clinical study protocol - wrhi...clinical study protocol a randomised, open label switch study...
TRANSCRIPT
CLINICAL STUDY PROTOCOL
A randomised, open label switch study comparing darunavir/ritonavir
400mg/100mg daily with lopinavir/ritonavir 800mg/200mg daily, in HIV-
positive participants.
PROTOCOL NO. WRHI052
Sponsor: Wits Reproductive Health and HIV Institute (Wits RHI)
Physical Address
University of the Witwatersrand
Hillbrow Health Precinct
Hugh Solomon Building
Corner Esselen Street, and Klein Street
Hillbrow, 2001
South Africa
Postal Address
University of the Witwatersrand
PO 18512
Hillbrow, 2038
South Africa
Sponsor Contact: Prof WD Francois Venter, FCP (SA)
Deputy Executive Director, Wits Reproductive Health and HIV Institute (Wits
RHI)
Associate Professor, Department of Medicine
University of the Witwatersrand, Johannesburg, South Africa
Telephone: +27 (0) 11 358 5453
Fax: +27 (0)11 358 5439
E-mail: [email protected]
www.wrhi.ac.za
Version and Date of Protocol:
Protocol Version 3.0 – 26 October 2017
CONFIDENTIAL
The concepts and information contained in this document or generated during the study are considered proprietary and may
not be disclosed in whole or in part without the expressed, written consent of
Wits Reproductive Health and HIV Institute.
The study will be conducted according to the International Conference on Harmonisation harmonised tripartite guideline
E6(R1): Good Clinical Practice.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 2
Table of Contents
Protocol Approval ............................................................................................................ 5
Declaration of Investigator .............................................................................................. 6
List of Abbreviations........................................................................................................ 7
Protocol Synopsis............................................................................................................. 8
1 Introduction ..................................................................................................................11
1.1 Background Information ..................................................................................11
1.2 Current Therapy ............................................................................................... 12
1.3 Rationale .......................................................................................................... 13
1.4 Other Study Medications ................................................................................. 15
2 Study Objectives ......................................................................................................... 15
2.1 Primary Objective ............................................................................................ 15
2.2 Secondary Objective ........................................................................................ 15
3 Study Design ............................................................................................................... 15
4 Selection of Study Population ..................................................................................... 16
4.1 Inclusion Criteria ............................................................................................. 17
4.2 Exclusion Criteria: ........................................................................................... 17
5 Study Procedures ........................................................................................................ 18
5.1 Screening: ........................................................................................................ 18
5.2 Enrolment: ....................................................................................................... 18
5.3 Follow-up visit procedure: .............................................................................. 19
5.4 Efficacy Assessments ...................................................................................... 19
5.5 Early withdrawal ............................................................................................. 20
5.6 Replacements ................................................................................................... 20
6 Safety Assessments ..................................................................................................... 20
6.1 Adverse Events ................................................................................................ 20
6.2 Serious Adverse Events ................................................................................... 21
6.3 Assessment of AEs .......................................................................................... 22
6.5 Management of Pregnancy .............................................................................. 22
6.6 Physical Examination and Vital Sign Measurements ...................................... 23
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 3
7 Study Treatments ........................................................................................................ 23
7.1 Medication Supplies ........................................................................................ 24
7.2 Study Medication Accountability .................................................................... 25
7.3 Prior, Concomitant and Subsequent Therapy .................................................. 25
7.4 Process for Antiretroviral Switch .................................................................... 25
7.5 Post-trial access to darunavir 400mg ............................................................... 26
8 Statistical Analysis Plans ............................................................................................ 26
8.1 Primary Efficacy Endpoint .............................................................................. 26
8.2 Secondary Efficacy Endpoints......................................................................... 26
8.3 Safety Endpoints .............................................................................................. 26
8.4 Sample Size Calculations ................................................................................ 26
8.5 Analysis Sets .................................................................................................... 27
8.6 Statistical Analysis ........................................................................................... 27
8.7 Primary Efficacy Analysis ............................................................................... 28
8.9 Safety Analyses ............................................................................................... 28
8.10 Interim Analyses ............................................................................................ 29
9 Data Management ....................................................................................................... 29
10 Other study Activities ............................................................................................... 30
10.1 Confidentiality ............................................................................................... 30
10.2 Reporting ....................................................................................................... 30
10.3 Investigator Documentation .......................................................................... 30
10.4 Monitoring of the Study ................................................................................ 31
10.5 Protocol Amendments ................................................................................... 31
10.6 Protocol Violations and Deviations ............................................................... 31
10.7 Inspection of Records .................................................................................... 32
10.8 Records Retention ......................................................................................... 32
10.9 Study Termination ......................................................................................... 32
10.10 Publications ................................................................................................. 32
11 Appendix: Schedule of Events .................................................................................. 33
12 Reference List ........................................................................................................... 35
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 4
List of Tables
Table 1 Treatment Regimen ........................................................................................... 16
Table 2 Study Medication Supplies ............................................................................... 24
Table 3 Schedule of Events ............................................................................................ 33
Table 4 Schedule of Post-Trial Access ........................................................................... 34
List of Figures
Figure 1 Study design .................................................................................................... 16
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 5
Protocol Approval
Study Title A randomised, open label switch study comparing
darunavir/ritonavir 400mg/100mg daily with lopinavir/ritonavir
800mg/200mg daily, in HIV-positive participants.
Protocol
Number
WRHI052
Protocol Date Protocol Version 3.0 – 26 October 2017
Protocol accepted and approved by:
Principal Investigator
Prof WD Francois Venter, FCP (SA)
Deputy Executive Director, Wits RHI
Associate Professor, Department of Medicine
University of the Witwatersrand, Johannesburg, South Africa
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 6
Declaration of Investigator
I have read and understand all sections of the protocol entitled “A randomised, open
label switch study comparing darunavir/ritonavir 400mg/100mg daily with
lopinavir/ritonavir 800mg/200mg daily, in HIV-positive participants” and the
accompanying current information for investigators.
I agree to supervise all aspects of the protocol and to conduct the clinical investigation
in accordance with the Protocol Version 3.0, dated 26 October 2017, the International
Conference on Harmonisation harmonised tripartite guideline E6 (R1): Good Clinical
Practice, and all applicable government regulations. I will not implement protocol
changes without HREC approval except to eliminate an immediate risk to participants.
I agree to administer study treatment only to participants under my personal
supervision or the supervision of a subinvestigator.
I will not supply the investigational drug to any person not authorised to receive it.
Confidentiality will be protected. Participant identity will not be disclosed to third
parties or appear in any study reports or publications without the permission of the
participant.
___________________________ 26 Oct 2017
Signature of Principal Investigator Date
Prof. WD Francois Venter .
Printed Name of Principal Investigator
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 7
List of Abbreviations
Abbreviation Definition
ADR adverse drug reaction
AE adverse event
ART antiretroviral therapy
BID twice daily
CYP cytochrome P450
DRV darunavir
DRV/r ritonavir-boosted darunavir
DSMB data and safety monitoring board
GCP Good Clinical Practice
HIV human immunodeficiency virus
HREC Wits Human Research Ethics Committee
ICF informed consent form
ICH International Conference on Harmonisation
LPV/r ritonavir-boosted lopinavir
NNRTI non-nucleoside reverse transcriptase inhibitor
NRTI nucleoside reverse transcriptase inhibitor
N(t)RTI nucleoside/nucleotide reverse transcriptase inhibitor
PP per protocol
SAE serious adverse event
SAP statistical analysis plan
Wits RHI Wits Reproductive Health and HIV Institute
WHO World Health Organisation
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 8
Protocol Synopsis
Protocol Number: WRHI052
Title: A randomised, open label switch study comparing darunavir/ ritonavir 400mg/100mg daily with
lopinavir/ ritonavir 800mg/200mg daily, in HIV-positive participants.
Study Phase: Phase 3b
Study Sites: Single-centre, South Africa
Objectives: The primary objective of this study is to assess the non-inferiority of DRV/r 400mg/100mg daily
when compared with LPV/r total dose 800mg/200mg daily, in combination with a nucleoside backbone, as
determined by the proportion of participants on each regimen with undetectable plasma HIV-1 RNA levels (<50
copies/mL) at week 48.
The secondary objective of this study is to assess the tolerability and safety of low dose DRV/r when switching
from LPV/r, over 48 weeks, using standard of care participant symptom report and laboratory measures.
Participant Population: HIV-1 infected male or female participants on a lopinavir-containing ART regimen,
with plasma HIV-1 RNA levels <50 copies/mL, will be considered for enrolment in the study if they meet all of
the inclusion criteria and none of the exclusion criteria.
Inclusion Criteria: Each participant must meet all of the following criteria to be enrolled in this study:
1. Participant is aged ≥18 years
2. Participant weight >40kg
3. Participant is on a LPV/r-containing regimen for at least 6 months with no history of other protease
inhibitors
4. Participant has a plasma HIV-1 RNA level <50 copies/mL in the last 60 days
5. Participant is informed and has the ability to comprehend the full nature and purpose of the study, and
give voluntary written informed consent before inclusion in the study
Exclusion Criteria: Participants meeting any of the following criteria will be excluded from the study:
1. Participants who are taking any antiretrovirals other than nucleoside/nucleotide reverse transcriptase
inhibitors and LPV/r
2. Any prior history of genotype-documented protease inhibitor resistance
3. Participants who are taking rifampicin or any other therapy with major cytochrome P450 interactions,
within the last month
4. Participants who are allergic to sulphonamides
5. Participants who have a current history of drug or alcohol abuse that, in the opinion of the investigator,
may be an impediment to participant adherence to the protocol
6. Female participants who are currently pregnant or breastfeeding
7. Female participants desiring pregnancy during the next year
8. Participants who have a strong likelihood of relocating far enough to make access to the study site
difficult
9. Any condition(s) or laboratory report that, in the opinion of the investigator, might put the participant
at risk, or interfere with the study objectives or the participant’s adherence to study requirements
Study Design
This is an open label, randomised, parallel-group, phase 3b, single-site switch study. The purpose of the study is
to demonstrate non-inferiority of low-dose DRV/r 400/100 mg once daily compared with LPV/r 800/200mg
when administered over 48 weeks in combination with two nucleos(t)ide reverse transcriptase inhibitors in
participants infected with HIV-1. These participants are already virologically suppressed and stable on a
standard second-line regimen. All medications will be provided in an open-label design.
Approximately three hundred male and female participants infected with HIV-1 on standard second-line therapy
with LPV/r, with plasma HIV-1 RNA levels <50 copies/mL, will be randomly assigned in a 1:1 ratio
(approximately 150 participants per treatment group) to Treatment Group 1 (DRV/r + 2 N(t)RTIs) or Treatment
Group 2 (LPV/r + 2 N(t)RTIs).
The study includes screening and enrolment visits, 5 follow-up visits from Week 4 to Week 48, with Week 48
being an end-of-study (EOS) visit.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 9
Screening: Screening will take place between Days –60 and –1, prior to the first study treatment administration.
Within the 60-day period re-screenings may be done to confirm eligibility.
Enrolment: At enrolment participants who meet all inclusion criteria and none of the exclusion criteria will be
enrolled in the study, given a participant number, randomly assigned to either Treatment Group 1 or Treatment
Group 2, and provided with open label study medication. There will be no laboratory assessments at enrolment
if the necessary assessments were completed at the screening visit.
Treatment Period: Participants will return to the site at pre-defined time intervals for clinical assessments and
blood sampling. At all visits, participants will be questioned about concomitant medications and adverse events
(AEs) to assess their wellbeing.
Interim Analysis: A data safety monitoring board (DSMB) will monitor the study in order to ensure that harm
is minimised and benefits maximised for the study subjects: an interim trial data analysis to compare the
efficacy of the two regimens will be performed after 50% of the subjects have been enrolled for more than one
month, or if 10 participants in the darunavir arm fail; the DSMB will issue recommendations concerning trial
continuation. Membership of the DSMB will be completely independent of the study staff.
Stopping rules:
All participants with detectable viral loads (>50 copies/mL) will receive adherence counselling, with a repeat
test at 1 month. If detectable ≥200 copies/mL, a resistance test will be performed, and the participant terminated
from the study. Darunavir toxicity will be managed according to the PI’s discretion, and carefully documented.
Pregnancy will not be a reason for termination on the study, although women who elect to stay in the study on
the DRV arm will have their darunavir dose escalated to 800mg.
End-of-Study Visit/Early withdrawal: An end-of-study visit will occur either at the end of the study (Week
48) or earlier if the participant withdraws from the study. During the end-of-study visit, clinical assessments,
blood sampling, AE and concomitant medication monitoring will be conducted.
Efficacy Assessments: Efficacy will be assessed by the evaluation of plasma HIV-1 RNA (primary measure of
efficacy).
Primary Endpoint: The primary efficacy endpoint will be the proportion of participants with undetectable
plasma HIV-1 RNA levels (<50 copies/mL) at Week 48. Participants who do not have a HIV-1 RNA sample
taken at Week 48 will be considered as not having achieved undetectable plasma HIV-1 RNA levels
(<50 copies/mL) at Week 48.
Secondary Endpoints:
Efficacy
Time to virologic failure (defined as confirmed HIV-1 RNA levels ≥200 copies/mL)
Safety
Change in lipids measured at Baseline, 24, and 48
Change in fasting glucose at Baseline and 48
Creatinine clearance (Cockcroft-Gault formula) at Baseline, 12, 24 and 48
AST/ALT at Baseline, 12, 24 and 48
Safety Assessments: Safety analysis will be performed by presenting data on physical examination, vital sign
measurements, clinical laboratory analyses and monitoring AEs and concomitant medications throughout the
study.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 10
Study Medication, Dosage, and Route of Administration
Treatment Group 1: Darunavir (DRV; 400 mg QD) plus ritonavir (RTV; 100 mg QD) administered in
combination with 2 N(t)RTIs orally over 48weeks
Treatment Group 2: Lopinavir (LPV; total dose 800 mg/day) plus ritonavir (RTV; total dose 200 mg/day)
administered in combination with 2 N(t)RTIs orally over 48 weeks
Sample Size: 300 participants randomly assigned in a 1:1 ratio (approximately 150 participants per treatment
group).
Statistical Methods: We anticipate a low loss to follow-up, of around 10-20%. We intend to randomise 150
participants to each arm, and follow them up over the period of one year. A sample size of 150 participants per
arm (300 total) would provide over 80% power to establish non-inferior efficacy for the DRV/r arm, compared
to the LPV/r arm. This calculation assumes that at least 80% of participants in the LPV/r arm maintain HIV-
RNA suppression at the end of the study. This calculation also assumes an overall 5% significance level (two
one-sided tests). All data, where applicable, will be summarised by treatment group using descriptive statistics.
Analysis Sets
All-Randomised Set: The all-randomised set will consist of all randomised participants, regardless of whether
or not any study treatment dosing was completed. Participants will be analysed according to the treatment they
were randomly assigned to.
Per-Protocol (PP) Set: The PP set will consist of all randomised participants who fully comply with the
inclusion and exclusion criteria, have received at least 80% of all doses of study treatment up to Week 48, and
have an evaluable plasma HIV-1 RNA level assessment at Week 48. Participants will be analysed according to
the treatment they received.
Safety Set: The safety set will consist of all participants who receive at least 1 dose of randomly assigned study
treatments. All safety analyses will be performed using the safety set. Participants will be analysed according to
the treatment they received.
Primary Efficacy Analyses: All efficacy analyses will be performed using the all-randomised and PP sets.
The difference in proportions of participants who achieve the primary endpoint between the 2 treatment groups
will be analysed using the binomial non-inferiority test for difference in proportions variable will also be
tabulated, displaying the proportions of participants with undetectable plasma HIV-1 RNA levels (with 95% CI)
by treatment group, the estimate (with 95% CI) for the difference in proportion between both treatment group
and the corresponding non-inferiority test P value. A 10% non-inferiority margin will be used.
Secondary Efficacy Analyses: No formal assessment of non-inferiority will be performed for any of the
secondary efficacy variables. Time to virologic failure will be analysed using a Cox proportional hazard model
with treatment as a factor. Change from baseline in plasma HIV-1 RNA levels and plasma CD4 levels will be
summarised by treatment group and visit.
Safety Analyses: Treatment emergent AEs will be tabulated by treatment, system organ class, seriousness,
severity, and relationship to treatment. Tabulations will contain the number and percentage of participants with
an event as well as the number of events. All AEs will be listed.
Shift tables (change from baseline value to on-treatment values) based on laboratory normal ranges will be
presented for each laboratory measurement at each assessment time. In addition, laboratory parameters will be
summarised by descriptive statistics.
Change in lipids, fasting glucose, creatinine clearance (Cockcroft-Gault formula), ALT and AST, clinical
laboratory parameters, vital sign measurements, physical examination data, previous and concomitant
treatments will be summarised by treatment group and visit, where relevant.
Date of Protocol: 26 October 2017
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 11
1 Introduction
1.1 Background Information
Significant gains have been made in the last decade in terms of access to antiretroviral
care within developing countries through the support of local governments, international
donors, and agencies. However, as the number of participants on antiretroviral treatment
(ART) rises, there has been increased attention paid to treatment optimisation, whereby
drug dosage and manufacturing, clinical diagnosis and monitoring and health delivery
systems are all interrogated for increased efficiencies. Savings from these efforts can be
applied to treatment programmes, thus enabling more participants to receive life-saving
therapy. As antiretroviral drugs account for substantial cost within country human
immunodeficiency virus (HIV) treatment programmes, reducing costs associated with
individual medications would have a significant impact.
New, simpler, safer, more potent and potentially more cost-effective second line
antiretroviral therapy regimens are needed in South Africa. Some of the current second
line protease inhibitors that are routinely used in South Africa in both the public and
private sector have significant toxicity, limiting the durability of these regimens. There
is strong supportive evidence that darunavir, a protease inhibitor that can be dosed once
daily, with a significantly better side effect profile (better gastrointestinal profile, lower
impact on lipids) and greater resistance barrier compared to other protease inhibitors, can
have the dose halved from current levels. This will decrease the side effect profile further,
as well as reduce the cost of darunavir, as dose of drug is a major cost-driver for generic
manufacturers.
South Africa would hugely benefit from improved second line therapies, as it has the
largest number of people on antiretrovirals in the world. There are moves to improve first
line antiretroviral therapy further, by finding safer replacement drugs or reducing the
dose of currently used medication. However, even with better adherence with these
strategies, there will be a percentage of participants who will fail first line treatment.
Even using a very conservative 2% failure rate annually, this translates into around 10
000 participants transitioning to second line every year. A percentage of these, in turn,
will transition to the newly available South African third line regimens within the state
sector, which are an estimated 800% more expensive. Finding a second line regimen that
is more durable will limit transition to third line, protecting this class of drugs, and
limiting expense.
Decreasing total drug doses of antiretroviral agents, while maintaining efficacy,
represents an untapped possibility for decreasing costs and toxicity, if efficacy can be
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 12
maintained. Manufacturing costs for originator companies comprise only a tiny part of
the price of the drug. However, with the rise of generic manufacturers, as well as
increased licensing by innovator companies to other pharmaceutical companies, the cost
of raw materials to manufacture the drugs (active product ingredient) have become a
more significant component of cost as prices have decreased. Thus, a dose reduction
could have a notable impact on the overall cost of ART.
1.2 Current Therapy
Access to antiretroviral therapy (ART) has expanded rapidly within South Africa, with
over 2.5 million participants initiated on therapy since 2004, with early suggestions of
resultant increase in life expectancy and even decreased incidence1, 2. The state
programme has, since its inception, used the WHO-recommended combination of two
nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse
transcriptase inhibitor (NNRTIs), a combination that demonstrates excellent virological
suppression with good adherence. With the update in WHO and South African National
Department of Health Guidelines in 2014, South Africa has moved towards fixed dose
combinations of 2NRTIs and an NNRTI, with implications for individual participants,
especially concerning adherence, as well as implications at programme level.
However, the combination has a low resistance barrier and poor adherence invariably
results in virological failure. Data on the number of first line failures in South Africa is
still elusive but a study looking at several programmes suggested just over 2% of
participants migrate across to second line annually (a larger percentage are lost to follow-
up)3. There is speculation that this percentage will rise, as programmes get larger and
adherence counselling is spread across more participants4.
The South African programme uses two nucleoside reverse transcriptase inhibitors and a
booster protease inhibitor (PI), LPV/r, as its second line regimen for virological failures
on first line, with boosted atazanavir (ATV) recently becoming available for participants
intolerant to LPV/r5. However, intolerance to boosted protease inhibitors is well
described, and includes gastrointestinal and metabolic concerns. Recently, in response to
a growing number of participants failing second line therapy, third line drugs including
darunavir, raltegravir and etravirine, as well as genotype resistance testing, have been
made available within the South African state programme, and overseen by an expert
committee5.
First line failures are almost always due to adherence problems; current second line
adherence is invariably even more difficult, due to a higher pill burden, twice daily dosing
and greater toxicity7. Provision of a better tolerated second line, with a higher resistance
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 13
barrier and simplified dosing, would be a major advance in the provision of antiretroviral
care, for the accumulating participants on second line8.
1.3 Rationale
Dose finding of many currently licensed antiretrovirals was through identification of the
maximum tolerated dose that resulted in virological suppression, with the pharmaceutical
company’s focus on optimising the chance of success for that individual drug. Thus, dose
reduction was generally driven by toxicity, rather than virological suppression efficacy.
Darunavir is a second generation protease inhibitor, first licensed in 2006 by the Food
and Drug Administration and in South Africa in 2010. As with all protease inhibitors in
current use, it is routinely ‘boosted’ with ritonavir. While some international guidelines
allow for protease inhibitors to be prescribed in first line, WHO and South African
guidelines have reserved this class of drug for participants who virologically fail or
cannot tolerate non-nucleoside reverse transcriptase-based first line regimens9. DRV/r
was regarded as a major advance in developed countries, as it offered a formidable
resistance barrier in groups of participants who had been heavily pre-treated with sub-
optimal regimens, including protease inhibitor-based regimens. The POWER and TITAN
darunavir registration studies examined the outcomes of participants with resistant virus,
many of whom presented with advanced disease, and demonstrated benefit over other
protease inhibitors in terms of efficacy. It is estimated that 11 mutations are required to
develop resistance to DRV/r, far more than the two other commonly used protease
inhibitors, lopinavir and atazanavir10.
Importantly, the dose of darunavir was obtained largely from treatment-experienced
participants with at least one darunavir mutation. Healthy volunteer studies showed no
short-term difference in a 400mg/100mg dose versus a 600mg/200mg dose11. In 2 PK
studies in HIV-positive people, halving the 800mg dose resulted in a 37% AUC reduction,
but all participants retained blood levels above the EC50 range12, 13. The initial dose
ranging treatment studies on DRV/r (POWER 1 and POWER 2) showed that 600/100mg
twice daily was the optimal dose, and this was selected going forward12. However, the
study included 400mg/100mg twice daily and daily arms; participants who had no PI
mutations did as well in these arms as the 600mg/100mg arm15, 16. Subsequent studies,
including the ARTEMIS and ODIN studies, showed no correlation between PK levels
and virological suppression, at different doses17, 18.
Darunavir can be dosed daily, if there are less than three darunavir-specific mutations.
For the South African programme, most participants transition to a twice-daily
zidovudine-containing regimen; this is currently not a substantial gain over the twice a
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 14
day LPV/r combination. However, in future, there is the possibility that darunavir will be
combined with the once-daily dolutegravir, and studies are being designed to see if this
potentially potent, safe and once daily regimen will be an effective alternative to the
current twice-daily second line regimens.
DRV/r has traditionally not been considered as a substitute for the LPV/r or
atazanavir/ritonavir combination, due to its cost, even if it is highly discounted in South
Africa. However, at the CADO-2 meeting, (attended by the principal investigator for this
study), which evaluated potential future directions for drug development, identified that
the dose of this drug may be reduced from the current 800mg daily dose, to potentially
400 mg daily. This, with the Clinton Healthcare (CHAI) projected cost-savings if
volumes are attained, would mean that low dose DRV/r would be slightly cheaper than
conventional protease inhibitor formulations ($200/year, as opposed to $250 for
atazanavir/ritonavir and $300 for LPV/r). Subsequent communication at the end of 2014
with the originator company suggests that further price reductions than these, will be
possible with altered synthetic processes.
If it could be shown that the lower dose DRV/r was as virologically effective as LPV/r,
and had lower toxicity than LPV/r, this would decrease costs significantly, allowing
poorer countries, and potentially even richer countries, to continue use of this drug in
first line regimens. This study aims to demonstrate the non-inferiority of a lower dose of
DRV/r compared to LPV/r over 1 year of therapy, in terms of virological efficacy.
This switch study will be conducted according to International Conference on
Harmonisation (ICH) harmonised tripartite guideline E6(R1): Good Clinical Practice
(GCP) guidelines to support potential future registration of the lower dose of DRV/r by
regulatory agencies and consideration by guideline-forming groups to change policy
recommendations. The efficacy and safety of either DRV/r (400/100 mg once daily [QD])
or LPV/r (total dose per day 800/200 mg) administered in combination with 2 N(t)RTIs
will be evaluated in participants with HIV-1 who are stable and virologically suppressed
on standard of care second line ART over 48 weeks. The route of administration, dose
regimen, and study population have been outlined in consideration of the package inserts
for the commercial products used in this study and the target population currently in
receipt of these medications as the standard of care and in consideration of relevant
regulatory guidance documents.
There are several generic drug manufacturers that have the capability to produce the
lower dose of darunavir. CHAI will assist in securing a quality generic product, including
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 15
negotiating entry into South Africa, in the event of international manufacture. The other
drugs in the regimens are commercially available locally, or will be provided by the local
Department of Health site.
Designed in non-inferiority fashion, this study will enrol approximately 300 participants
for 80% power to detect a 10% non-inferiority margin in the per-protocol (PP) analysis.
Robust safety analyses are included in the study design to enable the detection of adverse
events (AEs) at an early and reversible stage.
1.4 Other Study Medications
Participants will continue to receive the 2 N(t)RTI backbone drugs that they were on at
the time of screening. These will vary according to which N(t)RTI backbone they
received in the failed first line ART regimen. Women who become pregnant on the
darunavir arm and elect to stay in the study will have their darunavir dose escalated to
800mg. Refer to the package inserts of these drugs for further information on the
respective safety profiles.
2 Study Objectives
2.1 Primary Objective
The primary objective of this study is to assess the non-inferiority of DRV/r
400mg/100mg daily when compared with LPV/r total dose 800mg/200mg per day in
combination with a nucleoside backbone, as determined by the proportion of participants
on each regimen with undetectable plasma HIV-1 RNA levels (<50 copies/mL) at week
48.
2.2 Secondary Objective
The secondary objective of this study is to assess the tolerability and safety of low dose
DRV/r when switching from LPV/r, over 48 weeks, in participants infected with HIV-1
who are virologically suppressed and stable on standard second line therapy.
3 Study Design
This is an open label, randomised, parallel-group, phase 3b, single-site switch study. The
study includes a screening period (Days –60 to –1), an enrolment visit (Week 0), and a
48-week treatment period. The study design is displayed in figure 1.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 16
Screening and
Re-screening
Days -60 to -1
Treatment Group 1
DRV/r + 2 N(t)RTIs
Treatment Group 2
LPV/r + 2 N(t)RTIs
Enrolment
(Week 0)
Randomisation
Visit 1
(Week 4)
Visit 2
(Week 12)
Visit 3
(Week 24)
Visit 4
(Week 36)
End of
study visit
(Week 48)
EOS
Figure 1 Study design
Three hundred male and female participants infected with HIV-1 who are on standard of
care second line antiretroviral therapy (ART), with plasma HIV-1 RNA levels <50
copies/mL, will be randomly assigned in a 1:1 ratio (approximately 150 participants per
treatment group) to either Treatment Group 1 (low dose DRV/r + 2 N(t)RTIs) or
Treatment Group 2 (continuing existing LPV/r regimen + 2 N(t)RTIs), as shown in table
1. The randomisation will be electronically generated (using www.randomization.com)
and the site pharmacist will manage a system of manual envelopes. All medications will
be administered in an open label design.
All participants will be assigned a unique participant number by the randomisation
system. After a participant number has been assigned, the number will not be reused even
if the participant withdraws before receiving any study medication.
Table 1 Treatment Regimen
Study Medications Tablet/Capsule Strength Dosage Regimen
Treatment Group 1
DRV/r 400/100 mg Once daily
2 N(t)RTIs Depends on participant’s regimen Once or twice daily
Treatment Group 2
LPV/r 800/200 mg Total dose per day
2 N(t)RTIs Depends on participant’s regimen Once or twice daily
Abbreviations: DRV/r, boosted darunavir; N(t)RTIs, nucleoside/nucleotide reverse transcriptase inhibitors;
LPV/r, boosted lopinavir.
4 Selection of Study Population
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 17
Three hundred participants infected with HIV-1 who are on standard of care second line
antiretroviral therapy (ART), with plasma HIV-1 RNA levels <50 copies/mL, will be
considered for enrolment in the study if they meet all of the inclusion criteria and none
of the exclusion criteria.
Before performing any study procedures, all potential participants will provide written
informed consent, and will sign an informed consent form (ICF). Participants will have
the opportunity to have any questions answered before signing the ICF. The informed
consent process and all questions raised by the participant must be documented. The
study staff will also sign the ICF.
4.1 Inclusion Criteria
Each participant must meet all of the following criteria to be enrolled in this study:
1) Participant is aged ≥18 years
2) Participant weight >40kg
3) Participant is on a LPV/r-containing regimen for more than 6 months with no
history of other protease inhibitors
4) Participant has a plasma HIV-1 RNA level <50 copies/mL within 60 days
5) Participant is informed and has the ability to comprehend the full nature and
purpose of the study, and give voluntary informed written consent before
inclusion in the study
4.2 Exclusion Criteria:
Participants meeting any of the following criteria will be excluded from the study:
1) Participants who are taking any antiretrovirals other than nucleoside/nucleotide
reverse transcriptase inhibitors and LPV/r
2) Any prior history of genotype-documented protease inhibitor resistance
3) Participants who are taking rifampicin or any other therapy with major
cytochrome P450 interactions within last month
4) Participants who are allergic to sulphonamides
5) Participants who have a current history of drug or alcohol abuse that, in the
opinion of the investigator, may be an impediment to participant adherence to
the protocol
6) Female participants who are currently pregnant or breastfeeding
7) Female participants desiring pregnancy during the next year
8) Participants who have a strong likelihood of relocating far enough to make
access to the study site difficult
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 18
9) Any condition(s) or laboratory report that, in the opinion of the investigator,
might put the participant at risk, or interfere with the study objectives or the
participant’s adherence to study requirements
5 Study Procedures
Refer to Schedule of Events (Table 3)
5.1 Screening:
1) Informed consent process
2) Confirm HIV-1 status
3) Demography data
4) Pre-existing medical condition(s)
5) Physical examination, height, weight and vital sign measurements
6) Urine pregnancy test
7) Concomitant medications
8) Clinical laboratory testing:
Full blood count
HIV-1 RNA
CD4 count
Hepatitis B surface antigen test (HBsAg)
Alanine amino transaminase (ALT) and Aspartate aminotransferase (AST)
Creatinine and calculated clearance
Lipid panel
9) Inclusion/exclusion criteria determination
Re-Screening (Days -60 to -1)
During the 60-day screening period, a participant may be re-screened to determine
eligibility. Re-screening will involve retesting of subsequent biological samples,
and/or re-assessment of any inclusion and exclusion criteria that previously failed the
participant.
5.2 Enrolment:
1) Review inclusion/exclusion criteria
2) Review pre-existing medical condition(s)
3) Symptom-led physical examination
4) Weight measurement
5) Blood pressure measurement
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 19
6) Urine pregnancy test
7) Fasting plasma glucose
8) Concomitant medications
9) Clinical laboratory testing as necessary
10) Randomisation
11) Study medications dispensing and patient education
12) Study medication accountability
13) Monitor adverse event
5.3 Follow-up visit procedure:
1) Assess adverse events
2) Urine pregnancy test
3) Physical examination at end of study visit and symptom-led at other visits
4) Weight and blood pressure measurement
5) Concomitant medications
6) Clinical laboratory testing:
Plasma HIV-1 RNA (week 12, 24, 36 and 48)
CD4 count (Week 48)
Haemoglobin (Week 12, 24, 36); Full blood count (Week 48)
Creatinine (Week 12, 24 and 48)
Alanine amino transaminase (ALT) and Aspartate aminotransferase (AST)
(Week 12, 24 and 48)
Lipids (Week 24 and 48)
Glucose (Week 48)
7) Study medications dispensing and patient education
5.4 Efficacy Assessments
Efficacy will be assessed by the evaluation of plasma HIV-1 RNA level. The primary
efficacy endpoint will be the proportion of participants with undetectable plasma HIV-1
RNA levels (<50 copies/mL) at Week 48. Participants who do not have a HIV-1 RNA
sample taken at Week 48 will be considered as not having achieved undetectable plasma
HIV-1 RNA levels (<50 copies/mL) at Week 48.
All participants with detectable HIV-1 RNA (>50 copies/mL) will receive adherence
counselling, with a repeat test at 1 month from the date of counseling. If repeated HIV-1
RNA ≥200 copies/mL, a resistance test will be performed, and the participant terminated
from the study. In instances where HIV-1 RNA copies cannot be amplified, investigator’s
discretion will apply.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 20
5.5 Early withdrawal
Participants are free to withdraw from the study at any time for any reason. If a participant
withdraws from the study early, all procedures for the end-of-study visit should be
conducted. The investigator may also withdraw the participant at any time in the interest
of participant safety or if the study is terminated. The primary reason for withdrawal must
be recorded in the source document.
Participants who fail to return for final assessments will be contacted by the site in an
attempt to have them comply with the protocol. At least 2 attempts (by telephone,
personal visit, or e-mail) will be made before the participant is considered lost to follow-
up. All follow-up attempts (method, date, and time) must be documented in the source
document.
The investigator may withdraw a participant from the study if the participant:
Is in violation of the protocol
Experiences a serious or intolerable AE which interferes with study procedures
Has laboratory safety assessments that reveal clinically significant changes from
the baseline values
Experiences virological failure
Requires a medication that is prohibited by the protocol
Consent is withdrawn or the participant refuses to continue participation and/or
procedures/observations
A participant can also be withdrawn at the discretion of the investigator.
5.6 Replacements
Participants who discontinue participation in the study for any reason after randomisation
will not be replaced.
6 Safety Assessments
Safety evaluations will include the monitoring of AEs and concomitant medications,
clinical laboratory assessments, physical examinations, vital sign measurements, and
evaluation of changes in lipids, fasting glucose, ALT, AST and creatinine clearance.
Safety issues will be discussed in detail among study doctors and with the participant
before taking any decisions.
6.1 Adverse Events
An AE is defined as any untoward medical occurrence in a participant in a clinical
investigation with a medicinal product regardless of its causal relationship to study
medication. Participants will be instructed to contact the principal investigator or
designee at any time after randomisation if any symptoms develop.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 21
A treatment-emergent AE is defined as any event, including laboratory abnormalities, not
present before exposure to study medication or any event already present that worsens in
either intensity or frequency after exposure to study medication.
An AE is also any of the following occurring after study randomisation:
Complications that occur as a result of a protocol-mandated procedure after
randomisation to study medications
Any pre-existing condition that increases in severity or changes in nature during
or as a consequence of the study after randomisation to study medications
Reasons for and complications arising from a termination of pregnancy due to
medical and/or surgical reasons
An AE does not include the following:
Medical or surgical procedures performed. However, the condition that leads to
the procedure is an AE
Pre-existing diseases or conditions or laboratory abnormalities present or
detected before screening visit that do not get worse
Situations where an untoward medical occurrence has not occurred (e.g.
hospitalisation for elective surgery)
Overdose without clinical sequelae
Uncomplicated pregnancy
An induced elective abortion to terminate a pregnancy without medical reason
Adverse events will be assessed (reported and/or observed) and documented from
enrolment once the participant is randomised to study medications, until exit from the
study (i.e. early withdrawal or end-of-study visit at week 48). Any medical conditions
observed at screening and which do not exclude the participant from the study will be
documented as pre-existing medical conditions. All AEs will be followed to adequate
resolution. Any ongoing AE at early withdrawal or the end-of-study visit will be further
followed until satisfactory resolution or until the investigator deems the event to be
chronic or the participant to be stable, up to a maximum of 30 days after the last visit.
AEs will be documented in chart notes and those of grade 3 and 4 and unexpected ADR
will be entered into the AE CRF.
6.2 Serious Adverse Events
An SAE is defined as any AE that:
Results in death
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 22
Is immediately life threatening (includes events which put participants at risk of
death at the time of the event but not events which may have caused participant
death if more severe)
Requires in-patient hospitalisation or prolongation of existing hospitalisation
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Of clinical significance in the opinion of the investigator
Any SAE must be documented in an SAE CRF. All SAEs and unexpected ADRs will be
reported to the Wits RHI Safety Committee (WSC), by email, within 24 hours from the
time site personnel first learn of the event.
6.3 Assessment of AEs
The severity or intensity of an AE refers to the extent to which an AE affects the
participant’s daily activities. The severity of all AEs, including laboratory
abnormalities, will be graded according to the Division of AIDS grading table (version
2.0, November 2014).
The relationship or association of the study medication in causing or contributing to the
AE will be characterised using the following classification and criteria:
Unrelated: This relationship suggests that there is no association between the study
medication and the reported event.
Related: This relationship suggests that a definite causal relationship exists between drug
administration and the AE, and other conditions (concurrent illness,
progression/expression of disease state, or concurrent medication reaction) do
not appear to explain the event.
All SAEs that occur during the study (regardless of relationship to study medication)
must be reported in detail and followed until the events resolve, stabilise, or become
nonserious. All SAEs will be reported to HREC according to HREC requirements.
Medical and scientific judgement should be exercised in deciding whether an AE, which
does not meet the routine definition of an SAE but is important from a safety perspective
and may jeopardise the participant or require intervention to prevent one of the other
outcomes listed in the definition of serious, should be considered as serious.
6.5 Management of Pregnancy
A urine pregnancy test will be performed in all female participants of childbearing
potential at every visit from screening to the end-of-study (Week 48)/early withdrawal
visit, and as required during the study according to local standard practice for clinical
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 23
care or according to the investigator’s discretion, where pregnancy may be suspected.
All pregnant women will be followed until post-partum, and children will be followed to
6 months; these follow-ups can only be done during study lifecycle. . If a woman
becomes pregnant during the study and consents to further participation, they may elect
to remain in the study. Women on darunavir will have their DRV dose doubled for the
duration of the pregnancy. Any women who become pregnant during the study will be
fully counselled on the risks. Both darunavir and lopinavir are assigned to pregnancy
category C by the US Food and Drug Administration, which indicates that risk cannot be
ruled out. Nonclinical studies do not indicate direct or indirect harmful effects with
respect to pregnancy but no well-controlled studies have been performed in pregnant
women.
6.6 Physical Examination and Vital Sign Measurements
A physical examination will be performed at screening, and where clinically indicated
thereafter. Height and weight will be recorded at the screening visit and weight will be
measured at all clinic visits from baseline to the end-of-treatment (Week 48)/early
withdrawal visits, inclusive.
Vital sign measurements (temperature, pulse rate, systolic and diastolic blood pressure)
will be collected at screening. At all other study visits only blood pressure will be
measured and other vital signs only if indicated.
7 Study Treatments
All study medications (Table 2) are to be orally self-administered as directed according
to the package insert. Open label study medication will be supplied to the participant at
enrolment and Week 4 - 36. All medications used in this study will be provided as open-
label medications. Participants will be instructed to bring all used and unused study
medication bottles with them to each study visit.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 24
Table 2 Study Medication Supplies
Product Formulation Manufacturer
Darunavir 400 mg tablets Hetero Drugs Ltd, India
Ritonavir 100 mg tablets Hetero Drugs Ltd, India
Lopinavir/ritonavir
(FDC) 400/100 mg tablets Abbott Laboratories/Abbvie
N(t)RTIs Depends on participant’s
regimen
Depends on participant’s
regimen
Abbreviations: FDC, fixed dose combination; N(t)RTIs, nucleoside/nucleotide reverse
transcriptase inhibitors
Darunavir
Darunavir tablets will be manufactured and supplied by Hetero Drugs Limited, India.
Each tablet contains darunavir ethanolate equivalent to 400mg of darunavir. The tablet
is an orange, oval shaped, bevel edged, biconvex, film coated tablet de-bossed with “H”
on one side and “189” on the reverse side. The tablets will be stored at 25°C (77°F); with
excursions permitted to 15°-30°C (59°-86°F).
Ritonavir
Ritonavir tablets will be manufactured and supplied by Hetero Drugs Limited, India.
Each tablet contains 100mg of ritonavir. Ritonavir will be supplied as white to off white,
capsule shaped, film coated tablets debossed with H on one side and R9 on other side.
The medication will be stored at 25°C (77°F); with excursions permitted to 15°-30°C
(59°-86°F).
Lopinavir/ritonavir
Lopinavir/ritonavir tablets are a co-formulation of 200mg lopinavir and 50mg ritonavir
as a film-coated tablet. The medication is packed in a white plastic bottle of 112 tablets,
and will be stored at room temperature (below 30 0C).
N(t)RTIs
Consult package insert of appropriate drug.
All study medications will be stored per manufacturer’s specifications in the package
insert.
7.1 Medication Supplies
The study site will acquire study medication from commercial suppliers. All study
medications will be administered in an unblinded fashion and supplied as commercial
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 25
drug, over-labelled for clinical trial use in accordance with local regulatory requirements.
At the site, all study medications must be kept in a secure cabinet or room with access
restricted to only necessary study site personnel. Storage instructions for site personnel
and participants will be provided on the label. Study medication labels will contain
information to meet the applicable regulatory requirements.
7.2 Study Medication Accountability
The investigator will maintain accurate records of receipt of all study medications,
including dates of receipt. In addition, accurate records will be kept regarding when and
how much study medication is dispensed and used by each participant in the study. At
the completion of the study, to satisfy regulatory requirements regarding drug
accountability, all study medications will be reconciled and retained or destroyed
according to applicable regulations. Participant compliance will be evaluated through
review of drug dispensing and administration records.
7.3 Prior, Concomitant and Subsequent Therapy
Protease inhibitors are known to have varying effects on cytochrome P450 (CYP)3A,
with the major effect being inhibition. Co-administration of PIs with drugs primarily
metabolised by these isozymes may result in altered plasma concentrations of the co-
administered drug and of the PI, and interactions may be hard to predict. Therefore,
appropriate dose adjustments may be necessary for these drugs. Drugs that induce
CYP3A activity (e.g. phenobarbital, rifampicin, rifabutin) would be expected to increase
the clearance of PIs resulting in lowered plasma concentrations.
Any drugs with significant interactions with cytochrome P450 enzymes will be
discouraged, or used as an exclusion criterion. Use of all concomitant medications will
be recorded in the participant’s CRF. This will include all prescription drugs, herbal
products, vitamins, minerals, and over-the-counter medications.
7.4 Process for Antiretroviral Switch
In certain cases, including but not limited to drug toxicity and/or pregnancy, substitution
of NRTIs with an alternate antiretroviral per standard of care is permissible at the
investigator’s discretion.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 26
7.5 Post-trial access to darunavir 400mg
Darunavir/ritonavir 400mg/100mg will be provided to study participants if not available
in the public sector. Post-trial access will be limited to patients who were randomised and
received this study drug up to the end-of-study visit (week 48). In the event that
darunavir/ritonavir 400mg/100mg is not available, darunavir/ritonavir 600mg/100mg
once daily will be provided as post-trial access in the interim until the usual stock of
darunavir/ritonavir 400mg/100mg becomes available at the study site or government
provision of darunavir has commenced in the public sector. Post-trial access will be
conducted according to Table 4, section 11 of this protocol.
8 Statistical Analysis Plans
8.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of participants with undetectable plasma
HIV-1 RNA levels (<50 copies/mL) at Week 48. Participants who do not have a HIV-1
RNA sample taken at Week 48 will be considered as not having achieved undetectable
plasma HIV-1 RNA levels (<50 copies/mL) at Week 48.
8.2 Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:
Time to virologic failure (defined as confirmed HIV-1 RNA levels ≥200
copies/mL at any visit)
Change from baseline in plasma HIV-1 RNA levels by visit
8.3 Safety Endpoints
The primary safety endpoint is the assessment of the tolerability and safety of low dose
DRV/r as measured by the nature and frequency of AEs and changes in vital sign
measurements, physical examination findings, and clinical laboratory analyses.
Secondary safety endpoints are as follows:
Change in lipids measured at Baseline, 24 and 48
Fasting glucose at Baseline and 48
Creatinine clearance (Cockcroft-Gault formula) at Baseline, 12, 24, 36 and 48
8.4 Sample Size Calculations
A total of 300 male and female participants infected with HIV-1 who are virologically
suppressed and stable on a standard of care second line regimen will be randomised in a
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 27
1:1 ratio (150 participants per treatment group) to Treatment Group 1 (DRV/r + 2
N(t)RTIs) or Treatment Group 2 (LPVV/r + 2 N(t)RTIs). Participants are stable on
treatment. We anticipate a low loss to follow-up, of around 10-20%. We intend to
randomise 150 participants to each arm, over a year period, and follow them over a year.
A sample size of 150 participants per arm (300 total) would provide over 80% power to
establish non-inferior efficacy for the DRV/r arm, compared to the LPV/r arm. This
calculation assumes that at least 80% of participants in the LPV/r arm maintain HIV RNA
suppression at the end of the study. This calculation also assumes an overall 5%
significance level (two one-sided tests). All data, where applicable, will be summarised
by treatment group using descriptive statistics.
8.5 Analysis Sets
The following analysis sets will be used in the statistical analyses:
All-randomised set: The all-randomised set will consist of all randomised participants,
regardless of whether or not any study treatment dosing was completed. Participants will
be analysed according to the treatment they were randomly assigned to.
Per-protocol set: The PP set will consist of all randomised participants who fully comply
with the inclusion and exclusion criteria, have received at least 80% of all doses of study
treatment up to Week 48, and have an evaluable plasma HIV-1 RNA level assessment at
Week 48. Criteria will be defined in more detail in the statistical analysis plan (SAP).
Participants will be analysed according to the treatment they received.
Safety set: The safety set will consist of all participants who receive at least 1 dose of
randomly assigned study treatments. All safety analyses will be performed using the
safety set. Participants will be analysed according to the treatment they received.
All efficacy analyses will be performed using the all-randomised and PP sets. All safety
analyses will be performed using the safety set.
8.6 Statistical Analysis
Where applicable, the calculation also assumes an overall 5% significance level (two
one-sided tests). All data, where applicable, will be summarised by treatment group using
descriptive statistics. Continuous variables will be summarised by number of participants,
the mean, standard deviation, the median, the minimum value, and the maximum value.
Categorical variables will be summarised using frequency counts and percentages. All
data collected will be listed. Baseline will be defined as the last measurement before first
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 28
intake of randomised study treatment. Further details on the statistical analysis
methodology will be provided in the SAP.
Missing data for the primary efficacy endpoint will be handled as per Section 0.
Sensitivity analyses will be performed to assess the impact of missing data on the
interpretation of the results, and further details will be provided in the SAP.
8.7 Primary Efficacy Analysis
The primary endpoint is the proportion of participants with undetectable plasma HIV-1
RNA levels (<50 copies/mL) at Week 48.
The difference in proportions of participants who achieve the primary endpoint between
the 2 treatment groups will be analysed. This variable will also be tabulated, displaying
the proportions of participants with undetectable plasma HIV-1 RNA levels (with 95%
CI) by treatment group, the estimate (with 95% CI) for the difference in proportion
between both treatment groups, and the corresponding non-inferiority test P value.
This non-inferiority study has been powered based on a non-inferiority margin of 10%.
This is the lowest, most conservative difference that has been found most useful when
comparing 1 component of a 3-drug regimen in treatment-naive individuals. The actively
compared treatments in this study are low-dose DRV/r and LPV/r. Assessing the
outcome of the trial using the 10% non-inferiority margin will determine if low-dose
DRV/r is, at worse, 10% below that of standard doses of LPV/r with regards to plasma
HIV-1 RNA levels at Week 48.
The consistency of the treatment effect across subgroups will be investigated. All efficacy
analyses will be performed using the all-randomised and PP sets.
8.9 Safety Analyses
Treatment-emergent AEs will be tabulated by treatment, system organ class, preferred
term, seriousness, severity, and relationship to treatment. Tabulations will contain the
number and percentage of participants with an event as well as the number of events. All
AEs will be listed.
Shift tables (change from baseline value to on-treatment values) based on laboratory
normal ranges will be presented for each laboratory measurement at each assessment
time. In addition, laboratory parameters will be summarised by descriptive statistics.
Change in lipids, fasting glucose and creatinine clearance (Cockcroft-Gault formula),
clinical laboratory parameters, vital sign measurements, physical examination data,
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 29
previous and concomitant treatments, and medical history will be summarised by
treatment group and visit, where relevant.
8.10 Interim Analyses
A data safety monitoring board (DSMB) will monitor the study in order to ensure that
harm is minimised and benefits maximised for the study subjects. Membership of the
DSMB will be completely independent of the study staff.
An interim trial data analysis to compare the efficacy of the two regimens will be
performed after 50% of the subjects have been enrolled for more than one month, or if
10 participants in the darunavir arm fail; the DSMB will issue recommendations
concerning trial continuation.
Stopping rules:
All participants with detectable viral loads will receive adherence counselling, with a
repeat test at 1 month. If persistently detectable above 200 copies/mL, a resistance test
will be performed, and the participant terminated from the study. Darunavir toxicity will
be managed according to the PI’s discretion, and carefully documented. Pregnancy will
not be a reason for termination on the study. No formal stopping rules will be used by the
DSMB for safety outcomes. The DSMB will provide an independent clinical assessment
to determine if lack of efficacy on low dose DRV/r warrants the early termination of the
study in the best interest of the participants.
9 Data Management
At every visit, participants’ information will be recorded in source documents including
chart notes and laboratory test results. Data from CRFs and other data sources will be
entered into an electronic database as specified in the data management SOP. Quality
control and data validation procedures will be applied to ensure the validity and accuracy
of the data. The electronic database will be designed in REDCap (REDCap Software -
Version 6.2.5 - © 2015 Vanderbilt University).
Each person involved with the study will have an individual logon and password that
allows for record traceability. Thus, the system, and subsequently any investigative
reviews, can identify coordinators, investigators, and individuals who have entered or
modified records.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 30
10 Other study Activities
10.1 Confidentiality
All laboratory specimens, evaluation forms, reports, and other records will be identified
in a manner designed to maintain participant confidentiality. All records will be kept in a
secure storage area with limited access. Clinical information will not be released without
the written permission of the participant, except as necessary for monitoring and auditing
by the regulatory authorities or the HREC.
The principal investigator or designee and all employees and co-workers involved with
this study may not disclose or use for any purpose other than performance of the study,
any data, record, or other unpublished confidential information disclosed to those
individuals for the purpose of the study. All computers are password-protected and
records can only be accessed by permitted study staff.
10.2 Reporting
The protocol and relevant supporting documents must be submitted to the Medicine
Control Council (MCC) and HREC for approval. The study protocol will be registered
with the South African National Clinical Trial Registry (www.sanctr.gov.za)/ National
Human Research Ethics Committee (www.ethicsapp.co.za) and the ClinicalTrial.gov.
Six monthly progress reports will be submitted to MCC and HREC for the duration of
the study. Annual recertification will be obtained from HREC. Upon completion or
premature termination of the study, the investigator will provide HREC with a summary
of the study’s outcome, and the regulatory authorities with any reports required.
10.3 Investigator Documentation
Prior to beginning the study, the principal investigator will be asked to comply with ICH
E6(R1) 8.2 by providing the following essential documents, including but not limited to:
An original investigator-signed investigator agreement page of the protocol
An HREC-approved ICF, samples of site advertisements for recruitment for this
study, and any other written information regarding this study that is to be provided
to the participants
HREC approval
Curriculum vitae for the principal investigator and each investigator. Current
licensure must be noted on the curriculum vitae. They will be signed and dated
by each investigator at study start-up, indicating that they are accurate and current
Laboratory certifications and normal ranges for any local laboratories used by the
site
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 31
10.4 Monitoring of the Study
The study monitor has the obligation to follow the study closely. In doing so, the monitor
will visit the study facility at periodic intervals, in addition to maintaining necessary
telephone and email contact. The monitor will maintain current personal knowledge of
the study through observation, review of study records and source documentation, and
discussion of the conduct of the study with the principal investigator and study staff. All
aspects of the study will be carefully monitored for compliance with applicable
government regulation with respect to current ICH GCP guidelines and current standard
operating procedures.
10.5 Protocol Amendments
Amendments to the protocol must be submitted in writing to the MCC and HREC for
approval before participants are enrolled into an amended protocol, except where it is
necessary to eliminate an immediate hazard to participants or where the changes involve
only logistical or administrative aspects of the clinical study. This should be fully
documented.
10.6 Protocol Violations and Deviations
The principal investigator or designee must document and explain in the participant’s
source documentation any deviation from the approved protocol. The principal
investigator or designee may implement a deviation from, or a change of, the protocol to
eliminate an immediate hazard to trial participants without prior HREC approval. As
soon as possible after such an occurrence, the implemented deviation or change, the
reasons for it, and any proposed protocol amendments should be submitted to the HREC
for review and approval and to the regulatory authorities, if required.
A deviation from the protocol is an unintended or unanticipated departure from the
procedures or processes approved by the HREC and agreed to by the principal
investigator or designee. Deviations usually have an impact on individual participants or
a small group of participants and do not involve inclusion, exclusion or primary endpoint
criteria. A protocol violation occurs when there is nonadherence to the protocol that
results in a significant, additional risk to the participant, when the participant or principal
investigator or designee has failed to adhere to significant protocol requirements
(inclusion and exclusion criteria) and the participant was enrolled without prior approval,
or when there is nonadherence to regulations or some ICH GCP guidelines. Protocol
violations and deviations will be documented by the clinical monitor throughout the
course of monitoring visits. Principal investigators or designees will be notified in
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 32
writing by the monitor of violations and deviations. The HREC should be notified of all
protocol violations and deviations in a timely manner.
10.7 Inspection of Records
Principal investigators or designee and institutions involved in the study will permit trial-
related monitoring, audits, HREC review, and regulatory inspections by providing direct
access to all study records.
10.8 Records Retention
All correspondence (e.g. with HREC, or MCC) relating to this clinical study should be
kept in appropriate study folders. Records of participants, source documents, CRFs, and
drug inventory sheet pertaining to the study must be kept on file. Essential documents
should 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. These documents should be retained
for a longer period, if required by the applicable regulatory requirements. If an
investigator moves, withdraws from an investigation, or retires, the responsibility for
maintaining the records may be transferred to another person, who is willing to accept
the responsibility.
10.9 Study Termination
Although Wits RHI has every intention of completing the study, Wits RHI reserves the
right to discontinue the study at any time for clinical or administrative reasons. The end
of the study is defined as the date on which the last participant completes the last visit.
10.10 Publications
After completion of the study, the data may be considered for reporting at a scientific
meeting or for publication in a scientific journal. In these cases, the investigator will be
responsible for these activities and will determine how the manuscript is written and
edited, the number and order of authors, the publication(s) to which it will be submitted,
and other related issues according to the Wits RHI publication guidelines.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 33
11 Appendix: Schedule of Events
Table 3 Schedule of Events
Study Visit Baseline
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5
/EOS Screening Enrolment
Study Week – 0 4 12 24 36 48
Study Day/Window –60 to –1 0 15-42 71–98 155–182 239–266 323–350
Informed consent X
Demography X
Medical history/pre-existing conditions X X
Urine pregnancy testing X X X X X X X
Physical examination1 X X X X X X X
Height measurement X
Weight measurement X X X X X X X
Vital sign measurements2 (BP, Temp, Res rate, Pulse) X X X X X X X
Hepatitis B antigen X
Creatinine clearance (Cockcroft-Gault formula) X X X X
Haemoglobin X X X
FBC X X
CD4 cell count X X
HIV ELISA (optional) X
Plasma HIV-1 RNA X X X X X
Fasting plasma glucose X X
Lipid panel X X X
AST/ALT X X X X
Previous/concomitant medications X X X X X X X
Inclusion/exclusion criteria X X
Randomisation X
Study medications dispensed X X X X X
Study treatment/medication accountability X X X X X X
Adverse event monitoring X X X X X X
1. Physical examination must be done at screening and EOS visit, but symptom-led at other visits.
2. Only blood pressure will be measured at visits: Baseline, 1, 2, 3 and 4; other vitals will be done only if indicated.
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 34
Table 4 Schedule of Post-Trial Access
1 Quantity of medication dispensed is at pharmacist’s discretion
Study Visit Visit 6 Visit 7 Visit 8 Visit 9 Visit 10
Study Month 6 12 18 24 36
Study Month/Window ±2 weeks ±2 weeks ±2 weeks ±2 weeks ±2 weeks
Urine pregnancy testing X X X X X
Physical examination X X X X X
Weight measurement X X X X X
Vital sign measurements (BP, Temp, Res rate, Pulse) X X X X X
Creatinine clearance (Cockcroft-Gault formula) X X X X X
FBC (including Hg) X X X X X
CD4 cell count X X X X X
Plasma HIV-1 RNA X X X X X
Fasting plasma glucose X X X X X
Lipid panel X X X X X
AST/ALT X X X X X
Previous/concomitant medications X X X X X
Study medications dispensedi X X X X X
Study treatment/medication accountability X X X X X
Adverse event monitoring X X X X X
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 35
12 Reference List
1. Pillay Y. Treatment 2013 – Current Issues and Future Directions, 7th IAS
Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013), Kuala
Lumpur, Malaysia, June 2013, http://pag.ias2013.org/session.aspx?s=63, accessed
20 August 2013
2. Tanser F, Bärnighausen T, Grapsa E, Zaidi J, Newell ML. High coverage of ART
associated with decline in risk of HIV acquisition in rural KwaZulu-Natal, South
Africa. Science. 2013 Feb 22;339(6122):966-71. doi: 10.1126/science.1228160
3. ART-LINC of IeDEA Study Group, Keiser O, Tweya H, Boulle A, Braitstein P,
Schecter M, Brinkhof MW, Dabis F, Tuboi S, Sprinz E, Pujades-Rodriguez M,
Calmy A, Kumarasamy N, Nash D, Jahn A, MacPhail P, Lüthy R, Wood R, Egger
M. Switching to second-line antiretroviral therapy in resource-limited settings:
comparison of programmes with and without viral load monitoring., AIDS. 2009
Sep 10;23(14):1867-74. doi: 10.1097/QAD.0b013e32832e05b2.
4. Boulle A, Van Cutsem G, Hilderbrand K, Cragg C, Abrahams M, Mathee S, Ford
N, Knight L, Osler M, Myers J, Goemaere E, Coetzee D, Maartens G. Seven-year
experience of a primary care antiretroviral treatment programme in Khayelitsha,
South Africa, AIDS. 2010 Feb 20;24(4):563-72. doi:
10.1097/QAD.0b013e328333bfb7
5. South African Department of Health 2013 Antiretroviral Guidelines
6. Southern African HIV Clinicians Society 2012 Guidelines for antiretroviral
resistance
7. 2013 Second Conference on Antiretroviral Drug Optimization Meeting Report,
http://hivtreatmentoptimization.org/sites/default/files/documents/2010-
11/cado2meetingreportfinaljuly2013.pdf
8. South African Department of Health 2013 Antiretroviral Guidelines
9. Robertson J, Feinberg J. Darunavir : a nonpeptidic protease inhibitor for
antiretroviral-naive and treatment-experienced adults with HIV infection, Expert
Opin Pharmacother. 2012 Jun;13(9):1363-75. doi: 10.1517/14656566.2012.681776
10. Hoetelmans R, Van der Sandt I, De Pauw M, et al. TMC114, a next generation HIV
protease inhibitor: pharmacokinetics and safety following oral administration of
Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017
Page 36
multiple doses with and without low doses of ritonavir in healthy volunteers. 10th
Conference on Retroviruses and Opportunistic Infections, Boston, USA, February
10–14 2003. Abstract and poster 549
11. Arasteh K, Clumeck N, Pozniak A, et al. First clinical results on antiretroviral
activity, pharmacokinetics, and safety of TMC114, an HIV-1 protease inhibitor, in
multiple PI experienced participants. 10th Conference on Retroviruses and
Opportunistic Infections, Boston, USA, February 10–14 2003. Abstract 8.
12. Sekar V, De Meyer S, Vangeneugden T et al. Pharmacokinetic/pharmacodynamic
(PK/PD) analyses of TMC114 in the POWER 1 and POWER 2 trials in treatment-
experienced HIV-infected participants. 13th Conference on Retroviruses and
Opportunistic Infections, Denver, USA, February 2006 [Abstr J-121]
13. Katlama C, Esposito R, Gatell JM, et al. Efficacy and safety of TMC114/ritonavir
in treatment-experienced HIV participants: 24-week results of POWER 1. AIDS.
2007;21:395–402.
14. Haubrich R, Berger D, Chiliade P, et al. Week 24 efficacy and safety of
TMC114/ritonavir in treatment-experienced HIV participants. AIDS. 2007;21:F11–
F18.
15. Sekar V, De La Rosa G, de Castele T et al. Pharmacokinetic (PK) and
pharmacodynamic (PD) analyses of once- and twice-daily DRV/r in the ODIN
Trial. J Int AIDS Society 2010, Vol 13 (Suppl 4): p 98 [abstr P185]
16. Sekar V, Vanden Abeele C, Van Baelen B, Vis P, Lavreys L, De Pauw M.
Pharmacokinetic-pharmacodynamic analyses of once-daily darunavir-ritonavir in
the ARTEMIS study. 15th Conference on Retroviruses and Opportunistic
Infections, Boston, MA, USA, February 3–6 2008. Abstract 769