 1

Eligible children


Complete tympanostomy data

available

Hospital

tympanostomy data

available

25

Case ascertainment for tube placement

• Fully evaluated children (Analysis population 1)

– Parental interview

– Hospital records from Tampere University Hospital, three

district hospitals (78%)

– Medical records from private physician offices for verification

(22%)

• Eligible children (Analysis population 2)

– Hospital records from Tampere University Hospital, three

district hospitals


26

Tube placement during the Vaccine Trial

• Included in the study services

• Close follow-up in the study clinics, active treatment

strategy, specific criteria for referral in the SOP

• Tampere University Hospital

• Free of charge

• Within 4 to 8 weeks of referral

FinOM Studies

27

Tube placement after the Vaccine Trial

• Public hospitals

– Nominal charge

– Waiting time 3 to 4 months

– 78%

• Private medical centers and hospitals

– Charge 10 x public sector charge

– No waiting time

– 22%

FinOM Studies

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0

2

4

6

8

10

12

14

<2 2 - 4

FinOM control group

Finland overall

Incidence of tube placement

*

* National hospital discharge register and national sick insurance reimbursement

database

/ 100 person-years

*

Age, years

29

0 10 20 30 40 50 60

1597

Study flow


Children, N


65 dropped out

during the trial

1662

756

1490

107 moved out of

Tampere Area

Age, months

Fully evaluated children


Eligible children


30

Tympanostomy tube placement

in fully evaluated children*

PncCRMN=403

HBVN=353

Vaccineefficacy

95% CI

2 months to 2 years

% with events 20.3 23.8

Rate of events* 12.9 14.812% (-1734)

2 years to 4-5 years


Rate of events* 3.5 5.739% (461)


Intention to treat follow-up

*Per 100 person-years *Analysis population 1

31

Tympanostomy tube placement

in all eligible children*

PncCRM HBV Vaccineefficacy

95% CI

2 months to 2 years N=831 N=831


Rate of events* 12.0 12.74% (-1923)

2 years to 4-5 years N=746 N=744


Rate of events* 2.4 4.144% (1962)

Intention to treat follow-up

*Per 100 person-years


*Analysis population 2

32

0,00

0,05

0,10

0,15

0,20

0,25

0,30

0,35

0,40

0,45

0 10 20 30 40 50 60 70

Age,months

Cumulative hazard of tympanostomy

tube placement


Cumulative

hazard


Fully evaluated

children

HBV

PncCRM

33

0,00

0,05

0,10

0,15

0,20

0,25

0,30

0,35

0,40

0 10 20 30 40 50 60 70

Age,months

Cumulative hazard of tympanostomy

tube placement


Cumulative

hazard


All eligible

children

HBV

PncCRM

34

0,01

0,1

1

10

0 10 20 30 40 50 60

Kinetics of anti-23F


g/ml


HBV

PncCRM

35

0,01

0,1

1

10

0 10 20 30 40 50 60

Kinetics of anti-19F


g/ml


PncCRM

HBV

36

0,01

0,1

1

10

0 10 20 30 40 50 60

Kinetics of anti-6B


g/ml


PncCRM

HBV

37

Long-term effect on otitis media and carriage


PncCRMN 403

HBVN 353

Children with AOM after 24 mo of age,% 67.3 72.7

Diagnosed with OM at the Follow-up visit,% 11.4 12.5

Vaccine type Pnc carriage, % 8.5 13.6 P=0.05

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PncCRM

• PncCRM reduces tube placement due to OM

• Vaccine efficacy against OM persists for several years

FinOM Follow-up Study Conclusions

Back-up slides

40


EpisodesSerotype


%95 %

lower CL95 %

upper CL

9V 5 11 54 -48 86

9N 2 8 75 -24 95

18C 7 17 58 -4 83

18B 2 1 -103 -213 82

23F 33 82 59 35 75

23A 1 4 75 -24 95

FinOM Vaccine Trial


Acute Otitis Media

41


EpisodesSerotype


%95 %

lower CL95 %

upper CL

6A 19 45 57 24 76

9N 2 8 75 -24 95

18B 2 1 -103 -213 82

19A 17 26 34 -26 65

23A 1 4 75 -24 95

FinOM Vaccine Trial


Acute Otitis Media

42

Vaccine efficacy by dose

Interval

from dose to doseVaccine efficacy

%95 % lower CL 95 % upper CL

1 2 22 -74 65

2 3 46 -4 72

3 4 57 36 71

4 end 55 39 67

FinOM Vaccine Trial

Intention to treat analysis

43

Efficacy of PncCRM with subsequent

episodes due to same serotypes excluded

Vaccine efficacy %(95% CI)AOM episodes

All episodes First episodes*

due to vaccine serotypes 57 55

(4467) (4365)

any Pnc 34 34

(21-45) (2144)

FinOM Vaccine Trial

*due to a given serotype

44

0,01

0,1

1

10

0 10 20 30 40 50 60

Kinetics of anti-14


g/ml


PncCRM

HBV

45

0,01

0,1

1

10

0 10 20 30 40 50 60

Kinetics of anti-18C


g/ml


PncCRM

HBV

46

0,1

1

10

0 10 20 30 40 50 60

Kinetics of anti-9V


g/ml


PncCRM

HBV

47

0,01

0,1

1

10

0 10 20 30 40 50 60

Kinetics of anti-4


g/ml


PncCRM

HBV

48

Efficacy of PncCRM and PncOMPC

Vaccine efficacy %(95% CI)AOM episodes due to

PncCRM* PncOMPC**

6B 84 79

(6293) (5889)

19F 25 37

(-1451) (159)

23F 59 52

(3575) (2868)

FinOM Vaccine Trial

*Eskola et al. N Engl J Med J 2001;344:403-9 ** Kilpi et al. ICAAC 2000

49

Nasopharyngeal carriage of any Pnc

0

5

10

15

20

25

30

12 mo 18 mo 4-5 yrs

PncCRM

Control

%

FinOM Vaccine Trial

Age

50

Nasopharyngeal carriage of Pnc serotypes

0

5

10

15

Vaccine Cross-reactive Other

PncCRM

Control

%

FinOM Vaccine Trial

12 months of age

51


0

5

10

15


PncCRM

Control

%

FinOM Vaccine Trial

18 months of age

P<0.001 P=0.02

52


0

5

10

15


PncCRM

Control

%

FinOM Vaccine Trial

4-5 years of age

P=0.05

53

Relative risk of Pnc AOM in PncCRM vs.

control group

0

0,2

0,4

0,6

0,8

RR

FinOM Vaccine Trial

Vaccine serotypes

6.5 -11 mo 12 -17 mo 18 -24 mo

Per-protocol follow-up

54

Relative risk of Pnc AOM and carriage

in PncCRM vs. control group

0

0,2

0,4

0,6

0,8

AOM Carriage AOM Carriage AOM Carriage

RR

FinOM Vaccine Trial

Vaccine serotypes

6.5 -11 mo 12 mo 12 -17 mo 18 mo 18 -24 mo 4-5 yrs


55



0

0,2

0,4

0,6

0,8

1

1,2


RR

FinOM Vaccine Trial

Type 6B Per-protocol follow-up

6.5 -11 mo 12 mo 12 -17 mo 18 mo 18 -24 mo 4-5 yrs

56



0

0,5

1

1,5

2


RR

FinOM Vaccine Trial

Type 6A

6.5 -11mo 12 mo 12 -17 mo 18 mo 4-5 yrs


57

Efficacy for first and subsequent

episodes: Vaccine specific serotypes

Proportionat risk forfirstepisode

Rate ofAOM forfirstepisode

Proportionat risk forsubsequentepisode

Rate ofAOM forsubsequentepisode

Over-allrate of AOM

PncCRM 0.9 0.08 + 0.1 0.25 = 0.09

Control 0.8 0.17 + 0.2 0.47 = 0.21

VE 52% 45% 57%

58

Rate of tympanostomy tube placement

before the date of unblinding*

0

5

10

Before unblinding Total

PncCRM

HBV


Per-protocol follow-up Fully evaluated

children >2 years

*1 Oct 1999

/ 100 person-years

59

Rate of tympanostomy tube placement

before the date of unblinding*

0

5

10

Before unblinding Total

PncCRM

HBV


Per-protocol follow-up All eligible

children >2 years

*1 Oct 1999

/ 100 person-years

finom-rokotetutkimuksen tulosten esitys fda:n asiantuntijakokouksessa

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