Clinical trial NCT05349838
Conditions: HIV-1-infection
Sponsor: NEAT ID Foundation
Start date: 2018-11-05; Completion date: 2022-11-09
Enrollment: 140 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
HIV-1 infected subjects that experience virological failure while on non nucleoside reverse-transcriptase inhibitors (NNRTIs), including those with the K103N mutation, are usually switched to a boosted Protease Inhibitor (PI)-based regimen or other antiretroviral (ARV) combinations. The same is true for subjects who need to start antiretroviral therapy and have acquired virus that is already resistant to antiretrovirals. These "second line" combinations are often associated with numerous issues that can have a potential impact on the quality of life (QoL) of these patients. Therefore a simpler and better tolerated alternative second line treatment option would be a useful tool for the clinical management of these patients.

The aim of this study is to assess the efficacy and tolerability of a dual combined therapy of Dolutegravir (DTG) 50 mg Once Daily (OD) + Rilpivirine (RPV) 25 mg OD in virologically suppressed participants with previous virological failure with NNRTIs and having the clinically significant mutation K103N. The secondary objective of the study is to assess whether a simplification of the treatment in terms of pill burden, long term metabolic toxicity and potential for drug interactions improves the QOL of the participants. The study will also evaluate DTG \& RPV concentrations in the blood plus changes in cell associated virus.

In order to compare the first line treatment (boosted PI and/or other antiretroviral combinations) and the DTG+RPV combination, two thirds of study participants will be switched to DTG+RPV immediately and receive DTG+RPV for 96 weeks. The other third will be switched after 48 weeks of continuing on their first line treatment and receive DTG+RPV for 48 weeks. All participants will then be followed up for a further 30 days. Participants will be recruited from sites across Europe, and randomised onto either arm of the study. After randomisation, participants will attend approximately 10 visits over the course of two years.

Detailed description:

Arms: arm 1: One combined Dolutegravir 50mg /Rilpivirine 25mg FDC tablet taken orally once daily arm 2: Patients will continue the current boosted PI regimen (or other antiretroviral combination) for 48 weeks. Patients will then be switched to one combined Dolutegravir/Rilpivirine FDC tablet taken orally once daily for 48 weeks.
Interventions: intervention 1: Dolutegravir & Rilpivirine 2 drug fixed dose combined therapy
Intervention descriptions: intervention 1: Daily oral tablet

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan
WISARD
 
  
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title:
An open-label, multi-centre, randomised, switch study to 
evaluate the virological efficacy over 96 weeks of 2-drug 
therapy with DTG/RPV FDC in antiretroviral treatment- 
experienced HIV-1 infected subjects virologically suppressed 
with NNRTIs resistance mutation K103N 
SHORT 
TITLE/ACRONYM 
WISARD: 
SPONSOR NUMBER
SSCR105/NEAT33 
CLINICAL PHASE 
3b 
EUDRACT NUMBER
2017-004040-38 
SAP VERSION 
1.0 
SAP VERSION DATE 
10.12.2020 
 
 
Prepared by Study Analyst: 
 
Name: Lambert ASSOUMOU 
 
Date:  
 
Signature: 
 
 
DOCUMENT HISTORY 
Document version 
number 
Date 
Reason for change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
TABLE OF CONTENTS 
 
1. 
ABBREVIATIONS AND DEFINITIONS .................................................................................................................. 4 
2. 
INTRODUCTION ................................................................................................................................................ 6 
2.1 
PREFACE ............................................................................................................................................................ 6 
2.2 
PURPOSE OF THE ANALYSES ................................................................................................................................... 6 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................................ 6 
3.1 
STUDY OBJECTIVES .............................................................................................................................................. 6 
3.2 
STUDY ENDPOINTS ............................................................................................................................................... 7 
3.3 
DERIVED VARIABLES ........................................................................................................................................... 11 
4. 
STUDY METHODS ........................................................................................................................................... 12 
4.1 
GENERAL STUDY DESIGN AND PLAN ...................................................................................................................... 12 
4.2 
RANDOMISATION SCHEME AND BLINDING .............................................................................................................. 13 
4.2.1 
Randomisation scheme ............................................................................................................................ 13 
4.2.2 
Blinding .................................................................................................................................................... 13 
4.3 
STUDY VARIABLES ............................................................................................................................................. 13 
5. 
SAMPLE SIZE CALCULATION ............................................................................................................................ 17 
6. 
GENERAL CONSIDERATIONS ........................................................................................................................... 19 
6.1 
TIMING OF ANALYSES ......................................................................................................................................... 19 
6.2 
TIMING OF OUTCOME ASSESSMENTS ..................................................................................................................... 19 
6.3 
ANALYSIS POPULATIONS ..................................................................................................................................... 20 
6.3.1 
Full Analysis Population ........................................................................................................................... 20 
6.3.2 
Per-Protocol Population ........................................................................................................................... 20 
6.3.3 
Switch Included Population ...................................................................................................................... 20 
6.3.4 
Safety Population ..................................................................................................................................... 20 
6.4 
COVARIATES AND SUBGROUPS ............................................................................................................................. 20 
6.4.1 
Subgroup analysis .................................................................................................................................... 20 
6.4.2 
Adjusted analysis ..................................................................................................................................... 20 
6.5 
MISSING DATA .................................................................................................................................................. 21 
6.6 
INTERIM ANALYSIS ............................................................................................................................................. 21 
6.7 
MULTI-CENTRE STUDIES ..................................................................................................................................... 22 
6.8 
MULTIPLE TESTING ............................................................................................................................................ 22 
7. 
SUMMARY OF STUDY DATA ........................................................................................................................... 22 
7.1 
SUBJECT DISPOSITION ........................................................................................................................................ 22 
7.2 
PROTOCOL DEVIATIONS ...................................................................................................................................... 23 
7.3 
DEMOGRAPHIC AND BASELINE VARIABLES ............................................................................................................... 24 
7.4 
CONCURRENT ILLNESSES AND MEDICAL CONDITIONS ................................................................................................ 24 
7.5 
PRIOR AND CONCURRENT MEDICATIONS ............................................................................................................... 24 
7.6 
TREATMENT COMPLIANCE ................................................................................................................................... 24 
8. 
EFFICACY ANALYSES ....................................................................................................................................... 25 
8.1 
PRIMARY EFFICACY ANALYSIS ............................................................................................................................... 25 
8.2 
SECONDARY EFFICACY ANALYSES .......................................................................................................................... 25 
8.2.1 
Virological evaluation .............................................................................................................................. 25 
8.2.2 
Immunological evaluation ....................................................................................................................... 27 
9. 
SAFETY ANALYSES: ......................................................................................................................................... 28 
10. 
PHARMACOKINETICS .................................................................................................................................. 29 
11. 
OTHER ANALYSES ....................................................................................................................................... 31 
12. 
REPORTING CONVENTIONS ........................................................................................................................ 33 


Statistical Analysis Plan
WISARD Study Protocol
 
 
13. 
TECHNICAL DETAILS ................................................................................................................................... 33 
14. 
REFERENCES ............................................................................................................................................... 34 
APPENDIX: PITTSBURGH SLEEP QUALITY INDEX (PSQI) ................................................................................... 35 
 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
1. Abbreviations and Definitions 
 
Acronym
Description
ACR
Albumin: Creatinine Ratio 
ACTG 
AIDS Clinical Trial Group 
AE 
Adverse Event 
ALT 
Alanine Amino Transferase 
ART 
Anti Retroviral Therapy 
ARV 
Antiretroviral 
AST 
Aspartate aminotransferase 
CD4 
Cluster of Differentiation 4 
CD8 
Cluster of Differentiation 8 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
DAIDS 
The Division of AIDS 
DDI 
Drug-Drug Interaction 
DTG 
Dolutegravir 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration (United States of America) 
FDC 
Fixed-Dose Combination 
GFR 
Glomerular filtration rate 
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
HIV RNA 
Human Immunodeficiency Virus Ribonucleic Acid 
HS CRP 
High-Sensitivity C-reactive protein 
IMP 
Investigational Medicinal Product 
II 
Integrase Inhibitors 
INSTI 
Integrase Strand Transfer Inhibitor 
ISRCTN 
International Standard Randomised Controlled Trials 
IUD 
Intrauterine Device 
LDL 
Low Density Lipoprotein 
MCH 
Mean Cell Haemoglobin 
MCV 
Mean Cell Volume 
MDRD 
Modified Diet in Renal Disease 
NEAT ID 
The European treatment network for HIV, hepatitis and global infectious 
diseases 
NNRTI 
Nonnucleoside Reverse Transcriptase Inhibitors 


Statistical Analysis Plan
WISARD Study Protocol
 
 
 
NNRTIs 
Non-Nucleoside Reverse Transcriptase Inhibitors 
NRTIs 
Nucleoside Reverse Transcriptase Inhibitors 
NVP 
Nevirapine 
OD 
Overdose 
PBMC 
Peripheral Blood Monoclonal Cell 
PCR 
Protein: Creatinine Ratio 
PI 
Protease Inhibitor 
PIs 
Protease Inhibitors 
PK 
Pharmacokinetics 
QoL 
Quality of Life 
QP 
Qualified Person 
RAL 
Raltegravir 
RBC 
Red Blood Cell 
RNA 
Ribonucleic Acid 
RPV 
Rilpivirine 
SAE 
Serious Adverse Event 
TDR 
Drug Transmitted Resistance 
ULN 
Upper limit of Normal 
VL 
Viral Load 
WBC 
White Blood Cell 
WOCBP 
Women of Child Bearing Potential 


Statistical Analysis Plan
WISARD Study Protocol
 
 
2. Introduction 
 
2.1 
Preface 
 
HIV-1 infected subjects that experience virological failure while on NNRTIs (EFV or NVP) with 
development of K103N mutation (+/- other NNRTIs and/or NRTIs mutations) are usually switched to 
a boosted PI-based regimen or other complex ARV combinations. The same is true for subjects who 
need to start antiretroviral therapy and have acquired virus that is already resistant to antiretrovirals 
numerous issues that can have a potential impact on the quality of life (QoL) of these patients: high 
pill burden, high potential for drug-drug interactions (DDIs), persistent side effects and metabolic 
toxicity. Therefore, a simpler and better tolerated alterative 2nd line treatment option would be a 
useful tool for the clinical management of these patients. Dolutegravir (DTG) is a well-tolerated 2nd 
generation integrase strand transfer inhibitor (INSTI) with a low metabolic impact and low DDI 
potential; rilpivirine (RPV) is a well-tolerated NNRTI not affected by the presence of the K103N 
mutation, characterized by a lower DDI potential and metabolic impact compared to other NNRTIs, 
neither requires a PK boosting agent. 
 
2.2 
Purpose of the analyses 
 
This study will assess the efficacy and safety of switching from a boosted PI regimen to a dual 
combined therapy with DTG 50 mg OD + RPV 25 mg OD or continuing the current ART regimen in 
virologically suppressed patients with previous virological failure with NNRTIs, and having the 
clinically significant mutation K103N. The study will also assess whether a simplification of the 
treatment in term of pill burden, long term metabolic toxicity and potential of drug-drug interaction 
(DDI) improves the quality of life of the participants. 
 
3. Study Objectives and Endpoints 
 
3.1 
Study Objectives 
 
The primary objective of this trial is to compare viral load outcomes on DTG/RPV FDC regimen 
(experimental arm) to continued ART regimen (control arm) at 48 weeks as measured by HIV-1 RNA 
 
 
Secondary objectives are: 


Statistical Analysis Plan
WISARD Study Protocol
 
 
(a) To investigate whether switching patients to DTG/RPV FDC is associated with improvement 
of lipid profile, patient satisfaction, quality of life and potential for drug-drug interactions, 
investigated over time through 96 weeks with evaluation (and comparison to control arm) at 
week 24, 48 and 96. 
(b) To evaluate DTG and RPV trough concentrations 
(c) Changes in cell associated virus (using Peripheral Blood Monoclonal Cell (PBMC) analysis) 
 
3.2 
Study endpoints 
 
3.2.1 
Primary endpoint/outcome 
 
The primary endpoint is the proportion of participants free of therapeutic failure at week 48 (HIV 
RNA <50 copies/mL and no discontinuation). Therapeutic failure is defined as virologic failure or 
discontinuation with HIV RNA <50 copies/mL. Discontinuation is defined by the study follow-up 
stop or any change or modification in the study treatment regimen. 
 
The following procedure will be used to classify the participants. 
1. Virological failure: 
(a) Any patient with HIV 
a second measurement within 2 weeks apart. If the result from the second measurement is <50 
copies/mL, the patient will be categorized as HIV-RNA <50 copies/mL. If the result from the 
 failure. 
 
(b) If a patient has HIV-
one drug from the study treatment combination for any reason, he or she will be categorized as 
virological failure. 
 
(c) If a patient discontinues the study or at least one drug from the study treatment combination at 
a given time point because of lack of efficacy then the patient will be categorized as virological 
failure. 
 
2. Discontinuation (no virological data) 
 
All discontinuations with HIV RNA <50 copies/mL will be considered as no virological data. 
There are three main reasons for no data at analysis time point: 
 
(a) Discontinuation due to Adverse Event (AE) or Death. 
 


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Any patient who discontinues the study or the study treatment with HIV-RNA is < 50 copies/mL 
because of AE or death will be classified as discontinuation due to AE or death at from the date  
of discontinuation. 
 
(b) Discontinuation for Other Reasons. 
 
If a patient discontinues the study follow-up or changes or modifies any drug in the study 
treatment when his or her HIV-1-RNA is <50 copies/mL, he or she will be categorized as 
discontinued for other reasons at from the date of discontinuation. 
 
(c) On study but missing data at analysis time point. 
 
For example, if a participant has no data at analysis time point, but there is an HIV-RNA 
measurement after the analysis time point, this patient will be considered On Study but with 
Missing Data at analysis time point. 
 
3.2.2 
Secondary endpoints/outcomes 
 
Secondary endpoints will include secondary efficacy endpoints, secondary safety endpoints, 
pharmacological endpoints, and secondary endpoints regarding patient related outcomes. 
 
Secondary efficacy endpoints: 
 
(a) Proportion of participants with virological failure (2 consecutive viral loads >50 copies at least 
2 weeks apart or a viral load>50 copies/mL followed by a discontinuation of the study or the 
study treatment), investigated over 96 weeks. 
(b) Incidence of genotypic resistance in case of confirmed HIV RNA>50 copies/mL and baseline 
factors associated with failure i.e. treatment emergent mutations (NRTI, NNRTI, PI and II 
regions) as compared with previous resistance tests. 
(c) Proportion of participants with plasma HIV-1 RNA <50 c/mL at week 24, 48 and 96. 
(d) Proportion of participants with virological suppression (<200 copies/ml HIV RNA) at week 
24, 48, 96 
(e) Changes from baseline in cell associated virus using PBMC Illumina MiSeq sequencing at 
week 48 and week 96. 
(f) Changes from baseline in CD4, CD8 and CD4/CD8 ratio over 96 weeks with evaluation at 
week 24, 48 & 96. 
 
 


Statistical Analysis Plan
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Secondary safety endpoints: 
 
(g) Number and percentage of participants with adverse events (AEs), severity of AEs, and 
treatment discontinuations due to AEs. 
(h) Changes from baseline in laboratory parameter at week 24, 48 and 96. 
(i) Changes from baseline in renal markers, bone markers, and fasting lipids at week 24, 48 and 
96. 
 
Secondary endpoints regarding pharmacological outcomes: 
 
(j) Pre-dose plasma concentrations of DTG and RPV at week 4 (experimental arm only), 48 
(experimental arm only) & 96. Plus pre/post-dose (as appropriate) at early termination visit 
and /or in the event of virological failure a post dose sample will be taken within 20-28 hours. 
(k) Number of potential drug-drug interactions (DDIs) avoided (This will be measured by 
comparing the drug interaction outcomes between antiretroviral therapy and co-medications 
before and after the switch by using the www.hiv-druginteractions.org/ website (within the 
same study arm and between study arms). The grading will be done by looking at how many 
interactions graded amber or red (score of 1) will be graded green (score of 0) after the switch. 
For example, if a patient on atorvastatin as a co- medication and on two NRTIs and 
darunavir/cobi
two 
favourable in terms of drug-drug interactions). 
Interaction antiretroviral treatment at screening and atorvastatin 
 
Atorvastatin 
score 
NRTI 1 
amber 
1 
NRTI 2 
amber 
1 
Darunavir 
green 
0 
Cobicistat 
green 
0 
Total number of interaction (a) 
 
2 
 
Interaction between rilpivirine/dolutegravir and atorvastatin 
 
Atorvastatin 
score 
rilpivirine 
green 
0 
doluteravir 
green 
0 
Total number of interaction (b) 
 
0 
 
The number of potential DDIs avoided will be calculated as followed: a-b=2-0=2. 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
Secondary endpoints regarding patient related outcomes: 
 
(l) Changes in quality of life from baseline. 
 
The quality of life will be assessed by the EQ-5D-3L questionnaire in the present study. The 
questionnaire will be a self-administrated questionnaire at baseline, week 24, 48 and 96. The 
EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility,  self-care, 
usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no 
problems (score of 1), some problems (score of 2), extreme problems (score of 3). And a 
health status score ranging from 0 to 100 (100 being worst quality of life) will be collected and 
will be considered as continuous variable. 
 
(m) Changes in patient satisfaction from baseline. 
 
-reported questionnaires at baseline 
(HIVTSQs (status)) and post-baseline (HIVTSQc (change)) at weeks 24, 48 and 96. The 
questionnaires comprise 12 items and are shown in table below. The HIVTSQs questionnaire 
items are scored from 0 (dissatisfied) to 6 (satisfied). The HIVTSQc questionnaire items are 
scored from -3 (much less satisfied now) to 3 (much more satisfied now). 
 
List of items used in HIVSTQs and HIVSTQc questionnaires. 
 
ID 
NAME 
1 
How satisfied are you with your current treatment? 
2 
How well controlled do you feel your HIV has been recently? 
3 
How satisfied are you with any side effects of your present treatment? 
4 
How satisfied are you with the demands made by your current treatment? 
5 
How convenient have you been finding your treatment to be recently? 
6 
How flexible have you been finding your treatment to be recently? 
7 
How satisfied are you with your understanding of your HIV? 
8 
How satisfied are you with the extent to which the treatment fits in with your lifestyle? 
9 
Would you recommend your present treatment to someone else who is being offered this HIV 
treatment? 
10 
How satisfied would you be to continue with your present form of treatment? 
11 
How easy or difficult have you been finding your treatment to be recently? 
12 
How satisfied are you with the amount of discomfort or pain involved with your present form of 
treatment? 
 
 
(n) Changes in Pittsburgh sleep quality index with evaluation a week 24, 48, 72 and 96. 
 
The Pittsburgh Sleep Quality Index (PSQI) contains 19 questions on the participant and 5 
questions on the bed partner or roommate (if one is available). Only questions on the 
participant are included in the scoring. The 19-participant items are combined to form seven 
"component" scores, each of which has a range of 0-3 points. ln all cases, a score of "0" 


Statistical Analysis Plan
WISARD Study Protocol
 
 
indicates no difficulty, while a score of "3" indicates severe difficulty. The seven component 
scores are then added to yield one "global" score, with a range of 0-21 points, "0" indicating 
no difficulty and "21" indicating severe difficulties in all areas. The seven components are: 
component 1 (Subjective sleep quality); component 2 (Sleep latency); component 3 (Sleep 
duration); component 4 (Habitual sleep efficiency); component 5 (Step disturbances); 
component 6 (Use of sleeping medication); component 7 (Daytime dysfunction). More details 
on the derived variables are shown in the Appendix. Multiple imputation using Chained 
Equations approach (MICE) will be used to fill in missing data. 
 
3.2.3 
Exploratory endpoints/outcomes 
 
(o) Changes in HS CRP over 96 weeks with evaluation at week 24, 48 and 96. 
 
3.3 
Derived variables 
 
The following derived variables will be studied: 
 
Variables
Calculation method
Age at inclusion, years 
Difference between the date of enrolment and the birth 
date divided by 365.25 
CD4/CD8 ratio
CD4 cell count divided by CD8 cell count
Duration on ART, years 
Difference between the date of enrolment and the date of 
first antiretroviral treatment initiation divided by 365.25 
Time since HIV diagnosis, years 
Difference between the date of enrolment and the date of 
HIV diagnosis divided by 365.25 
Duration of suppressed HIV RNA (<50 
copies/mL), year 
Difference between the date of enrolment and the date of 
last detectable viral load (HIV RNA >50 copies/mL) 
divided by 365.25 
Changes from baseline in continuous 
biological parameters 
Difference between value at each time point and the value 
at baseline 
Percent 
change 
from 
baseline 
in 
continuous biological parameters 
Difference between value at each time point and the value 
at baseline divided by the baseline value and multiply by 
100 
Number of potential DDIs avoided 
Difference between number of interactions 
amber
or red  before switching and number of interactions graded
rilpivirine 
Total cell associated HIV DNA copies 
per million PBMC 
Total cell associated HIV DNA will be analysed as log 
transformed, as a continuous variable 
 
Partial dates will be extrapolated. For example, all dates saved as NK/FEB/2020 will be recoded as 
15/FEB/2020 and those saved NK/NK/2020 will be recoded as 15/JUNE/2020. NK means not known. 
 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
4. Study Methods 
 
4.1 
General Study Design and Plan 
 
This trial is an open-label, randomised, 2 arms, parallel-group, multicentre trial, comparing an 
immediate versus a deferred switch from a boosted PI containing regimen to a dual therapy with DTG 
and RPV in HIV infected patients with a history of virological failure with NNRTIs or baseline 
transmitted drug resistance and having developed a K103N mutation. The trial will be conducted 
within the NEAT ID network and include sites in 7 countries that have an excellent track record in 
clinical research. After screening, participants will be randomised 2:1 to switch to DTG/RPV at 
baseline or at 48 weeks. 
 
The intervention will consist of immediate switch to DTG 50 mg OD + RPV 25 mg OD regimen at 
baseline or maintaining the current antiretroviral therapy for 48 weeks. At week 48, all participants in 
the deferred switch group with virological success will be switched to DTG 50 mg OD + RPV 25 mg 
OD therapy, and all participants will be followed for additional 48-weeks until week 96 (see figure). 
 
 
 
After the screening visit, participants will be seen at baseline, weeks 4, 12, 24, 48, 52, 60, 72, 96, and 
either a follow-up visit (30 days (+/- 7 days) after week 96 visit) or an early termination visit. A week 
60 visit may be an optional visit and performed for subjects on the control arm (3 months after 
therapeutic modification) as required per national guidelines. At each visit, participants will have 
routine investigations and will include viral load, CD4 & CD8, haematology (including haemoglobin, 
white cell count and differential, platelets), biochemistry (including sodium, potassium, creatinine, 
albumin, glucose, ALT, AST, ALP, total bilirubin, total cholesterol, HDL, LDL, triglycerides), PK, 
PBMC, quality of life questionnaires, patient satisfaction questionnaire, Pittsburgh sleep  
questionnaire, DDI assessment & urine sample (for haematuria, proteinuria, glycosuria, leukocytes) 
for full list of investigations please see section 4.4. 


Statistical Analysis Plan
WISARD Study Protocol
 
 
 
 
4.2 
Randomisation Scheme and Blinding 
4.2.1 
Randomisation scheme 
 
This study is open label and patients will be randomised to switch at baseline or after 48 weeks. 
Indeed, patients will be randomly allocated (2:1) to receive DTG/RPV at baseline in the experimental 
arm or to receive DTG/RPV after week 48 in the control arm. Randomisation will not be stratified by 
site because of the large number of sites relative to the sample size. The statistician of the trial will use 
central computer-generated permuted blocks of size 6 using a predefined randomised list to assign 
participants to treatment groups. Randomization will be done at Day 1 visit (date of the study 
treatment initiation in the experimental arm). 
 
The participants in the experimental arm (Baseline visit switch group) will receive one combined 
Dolutegravir 50mg /Rilpivirine 25mg tablet taken orally once daily (at the same time) for up to 96 weeks 
with a meal. The participants in the control arm (deferred week 48 switch group) will continue their 
current boosted PI regimen (or other antiretroviral combination regimen) for 48 weeks. Patients will then 
be switched to one combined Dolutegravir 50mg /Rilpivirine 25mg tablet taken orally once daily for up 
to 48 weeks with a meal. Dolutegravir and Rilpivirine combined therapy tablets will be labelled and 
certified by Almac Group Ltd who will provide supply directly to each site on request of the sponsor. 
Boosted PIs (or other antiretroviral combination regimen) will be sourced from usual commercial supply 
as per standard practice. 
 
This study is open label, therefore, all investigators, site pharmacists, study nurses and subjects will be 
unmasked and aware of the treatment allocation throughout the study. 
 
4.2.2 
Blinding 
 
This section is not applicable 
 
4.3 
Study Variables 
All the study variables are summarized in the following table. 
 
 
 
 
Both treatment arms to 
complete all visits. 
 
 
SCREENI 
NG 
BASELIN
E 
(within
28 days of
screening
) 
 
 
W4 
(+/- 7) 
 
 
W12 
(+/- 7)
 
 
W24 
(+/- 7)
 
 
W48 
(+/- 7)
 
 
W52 
(+/- 7)
 
 
W60 
(+/- 7)
 
 
W72 
(+/- 7)
 
 
W96 
(+/- 7)
30 Day FU
(+/- 7) 
(by 
phone)
 
 
ETV 
Eligibility Criteria Assessment
x 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
x 
 
 
 
 
 
 
 
 
 
 
 


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WISARD Study Protocol
 
 
Medical and Social History 
Including 
 
Recreational drug 
use 
 
Smoking history 
 
Alcohol intake 
 
Concomitant 
diseases 
 
Past & present 
medical history, 
including HIV- 
associated 
conditions 
 
Antiretroviral 
history 
(including 
resistance 
history 
i.e. 
record 
all 
resistance 
history by major 
mutations in 
NRTI, NNRTI, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
PI and II
regions) 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol intake, smoking habit 
and recreational drug use 
 
 
x 
 
 
 
x 
 
x 
 
 
 
 
x 
 
 
x 
Physical Examination 
(Including Height) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Symptom Directed Physical 
Exam 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
 
x 
 
 
x 
Vital sign 
 
Pulse 
 
Blood 
pressure 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
Urine pregnancy test 
for women of child 
bearing potential 
-HCG) 
only. 
Investigators to remind 
females of reproductive 
potential of the need to 
avoid pregnancy while in 
study and adherence to 
requirements. 
As a reminder, females of 
reproductive potential who 
changed their minds and 
desire to 
be pregnant 
should also be withdrawn 
from the 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
(Predose) 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 


Statistical Analysis Plan
WISARD Study Protocol
 
 
Urinalysis (all tests should 
be performed on random 
spot urine. If random spot 
testing is not possible then 
24hr 
urine 
can 
be 
performed, but only if pre- 
agreed with sponsor in 
writing) 
Including: 
 
Protein:Creatinine 
Ratio (PCR)2 
 
Albumin:Creatinine 
Ratio (ACR) 3 
 
urinary creatinine 
 
urinary phosphate 
 
urinary 
glucose 
(Can be performed 
quantitatively or by 
dipstick; optional if 
pre-agreed 
with 
sponsor in writing) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
beta-2 microglobulin (optional
if pre- agreed with sponsor in 
writing) 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
CD4 & CD8 (count / % and 
ratio) 
x 
x 
 
 
x 
x 
 
 
x 
x 
 
x 
HBV/HCV 
(HBV antigen test (including
HbsAG, anti-HBc and HBsAb)
and HCV antibodies test (if
test positive for HCV 
antibodies, test for HCV 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
RNA, if positive and chronic 
for either HBV or HCV, add 
AST test to the biochemistry 
panel at screening visit. 
Also include Hep B surface 
antibodies post vax levels) 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
Haematology Including: 
 
Platelet count 
 
RBC 
Count 
(indices MCV & 
MCH) 
 
WBC count 
(absolute) 
 
Haemoglobin 
 
Hamatocrit RBC 
Count indices: 
 
MCV 
 
MCH 
Automated WBC 
differentials: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
Basophils 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Clinical chemistry (Fasted 
for at least 10 hours 
except 
for 
screening) 
Including: 
 
Urea 
 
Chloride 
 
Alkaline 
phosphatise 
 
Creatine 
phosphokinase 
 
Creatinine 
 
Calcium 
 
Phosphate 
 
Glucose 
(optional in 
 
 
 
 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
 
 
 
x 
urine if agreed 
with sponsor in 
writing) 
 
Total bilirubin 
 
Potassium 
 
HsCRP (optional 
if 
agreed 
with 
sponsor in writing)
 
Total protein 
 
Sodium 
 
ALT 
 
Albumin 
 
Creatinine 
clearance 
(Calculations: 
Cockcroft-Gault 
(requires weight), 
MDRD, CKD-Epi)
(* including urinary chemistry)
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
Fasting 
Lipids 
(Fasted for at least 
10 hours except at 
screening) 
Including: 
 
Total cholesterol 
 
HDL cholesterol 
 
LDL cholesterol 
 
Triglycerides 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
HIV RNA viral load 
 
x
x
x
x
x
x
x
x
x
 
x
Predose Pharmacokinetic 
assessment 
(A post-dose sample will 
be 
taken 
at 
early 
termination visit and/or in 
the event of 
virological failure within 
20-28 hours of last dose) 
 
 
 
 
x    
(Experi 
men tal 
arm 
only) 
 
 
 
 
x    
(Exper 
imen 
tal arm 
only) 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Blood sampling for PBMC 
isolation (Required unless 
exemption documented in 
site contract i.e. if site 
does not have capacity to 
process PBMC samples) 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
x 
Quality of Life 
Questionnaire 
 
x 
 
 
x 
x 
 
 
 
x 
 
x 
Patient Treatment 
Satisfaction Questionnaire 
 
x 
 
 
x 
x 
 
 
 
x 
 
x 
Pittsburgh Sleep 
Questionnaire 
 
x 
 
 
x 
x 
 
 
 
x 
 
x 
DDI Assessment 
 
x 
 
 
x 
x 
 
 
 
x 
 
x 
Adherence 
Assessment 
(Self 
report 
at 
visit) 
(including date and time of 
last dose on PK days, 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
including ETV visit and/or 
in the event of virological 
failure) 
 
 
 
 
 
 
 
 
 
 
 
 
AE Assessment 
 
x
x
x
x
x
x
x
x
x
x
x
Con Med Check 
x
x
x
x
x
x
x
x
x
x
 
x
 
 
5. Sample Size calculation 
 
This is a pilot proof of concept study to investigate whether complex regimens taken by patients with 
resistance mutations can be replaced by a simple two class single pill regimen safely in terms of viral 
load and adverse events. 
 
No formal sample size calculation is performed. It is anticipated that data from 150 participants is 
adequate to meet the trial objectives (100 in the DTG/RPV arm and 50 in the control arm). The 
expected success rate is 95% based on the data reported by the SWORD 1 & 2 studies (1). If the 
observed success rate is 95% in the DTG/RPV arm at week 48 and varies from 95% to 100% in the 


Statistical Analysis Plan
WISARD Study Protocol
 
 
control arm, with 150 participants (100 in the DTG/RPV arm and 50 in the control arm), the lower 
bound of the confidence interval of the difference in the success rate between the 2 arms (DTG/RPV  
control) would varied from -9.3% to -7.4% (see table below). 
 
Success rate 
 
95% Confidence Interval 
DTG/RPV 
(n=100) 
Control 
(n=50) 
 
Difference
 
lower 
 
upper 
95% 
95% 
0.0% 
-7.4% 
7.4% 
95% 
96% 
-1.0% 
-7.9% 
5.9% 
95% 
97% 
-2.0% 
-8.4% 
4.4% 
95% 
98% 
-3.0% 
-8.8% 
2.8% 
95% 
99% 
-4.0% 
-9.1% 
1.1% 
95% 
100% 
-5.0% 
-9.3% 
-0.1% 
 
In addition, we would like to show whether the observed success rate in the DTG/RPV arm is above 
95%. Therefore, we estimated power for a one-sample proportion test (Binomial test) by varying the 
external threshold from 80% to 90% to detect the minimum effect size at which we will have 80% 
power to achieve the goal (see table below). 
 
Ho (null hypothesis): p = p0 versus Ha (alternative hypothesis): p > p0 
 
N 
alpha 
p 
p0 
delta 
power 
100 
5% 
95% 
80% 
15% 
100% 
100 
5% 
95% 
81% 
14% 
99.9% 
100 
5% 
95% 
82% 
13% 
99.6% 
100 
5% 
95% 
83% 
12% 
98.9% 
100 
5% 
95% 
84% 
11% 
97.2% 
100 
5% 
95% 
85% 
10% 
93.7% 
100 
5% 
95% 
86% 
9% 
93.7% 
100 
5% 
95% 
87% 
8% 
87.2% 
100 
5% 
95% 
88% 
7% 
76.6% 
100 
5% 
95% 
89% 
6% 
61.6% 
100 
5% 
95% 
90% 
5% 
43.6% 
 
We show that, with 100 individuals in the DTG/RPV arm, we will have a 95% probability to discard a 
combination for which efficacy is smaller than 87% and we will select with a power of 80% the 
strategy for which the efficacy is above or equal to 95%. 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
The power calculation was made using the statistical software package nQuery Advanced, using the 
exact test for single proportion module (Version 8.5.2.0). 
 
An interim analysis will be performed when 120 participants will reach the week 24 visit 
(corresponding to 80 participants in the DTG/RPV arm and 40 participants in the control arm). In the 
ANRS 163 ETRAL trial (Katlama et al., JAC 2019)(2), in which 10% of participants harboured 
viruses with K103N mutation, the proportion of participants in success at week 24 with a dual therapy 
with etravirine and raltegravir was estimated at 96.4% (95%CI 92.3 to 98.7). Therefore, for this 
interim analysis at week 24: The expected level of efficacy is 96%, and the unacceptable level of 
efficacy (p0) is 87%. With alpha = 5% (one-sided) and 80% power, if we include 80 participants in the 
DTG/RPV arm, we will consider that the treatment is effective to be continued if there are no more 
with an 80% chance that the lower bound of the 95% confidence interval would exclude 87% if the 
true success rate (p) is 96%. This gives a 5% chance of continuing if p = p0 and an 80% chance of 
continuing if p 
 
 
6. General Considerations 
 
6.1 
Timing of Analyses 
 
An interim analysis will be performed to show whether DTG/RPV is able to maintain virological 
suppression at week 24, when 80% of the total participants will reach the 24-week visit (i.e. 120 
participants: 80 in the DTG/RPV arm and 40 in the control arm) (anticipated to be November 2020). 
 
The primary efficacy analysis will be performed at week 48, when all enrolled participants will reach 
the 48-week visit (anticipated to be May 2021). 
 
The final analysis will be performed at week 96, when the last patient has completed his last scheduled 
visit in the protocol and when the database will be frozen (anticipated to be June 2022). 
 
6.2 
Timing of outcome assessments 
 
Table A:  Proposed Windows 
Visit 
Window (Through 
End-of-Study Week) 
Window (Days) 
12 
6-18 
43-126 
24 
18-30 
127-210 
48 
42-54 
295-378 
72 
66-78 
463-546 
96 
90-102 
631-714 
 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
6.3 
Analysis Populations 
 
6.3.1 
Full Analysis Population 
 
All randomly assigned participants will be included in the Full Analysis Population, except those who 
never received the study treatment. The participants who never received the study treatment will be 
excluded from the analysis. The primary endpoint and all secondary endpoints will be analysed on this 
Full Analysis population, called as a modified intention-to-treat (mITT) analysis. 
 
6.3.2 
Per-Protocol Population 
 
The per-protocol population will include all patients from the mITT population, excluding participants 
with serious protocol violations which could interfere with the reliability of the efficacy outcome. 
Examples would include taking other antiretroviral treatment during the course of the study, incorrect 
randomisation or early discontinuation from the study for reasons unconnected to efficacy or safety. 
This analysis will be conducted to check the reliability of the results from the primary efficacy 
analysis. 
 
6.3.3 
Switch Included Population 
 
discontinued randomised treatment for any reason. This analysis will follow the same methods as FDA 
Snapshot, but will include HIV RNA data from all participants with results available at Week 48, 
whether they are on or off randomised treatment. There will be no formal non inferiority outcome 
analysis as this is a pilot study. 
 
6.3.4 
Safety Population 
The safety population will include all subjects included in the mITT population who received at least one 
dose of the study treatment 
 
6.4 
 Covariates and Subgroups  
6.4.1 
Subgroup analysis 
 
The sample size of 150 patients is too small to allow meaningful subgroup analyses. The two analyses 
described above (Per Protocol and Switch Included) will assess the reliability of the results from the 
primary efficacy analysis. 
 
6.4.2 
Adjusted analysis 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
The treatment effect will also be assessed adjusted for baseline variables which might influence the 
48-week outcome. 
Factors associated with the outcome will be tested using univariable logistic regression models. The 
following baseline variables will be tested: Age, gender, ethnic (black vs white), transmission group 
(MSM vs Other), Known duration since HIV diagnosis, duration of ART therapy, Positive Hep B 
antigen (yes vs no), Positive Hep C antibody (yes vs no), CD4 (above versus below 350 cells/µL), 
CD4/CD8 ratio, NRTI-backbone, PI received at baseline (yes vs no), body mass index, alcohol intake 
(yes vs no), current smoking (yes vs no), recreational drug use (yes vs no), diabetes (yes vs no), 
metabolic parameters (LDL-c, HDL-c, total cholesterol (TC), triglycerides and TC/HDL ratio), 
glucose, total protein, hsCRP, Creatinine clearance (e-GFR), presence of M184V mutation at baseline 
(yes vs no), number of PI mutation, number of NRTI mutation and number of allowed NNRTI 
mutation. Continuous variables will be modelled as continuous or as tertiles based on the AIC of the 
corresponding univariable model. Variables with univariable p-value <0.10 will be retained for the 
multivariable analysis. 
All potential confounders that are known in the literature will also be included, such as the presence of 
M184V mutation at baseline and CD4 count at baseline (above versus below 350 cells/µL). 
 
6.5 
Missing data 
 
In the primary efficacy analysis (FDA Snapshot), participants with missing data at analysis time points 
will be considered as having lost undetectable plasma HIV-1 RNA levels. The analyses of overall 
patient disposition will show the number of patients who did not attend each protocol-defined visit. 
 
For all continuous efficacy and safety variables, we will use, in the mITT population, the LOCF (last 
observation carried forward) approach to deal with missing data. We will also use mixed model as a 
sensitivity analysis. 
For patients reported outcomes, we will use multiple imputation approach to fill in missing data. 
 
6.6 
Interim analysis 
 
One administrative statistical interim analysis is planned on the primary efficacy endpoint to show 
whether the efficacy of the dual therapy with DTG and RPV is above 96% after week 24. This interim 
analysis is planned to take place when 120 participants (80 in the DTG/RPV arm and 40 in the control) 
have reached the 24-week visit. It will be done following week 24 with the mITT population. The 95% 
two-sided confidence interval of the percentage of patients in therapeutic success will be calculated 
and DTG/RPV will be considered as an acceptable strategy if the lower bound is greater than 87%. 
The strategy will be considered unacceptable if there are 18 therapeutic failures or more. With 18 
failures among 80 subjects in the DTG/RPV arm, the observed proportion of success is 77.5% and the 
associated CI is 66.7% to 86.1%, so just excluding 87%. Additional issues could include treatment 


Statistical Analysis Plan
WISARD Study Protocol
 
 
emergent drug resistance, serious adverse events or high rates of discontinuation for adverse events. 
The interim analysis will also explore whether the lower limit of the 95% confidence interval of the 
difference in the percentage of participants with therapeutic success between the DTG/RPV arm and 
the control arm (DTG/RPV- control) remain in acceptable range (above -13%). 
 
6.7 
Multi-centre Studies 
 
Potential centre effects will not be taken into account in the analyses, as randomisation should make 
the two populations similar in all respects. 
 
6.8 
Multiple testing 
 
As only an administrative interim analysis will be conducted, no multiplicity adjustment is required. 
 
7. Summary of Study Data 
 
All continuous variables will be summarized using the following descriptive statistics: n (non-missing 
sample size), mean, standard deviation, 1st quartile, median, 3rd quartile, maximum and minimum. 
The frequency and percentages (based on the non-missing sample size) of observed levels will be 
reported for all categorical variables. 
 
7.1 
Subject Disposition 
 
The number of patients and the flowchart of the study will be presented. The period of enrolment and 
the total number of patients screened to be included in the study will be presented. The number of 
ineligible patients and the total number of randomised patients will be presented. The number of 
patients who never take the study treatment will also be presented by group and the reasons will be 
given and those who remained on the study treatment up to week 48 and 96 will be presented. The 
number of patients who discontinued the study will be presented and the reasons of discontinuation as 
well as the time from randomisation to discontinuation will be given. All these information will be 
shown in the study Flowchart as below (Figure 1). 
 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
Figure 1: Study Flowchart 
 
 
 
7.2 
Protocol Deviations 
 
The following violations are defined as protocol deviations for the purpose of analysis: The deviation 
might be related to: 
 
(a) Eligibility; 
(b) Study related assessments; 
(c) Social history; 
(d) PK sampling; 
(e) Drug dispensing; 
(f) Adherence; 
(g) Follow up (lost to follow-up, 
 
(h) Other (consent withdrawal, giving up, 
 
 
The following violations will be considered as a serious deviation for the purpose of analysis: Patients 
who will not take study treatment; Interruptions of study drug for >10% of total time on treatment; 
Patient who will not fulfil the eligibility criteria; Patients who will withdraw the consent; Patients who 
will not comply with their randomization arm; Patients with missing value at the primary endpoint 
evaluation: Patient who will be lost to follow-up. 
 
A patient will be considered lost to follow-up when he/she will not come to more than 2 visits of the 


Statistical Analysis Plan
WISARD Study Protocol
 
 
protocol. Patients who cannot be contacted on or before the last scheduled visit prior to the week 96 
and who will not have a known reason for discontinuation (eg, withdrew consent, giving up, etc.) will 
-
 
 
Patients will be considered in discontinuation of the study when they will refuse to continue the 
follow-up of the study. 
 
7.3 
Demographic and baseline variables 
 
be presented in a summary table. This table will be structured with a column for each treatment group 
and a column for the total population in the order (DTG/RPV, control, and Total population). This 
summary table will be annotated with the total population size for each treatment group and the total 
population. The following variables will be described at baseline: Age, gender, ethnic, transmission 
group, child bearing potential, year of HIV diagnosis, Known duration since HIV diagnosis, duration 
of ART therapy, Positive Hep B antigen, Positive Hep C antibody, CD4 and CD8 cell count, 
CD4/CD8 ratio, antiretroviral treatment at baseline, NRT-backbone, PI received at baseline, body 
mass index, alcohol intake, smoking, recreational drug use, diabetes, metabolic parameters (LDL-c, 
HDL-c, total cholesterol (TC), triglycerides and TC/HDL ratio), glucose, total protein, hsCRP, 
Creatinine clearance (e-GFR), presence of M184V mutation, number of PI mutation, number of NRTI 
mutation and number of allowed NNRTI mutation. The summary statistics will be produced in 
accordance with section 7. 
 
7.4 
Concurrent Illnesses and Medical Conditions 
 
The frequency of comorbidities will be described at baseline. The summary statistics will be produced 
in accordance with section 7. 
 
7.5 
Prior and Concurrent Medications 
 
All medications ongoing at the start of the treatment or started during the study treatment will be 
described. The summary statistics will be produced in accordance with section 7. 
 
7.6 
Treatment Compliance 
 
Adherence during the trial will be monitored by subject questioning regarding missed tablets at each 
visit. Compliance rate for each participant will be estimated by the number of pills consumed divided 
by the number of pills that will be theorically consumed and will be classified as low (<80%), medium 
(80-95%), and high (95-100%). The summary statistics will be produced in accordance with section 7. 
Generalised Estimating Equation (GEE) model will be used to compare the proportion of participants 


Statistical Analysis Plan
WISARD Study Protocol
 
 
with compliance rate <95% (not classified as high) between the 2 treatment groups over time with 
unstructured covariance matrix. This analysis will be performed if more than 20% of participants are 
not classified as high. The model will include treatment group, time and interaction between treatment 
group and time. Time will be considered as a categorical variable (0, 12, 24, 48, 60, 72, and 96 weeks) 
according to the planned visits. The proportion of participants with compliance rate <95% will be done 
at each visit. 
 
8. Efficacy Analyses 
 
8.1 
Primary Efficacy Analysis 
 
Virologic outcome will be determined by the last available measurement while the participant is on 
treatment and continued on trial within the time window (see Table A, section 6.2). 
The primary efficacy analysis will be performed at week 48 with the mITT population. The proportion 
of patients with treatment success will be estimated by the number of patients with HIV-RNA<50 
copies/mL up to week 48 with no discontinuation of the study or the study treatment at week 48 
divided by the total number of participants in the mITT population. The associated two-sided 95% 
confidence interval will be calculated for each treatment group. We will also calculate the difference 
in treatment efficacy between the two treatment groups by measuring the difference in the percentage 
of participants with therapeutic success (i.e., DTG/RPV success rate minus the control success rate). 
The two-sided 95% confidence interval of the difference in therapeutic success rate will be given by 
the following formula (A): 
 
. 
The effect of study treatment will also be assessed in the mITT population using logistic regression 
model with treatment group adjusted for the presence of M184V mutation at baseline and CD4 count 
at baseline (above versus below 350 cells/µL) as well as all baseline variables potentially associated 
with the outcome, with univariable P-value <0.10 as described above in the section 6.4.2. 
Sensitivity analyses will be performed with both the per-protocol and the switch included populations. 
 
8.2 
Secondary Efficacy Analyses 
 
All secondary efficacy outcome analyses will be performed with the mITT population. All p-values 
will be two-sided with a significant level set at 0.05. 
For all secondary efficacy outcomes the time window is shown in Table A (section 6.2). 
 
8.2.1 
Virological evaluation 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
(a) Proportion of participants with virological failure (2 consecutive VL 50 copies/mL or one 
VL 50 copies/mL and discontinuation of the study or the study treatment) over 96 weeks 
The Kaplan-Meier estimates will be used to determine the proportion of participants with virologic 
failure, investigated over the 96 weeks. The associated two-sided 95% confidence interval will be 
 formula. The Log-Rank test will be used to 
compare the virological failure rate between the 2 groups. An additional analysis using Cox regression 
model with treatment group adjusted for the presence of M184V mutation at baseline and CD4 count 
at baseline (above versus below 350 cells/µL) as well as all other potential confounders will be used to 
assess the effect of study treatment. We will also calculate the two-sided 95% confidence interval of 
the difference in the percentage of participants with virological failure (i.e., DTG/RPV failure rate 
minus the control failure rate) using the following formula (B):  
 is the standard error of the proportion calculated with the 
Kaplan-Meier Method based on the Greenwood pointwise variance estimate. 
The time from randomisation to virological failure is defined as the date of the first occurrence of 
virological failure or the date of last observation for participants without virological failure minus the 
date of initiating the study treatment. The date of virological failure is the date of the first of the 2 
measurements conferring virological failure. The event will be the occurrence of virological failure. 
Participants in discontinuation for reasons other than virological failure will be censored at the date of 
last observation before evaluation. 
 
(b) Incidence of genotypic resistance in case of confirmed HIV RNA >50 and baseline factors 
associated with failure i.e. treatment emergent mutations (NRTI, NNRTI, PI and II regions) as 
compared with previous resistance tests. 
 
Genotypic resistance testing will be performed in participants with confirmed pVL >50 copies/mL and 
compared to previous resistance tests. Resistance interpretation will be given by using the Stanford 
algorithm (https://hivdb.stanford.edu/hivdb/by-mutations). The incidence of new resistance mutations 
will be described and compared between the two treatment groups. The frequency of new mutations 
conferring resistance to any antiretroviral drug will be given. A table will be built listing all 
participants with drug resistance mutations by treatment group. The table will include the following 
information: Patient Id, ARV treatment at baseline, age, sex, CD4 nadir, CD4 count at baseline, 
CD4/CD8 ratio at baseline, ARV treatment at failure, 1st VL at failure, 2nd VL at failure, resistance 
mutation at baseline, resistance mutation at failure, drugs resistant at baseline, drugs resistant at 
failure, drugs concentration at failure. 
 
(c) Proportion of participants with plasma HIV RNA <50 copies/mL at week 24, 48 and 96. 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
The proportion of participants with plasma HIV RNA <50 copies/mL will be defined as the proportion 
of participants with HIV RNA <50 copies/mL and no discontinuation of the study or the study 
treatment. It will be estimated by the number of patients with HIV-RNA<50 copies/mL and no 
discontinuation at the analysis time point divided by the total number of patients in the mITT 
population. The associated two-sided 95% exact (Clopper Pearson) confidence intervals will be 
calculated for each group as well as the two-sided 95% confidence interval of the difference in the 
proportion between the two treatment groups. The confidence intervals for the difference in 
proportions will be calculated with formula (A) defined above. Discontinuation is defined by the 
discontinuation of the study or any change or modification in the study treatment. 
 
(d) Proportion of participants with plasma HIV RNA <200 copies/mL at week 24, 48 and 96. 
 
The proportion of participants with plasma HIV RNA <200 copies/mL will be defined as the 
proportion of participants with HIV RNA <200 copies/mL and no discontinuation of the study or the 
study treatment. It will be estimated by the number of patients with HIV-RNA<200 copies/mL and no 
discontinuation at the analysis time point divided by the total number of patients in the mITT 
population. The associated two-sided 95% confidence interval will be calculated for each group as 
well as the two-sided 95% exact (Clopper Pearson) confidence interval of the difference in the 
proportion between the two treatment groups. The confidence intervals for the difference in 
proportions will be calculated with formula (A) defined above. Discontinuation is defined by the 
discontinuation of the study or any change or modification in the study treatment. 
 
(e) Change from baseline in cell associated virus using PBMC Illumina sequencing at week 48 
and week 96 
 
The evolution of cell associated HIV DNA (based on log transformation) will be described by 
boxplots for each treatment group at baseline, week 48 and 96. HIV DNA values below the limit of 
quantification (LOQ) value will be replaced by the LOQ value. The changes from baseline to week 48 
and 96 will be compared between the two treatment group using mixed models for repeated measures 
with random intercept and unstructured covariance matrix, adjusted for baseline value. The models 
will include treatment group, time, interaction between treatment group and time, and baseline value 
as covariate. Time will be considered as categorical variable (0, 48, and 96 weeks). Visits window are 
shown in Table A (section 6.2). Data will be also summarised in tables by mean and standard error. 
If the residual of the mixed model is not normally distributed and therefore does not allow the use of 
parametric test, the changes from baseline to week 48 and 96 of HIV DNA will be compared between 
the 2 groups using Mann-Whitney-Wilcoxon test. 
 
8.2.2 
Immunological evaluation 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
(f) Change from baseline in CD4, CD8, and CD4/CD8 ratio over 96 weeks with evaluation at 
week 24, 48, and 96. 
 
The evolution of the CD4, CD8 and CD4/CD8 ratio over 96 weeks according to the treatment group 
will be described by boxplots for each treatment group at each visit. The changes will also be 
compared between the two treatment group using mixed models for repeated measures with random 
intercept and unstructured covariance matrix, adjusted for baseline value. The models will include 
treatment group, time, interaction between treatment group and time, and baseline value. Time will be 
considered as categorical variable (0, 12, 24, 48, 72 and 96 weeks) according the planned study visits. 
Visits window are shown in Table A (section 6.2). Data will be also summarised in tables by mean and 
standard error. 
If the residual of the mixed model is not normally distributed and therefore does not allow the use of 
parametric test, the changes from baseline to week 24, 48 and 96 of CD4 T cell count, CD8 T cell 
count and CD4/CD8 ratio will be compared between the 2 groups using Mann-Whitney-Wilcoxon test. 
 
9. Safety analyses: 
 
(g) Number and percentage of participants with adverse events (AEs), severity of AEs, and 
treatment discontinuations due to AEs. 
 
Adverse events (AE), especially grade 3 and 4 AE, serious adverse events (SAE), drug-related AE (all 
grades), treatment interruption due to AE (all grades), pregnancies and death will be summarized with 
descriptive statistics. The incidence rates of the events defined above will be compared between the 
treatment groups using a Poisson regression analysis which accounted for all adverse events and 
follow-up duration for each participant. The Poisson regression models will include the number of 
events, the treatment group and the duration of exposure in year in log. The number and percentage of 
death as well as the causes of death will be given. The number and percentage of pregnant women will 
also be given. A table will summarize the frequency of adverse events and pregnancies. This table will 
include the name of event, number and percentage of patients with events, number of events, and 
incidence rate (IR) per 100 person-years in the DTG/RPV group and the control group respectively, 
and incidence rate ratio (IRR) and 95%CI for IRR. All grades 3 or 4 AE related to the study drugs and 
treatment interruption due to AE will be put in the table. 
 
(h) Changes from baseline in laboratory parameters at week 24, 48 and 96. 
 
The evolution of haematology parameters (including haemoglobin, white cell count and differential, 
platelets) and biochemistry parameters (including sodium, glucose, ALT, AST, and total bilirubin) 
according to the treatment group will be described by boxplots for each treatment group at baseline, 
week 24, 48 and 96. The changes from baseline will be compared between the two treatment groups 


Statistical Analysis Plan
WISARD Study Protocol
 
 
using mixed models for repeated measures with random intercept and unstructured covariance matrix 
adjusted for baseline value. The model will include treatment group, time and interaction between 
treatment group and time, and baseline value. Time will be considered as categorical variables. Data 
will be also summarised in tables by mean and standard error. 
If the residual of the mixed model is not normally distributed and therefore does not allow the use of 
parametric test, the non-parametric Mann-Whitney-Wilcoxon test will be used to compare the changes 
from baseline to week 24, 48 and 96 between the two treatment groups. 
 
(i) Changes from baseline in renal markers, bone markers, and fasting lipids at week 24, 48 and 
96. 
The evolution of renal markers (including blood creatinine, blood creatinine clearance (eGFR), urine 
creatinine, urine protein, urine protein/creatinine ratio, blood albumin, urine albumin, urine 
albumin/creatinine ratio, urine beta 2 microglobulin, urine creatinine clearance (eGFR), potassium, 
blood phosphate, urine phosphate), bone markers (including ALP) and lipids fasting parameters 
(including total cholesterol, HDL, LDL, triglycerides) according to the treatment group will be 
described by boxplots for each treatment group at baseline, week 24, 48 and 96.  
The changes from baseline will be compared between the two treatment groups using mixed models 
for repeated measures with random intercept and unstructured covariance matrix adjusted for baseline 
value. The model will include treatment group, time and interaction between treatment group and time, 
and baseline value. Time will be considered as categorical variables. Data will be also summarised in 
tables by mean and standard error. 
If the residual of the mixed model is not normally distributed and therefore does not allow the use of 
parametric test, the non-parametric Mann-Whitney-Wilcoxon test will be used to compare the changes 
from baseline to week 24, 48 and 96 between the two treatment groups.  
 
 
10. Pharmacokinetics 
 
(j) Pharmacokinetic assessment 
 
Pre-dose plasma concentrations of DTG and RPV at week 4 (experimental arm only), 48 
(experimental arm only) and 96. Plus pre/post-dose (as appropriate) at early termination visit and 
/or  in the event of virological failure a post dose sample will be taken within 20-28 hours. 
 
At each time point, the AUC of DTG and RPV post administration will be summarized by the 
median, Q1, Q3, min, max and number of non-missing values. For each drug, we will compare the 
evolution of AUC over time using Wilcoxon paired test. 


Statistical Analysis Plan
WISARD Study Protocol
We will use the trapezoidal approach to calculate the area under the curve (AUC). For example, 
given data t0, t1,  , tN and y0, y1,     , yN , the area under the curve can be approximated as 
follows:
where ti is the time value and yi is the concentration of 
the antiretroviral drug.


Statistical Analysis Plan
WISARD Study Protocol
 
 
(k) Number of potential DDIs avoided assessment 
 
The number of potential DDIs avoided will be calculated by the difference between the number of 
amber or red
before and after switching to dolutegravir and rilpivirine. 
More details are shown in section 3.2.2. The number of DDI avoided will be compared between the 
two-treatment groups using Mann-Whitney Wilcoxon test. Data will be summarized by the median, 
Q1, Q3, min, max and number of non-missing values. 
 
11. Other analyses 
 
(l) Changes in quality of life from baseline to week 24, 48 and 96. 
 
The EQ-5D-3L quality of life questionnaires will be analysed using multiple imputation approach to 
replace missing values (assumption: Missing At Random). Multiple imputation using Chained 
Equations approach (MICE) will be used to fill in missing data. Therefore, we will create 10 datasets, 
questionnaires, to obtain valid inference and reduce sampling variability resulting from the imputation 
process.  The analysis will include all participants from the mITT population that will complete at least 
one of the 4 questionnaires (baseline, weeks, 24, 48, and 96). Participants with more than 20% missing 
data in a specific questionnaire will be excluded from the analysis of the questionnaire. 
The changes from baseline will be compared between the two treatment groups using mixed models 
for repeated measures with random intercept and unstructured covariance matrix adjusted for baseline 
value. The model will include treatment group, time and interaction between treatment group and time, 
and baseline value. Time will be considered as categorical variables. Analyses will be run on each of 
the 10 
p-values will be two-tailed, with a significant level of 0.05. Data will be summarised in tables by the 
mean and standard error. 
 
To assess the impact of study treatment in the evolution of each of the 5 dimensions (mobility, self- 
care, usual activities, pain/discomfort and anxiety/depression), a generalized estimating equation 
(GEE) model with a multinomial distribution (if 3 levels) or binomial distribution (if 2 levels) will be 
used. Each dimension: mobility, self-care, usual activities, pain/discomfort and anxiety/depression will 
be used as qualitative variables. If the numbers of reported level 3 problems are very low, we will 
group together level 2 and 3. Analyses will be run on each of the 10 datasets, including the imputed 
time and interaction between time and treatment group, and baseline score as covariate. Time will be 
considered as categorical variable. The p-values will be two- tailed, with a significant level of 0.05. 
 
(m) Changes in patient satisfaction from baseline. 


Statistical Analysis Plan
WISARD Study Protocol
 
 
d by self-reported questionnaires at baseline (HIVTSQs 
(status)) and post-baseline (HIVTSQc (change)) at weeks 24, 48 and 96. Each questionnaire include 
12 items scored from 0 (dissatisfied) to 6 (satisfied) for HIVTSQs and scored from -3 (much less 
satisfied now) to 3 (much more satisfied now) for HIVTSQc. A global satisfaction score will be 
calculated at each time point by summing the result of the 12 items, leading to a global HIVTSQs 
score at baseline ranging from 0 to 72 (72 being higher satisfaction) and global HIVTSQc (change) 
post-baseline score ranging from -36 to 36 (36 being much more satisfaction). The analysis will 
include all participants from the mITT population that will complete at least one of the 4 
questionnaires (baseline, weeks, 24, 48, 
-
baseline between the two treatment groups using mixed models for repeated measures with random 
intercepts and unstructured covariance matrix
(HIVTSQs). The models will include treatment group, time and interaction between treatment group 
 
variables. Data will be also summarised in tables by mean and standard error. 
 
(n) Pittsburgh Sleep Quality Questionnaire 
 
The Pittsburgh Sleep Quality Index (PSQI) contains 19 questions on the participant and 5 questions on 
the bed partner or roommate (if one is available). Only questions on the participant are included in the 
scoring. The 19-participant items are combined to form seven "component" scores, each of which has 
a range of 0-3 points. In all cases, a score of "0" indicates no difficulty, while a score of "3" indicates 
severe difficulty. The seven component scores are then added to yield one "global" score, with a range 
of 0-21 points, "0" indicating no difficulty and "21" indicating severe difficulties in all areas. The 
seven components are: component 1 (Subjective sleep quality); component 2 (Sleep latency); 
component 3 (Sleep duration); component 4 (Habitual sleep efficiency); component 5 (Step 
disturbances); component 6 (Use of sleeping medication); component 7 (Daytime dysfunction). 
Appendix shows how to calculate each component score. 
As some data will be missing and because it is better to input than to ignore them, a multiple 
imputation using Chained Equations approach (MICE) will be used to fill in missing data. Ten 
imputations (M=10) will be chosen to obtain valid inference and reduce sampling variability resulting 
from the imputation process.  
This analysis will include all participants from the mITT population that will complete at least one of 
the 4 questionnaires (baseline, weeks, 24, 48, 72, and 96). In each questionnaire, participants with 
more than 20% of missing data will be excluded from the analysis of the questionnaire. 
The changes from baseline to week 24, 48, 72 and 96 will be compared between the 2 groups using 
mixed models for repeated measures with random intercept and unstructured covariance matrix, 
tment group, time and interaction 


Statistical Analysis Plan
WISARD Study Protocol
 
 
as categorical variables. Analyses will be run on each of the 10 datasets, including the imputed values, 
and the results 
-values will be two-tailed, with a significant 
level of 0.05. Data will be also summarised in tables by mean and standard error. 
 
(o) Changes from baseline in hsCRP over 96 weeks with evaluation at week 24, 48 and 96 
 
The evolution of hsCRP over 96 weeks according to the treatment group will be described by 
boxplots for each treatment group at baseline, weeks 24, 48 and 96.  
The changes from baseline will be compared between the two treatment groups using mixed 
models for repeated measures with random intercept and unstructured covariance matrix adjusted 
for baseline value. The model will include treatment group, time and interaction between 
treatment group and time, and baseline value as covariate. Time will be considered as categorical 
variables. Data will be also summarised in tables by mean and standard error. 
If the residual of the mixed model is not normally distributed and therefore does not allow the use 
of parametric test, the non-parametric Mann-Whitney-Wilcoxon test will be used to compare the 
changes from baseline to week 24, 48 and 96 between the two treatment groups.  
 
12. Reporting Conventions 
 
P-
-values less than 0.001 will be reported as 
standard deviation, and any other statistics other than quantiles, will be 
reported to one decimal place greater than the original data. Quantiles, such as median, or 
minimum and maximum will use the same number of decimal places as the original data. 
Estimated parameters, not on the same scale as raw observations (e.g. regression coefficients) will 
be reported to 3 significant figures. 
 
13. Technical Details 
Data will be summarised using the IBM SPSS® statistics software version 24. The non-parametric 
analyses will be performed also with IBM SPSS statistics software version 24. The Poisson regression 
analysis, PK analysis and Figures will be done using Stata® SE software version 13. Generalised 
estimating equation and mixed models will be performed using SAS® software version 9.4. 


Statistical Analysis Plan
WISARD Study Protocol
 
 
14. References 
1. 
Llibre JM, Hung CC, Brinson C, Castelli F, Girard PM, Kahl LP, Blair EA, Angelis K, 
Wynne B, Vandermeulen K, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine 
for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, 
non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839-49. 
2. 
Katlama C, Assoumou L, Valantin MA, Soulie C, Martinez E, Beniguel L, Bouchaud O, Raffi 
F, Molina JM, Fellahi S, et al. Dual therapy combining raltegravir with etravirine maintains a 
high level of viral suppression over 96 weeks in long-term experienced HIV-infected 
individuals over 45 years on a PI-based regimen: results from the Phase II ANRS 163 ETRAL 
study. J Antimicrob Chemother. 2019;74(9):2742-51. 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
APPENDIX: PITTSBURGH SLEEP QUALITY INDEX (PSQI) 
 
INSTRUCTIONS: The following questions relate to your usual sleep habits during the past month only. 
Your answers should indicate the most accurate reply for the majority of days and 
nights in the past month. Please answer all questions. 
 
1. What time did the subject usually go to bed at night? (24 hour clock) 
USUAL BED TIME _ _ 
_ _ _ 
_ _ _ 
_ _ _ 
_ _ _ 
_ _ _ _ _ 
_ _ _ 
_ _ _ _ _ 
 
2. How long (in minutes) has it usually taken theb subject to fall asleep each night?       NUMBER 
OF MINUTES  
_ 
 
3. What time has the subject usually gotten up in the morning? 
 
 
 
 
 
 
USUAL GETTING UP TIME _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ 
 
4. How many hours of actual sleep did the subject get at night? {This may be different than the number of hours 
you spend in bed.) 
HOURS OF SLEEP PER NIGHT  
_ 
 
 
 
INSTRUCTIONS: For each of the remaining questions, enter the one best response. 
Please answer all questions. 
 
5. 
During the past month, how often has the subjject had trouble sleeping because they... 
 
 
 
 
Not during the 
 Lessthan 
 
Once or 
Three or more 
past month 
once a week 
twice a week 
 times a week 
(a) ...cannot get to sleep within 30 minutes 
 
 
 
 
{b) ...wake up in the middle of the night or 
 
(b)  wake up 
in the middle 
of the night or 
early morning 
  
    
    
   
(c)  ...have to get up to use the bathroom 
 
 
 
 
{d    ...cannot breathe comfortably 
 
 
 
 
(e) ...cough  or snore loudly 
 
 
 
 
(f) ...feel tao cold 
 
 
 
 
(g) ...feel tao hot 
 
 
 
 
{h)  ...had bad dreams 
 
 
 
 
(i) ...have pain 
 
 
 
 
(j) Other reason(s), please describe 
 
 
How often during the past month has the 
subject had trouble sleeping because of 
this (Other reason)? 
PSOI Page 1 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
 
 
6. How would the subject rate their sleep 
quality overall? 
 
 
7. How often has the subject taken   
Very good 
Fairly good 
Fairly bad 
very bad 
 
 
 
 
Not during the  
Less than 
 
Once or 
 Three or more 
past month 
once a week 
twice a week 
times a week 
medicine to help them sleep (prescribed 
or "over the counter")? 
8. How often has the subject had trouble 
 
 
 
 
 
 
 
 
 
staying awake while driving, 
eating 
meals, or engaging in social activity? 
 
 
9. How much of a problem has it been  
No problem 
Only a very 
Somewhat of 
Avery 
at ail 
slight problem 
a problem 
big problem 
for the subject to keep up enough enthusiasm 
to get things done? 
 
Partner / room mate information 
 
 
No bed 
Partner/ 
Partner in same 
partner or 
roommate in 
room, but not 
Partner in 
roommate 
 other room 
 same bed 
same bed 
10. 
Does the subject has a bed partner 
or room mate? 
If the subject has a roommate or bed partner, how often in the past month would the bed partner or room mate say 
the subject experienced: 
 
Not during the
Less than
Once or
Three or more
past month
once a week
twice a weektimes a week
(a) ...loud snoring  
 
 
(b)    ...long pauses  between  breaths while asleep 
 
 
 
(c) ...legs twitching or jerking while you sleep 
(d) ...episodes of disorientation or confusion 
during sleep 
  Has the subject experienced any other restlessness while sleeping? 
 Please describe 
(e) How often during the past month 
has the subject experienced this 
other restlessness ? 
 
 
 
 
 
 
 
 
PSQ/ Page 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
SCORING INSTRUCTIONS FOR THE PITTSBURGH SLEEP QUALITY INDEX: 
The Pittsburgh Sleep Quality Index (PSQI) contains 19 questions on the participant and 5 questions 
on the bed partner or roommate. Only questions on participnt are included in the scoring. The 19-
participant items are combined to form seven "component" scores, each of which has a range  of 0-3 
points. ln all cases, a score of "0" indicates no difficulty, while a score of "3" indicates severe difficulty. 
The seven component scores are then added to yield one "global" score, with a range of 
0-21 points, "0" indicating no difficulty and "21" indicating severe difficulties in all areas. 
Scoring proceeds as follows: 
Component 1: Subjective sleep quality 
Examine question #6, and assign scores as follows: 
Component 1 
Response 
"Very good" 
"Fairly good" 
"Fairly bad" 
"Very bad" 
score 
0 
1 
2 
3 
 
 
 
 
 
Component 1 score:   
 
 
Component 2: Sleep latency 
1. Examine question #2, and assign scores as follows: 
Respo\nse 
:::15 minutes 
16-30 minutes 
31-60 minutes 
> 60 minutes 
Score 
0 
1 
2 
3 
Question  #2 score: 
  
 
 
2. Examine question #5a, and assign scores as follows: 
Response 
Score 
Not during the past month 
0 
Less than once a week 
1 
Once or twice a week 
2 
Three or more times a week 
3 
Question  #Sa score: 
  
 
3. Add #2 score and #5a score 
Sum  of #2  and #Sa: 
  
 
4. Assign component 2 score as follows: 
Sum of #2 and #5a 
Component 2 score 
0 
0 
1-2 
3-4 
5-6 
PSOI Page 3 
1 
2 
3 
Component 2 score:   
 


Statistical Analysis Plan
WISARD Study Protocol
 
 
Component 3: Sleep duration 
Examine question #4, and assign scores as follows: 
 
Component 3 
Response 
> 7 hours 
6-7 hours 
5-6 hours 
<  5 hours 
score 
0 
1 
2 
3 
 
Component 3 score:  
 
_ 
 
Component 4: Habitual sleep efficiency 
1. Write the number of hours slept (question #4) here:  
 
_ 
2. Calculate the number of hours spent in bed: 
Getting up time (question #3):  
 
_ 
Bedtime (question #1):  
 
_ 
 
Number of  hours  spent in bed:  
 
_ 
 
3. Calculate habitual sleep efficiency as follows: 
(Number of hours slept/Number of hours spent in bed) X 100 = Habitual sleep efficiency (%) 
(  
/  
) X 100= % 
 
4. Assign component 4 score as follows: 
 
Habitual sleep efficiency % 
>85% 
75-84% 
65-74% 
< 65% 
 
 
Component 4 score 
0 
1 
2 
3 
 
Component 4 score:   
_ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSQ/ Page4 


Statistical Analysis Plan
WISARD Study Protocol
 
 
Component 5: Step disturbances 
1 . Examine questions #5b-5j, and assign scores for each question as follows : 
Response 
 
 
Score 
Not during the  past month 
0 
Less than once a week 
1 
Once or twice a week 
2 
Three or more times a week 
3 
5b score: 
  
 
5c score: 
  
 
5d score: 
  
 
5e score: 
  
 
5f score : 
  
 
5g score : 
  
 
5h score: 
  
 
5i score : 
  
 
5j score: 
  
 
 
2. Add the scores for questions #5b-5j: 
Sum  of #5b-5j: 
  
 
 
3. Assign component 5 score as follows: 
Sum of #5b-5j 
 
Component 5 score 
0 
0 
1-9 
10-18-4 
19-27 
1 
2 
3 
Component 5 score:  
 
_ 
 
Component 6: Use of sleeping medication 
Examine question #7 and assign scores as follows: 
Component 6 
Response 
 
 
     score 
Not during the past month 
0 
Less than once a week 
1 
Once or twice a week 
2 
Three or more times a week 
3 
 
 
 
 
 
 
 
 
 
 
Component 6 score:   
_ 
 
 
 
 
 
 
 
 
 
PSOI Page5 


Statistical Analysis Plan
WISARD Study Protocol
 
 
 
Component 7: Daytime dysfunction 
1. Examine question #8, and assign scores as follows: 
Response 
 
 
 
Score 
Never 
0 
Once or twice 
1 
Once or twice each week 
2 
Three or more times each week 
3 
Question#B score: 
  
 
 
2. Examine question #9, and assign scores as follows: 
Response 
 
 
 
Score 
No problem at all 
0 
Only a very slight problem 
1 
Somewhat of a problem 
2 
A very big problem 
3 
Question #9 score : 
  
 
 
3. Add the scores for question #8 and #9: 
Sum  of  #8 and #9: 
  
 
 
4. Assign component 7 score as follows: 
Sum of #8 and #9 
 
 
Component 7 score 
0 
0 
1-2 
1 
3-4 
2 
5-6 
3 
Component  7 score:  
 
_ 
 
 
Global PSQI Score 
Add the seven component scores together: 
Global PSOI Score:  
 
_ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSOI Page 6 
 

Prot_001.pdf: 
CONFIDENTIAL
 
 
WISARD Study Protocol
Page 1 of 91
Version 5.0 dated 30Oct2020
 
 
 
 
 
 
 
 
 
 
Version 5.0 dated 30Oct2020 
 
 
 
Sponsor number: SSCR105/NEAT33  
EudraCT: 2017-004040-38 
Sponsor: NEAT ID 
 
 
 
 
 
 
 
 
Private & Confidential 
AN OPEN-LABEL, MULTI-CENTRE, RANDOMISED, SWITCH STUDY TO EVALUATE THE 
VIROLOGICAL EFFICACY OVER 96 WEEKS OF 2-DRUG THERAPY WITH DTG/RPV 
FDC IN ANTIRETROVIRAL TREATMENT-EXPERIENCED HIV-1 INFECTED SUBJECTS 
VIROLOGICALLY SUPPRESSED WITH NNRTIS RESISTANCE MUTATION K103N. 
-WISARD- 
GCP Compliance Statement: 
This trial will be conducted in compliance with the protocol, the principles that have their origin 
in the Declaration of Helsinki and all applicable regulatory requirements 


CONFIDENTIAL
WISARD Study Protocol
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Version 5.0 dated 30Oct2020
SPONSOR AND CHIEF INVESTIGATOR SIGNATURE PAGE
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), 
amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial regulations, 
GCP guidelines, the Sponsor’s SOPs, and other regulatory requirements as amended.
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor.
I also confirm that I will make the findings of the study available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account 
of the study will be given; and that any discrepancies from the study as planned in this protocol will be 
explained.
For and on behalf of the trial Sponsor:
e-signature provided by: Prof Anton Pozniak, President – NEAT ID
Chief Investigator:
e-signature provided by: Dr Graeme Moyle, Chief Investigator


CONFIDENTIAL
WISARD Study Protocol
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Version 5.0 dated 30Oct2020
STATISTICIAN OR STUDY ANALYST SIGNATURE PAGE
The undersigned confirm that the following protocol has been agreed and accepted and that the 
Statistician or Study Analyst agrees to conduct the trial in compliance with the approved protocol, 
Statistical Principles for Clinical Trials, ICH E10 and will adhere to the principles outlined in the Medicines 
for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), amended regulations (SI 2006/1928) and
any subsequentamendmentsoftheclinicaltrialregulations, GCP guidelines, the Sponsor’sSOPsand other 
regulatory requirements as amended.
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor.
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account 
of the study will be given; and that any discrepancies from the study as planned in this protocol will be 
explained.
Statistician or Study Analyst:
e-signature provided by: Lambert Assoumou, Study Statistician


CONFIDENTIAL
 
 
WISARD Study Protocol
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Version 5.0 dated 30Oct2020
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
I agree to conduct the trial in accordance with ICH-GCP and the applicable regulatory requirements and 
with the approved protocol. 
 
 
I agree to comply with the procedures for data recording/reporting. 
 
 
I agree to permit monitoring, auditing and inspection at this site and to retain all trial related essential 
documentation for the duration of the study as required according to ICH-GCP. 
 
 
 
Principal Investigator: 
 
 
 
 
 
 
 
e-signature provided by: FULL NAME, TITLE/ROLE 


CONFIDENTIAL
 
 
WISARD Study Protocol
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Version 5.0 dated 30Oct2020
TABLE OF CONTENTS 
SPONSOR AND CHIEF INVESTIGATOR SIGNATURE PAGE .......................................................................... 2 
STATISTICIAN OR STUDY ANALYST SIGNATURE PAGE............................................................................... 3 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ........................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................................ 5 
KEY TRIAL CONTACTS ............................................................................................................................... 8 
STUDY SYNOPSIS ...................................................................................................................................... 9 
LIST OF ABBREVIATIONS......................................................................................................................... 12 
1. 
BACKGROUND & RATIONALE ......................................................................................... 16 
1.1. 
ASSESSMENT AND MANAGEMENT OF RISK ........................................................................................... 16 
2. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS .................................................... 23 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................ 23 
2.2 
SECONDARY OBJECTIVES ....................................................................................................................... 23 
2.3 
OUTCOME MEASURES/ENDPOINTS ........................................................................................................ 23 
  
2.3.1 PRIMARY ENDPOINT/OUTCOME ................................................................................................ 23 
  
2.3.2 SECONDARY ENDPOINTS/OUTCOMES ..................................................................................... 23 
2.4 
EXPLORATORY ENDPOINTS/OUTCOMES ............................................................................................... 24 
3 
TRIAL DESIGN ................................................................................................................. 25 
3.1 
STUDY SCHEMA ........................................................................................................................................ 26 
4 
STUDY SETTING .............................................................................................................. 26 
5 
ELIGIBILITY CRITERIA ...................................................................................................... 27 
5.1 
INCLUSION CRITERIA ................................................................................................................................ 27 
5.2 
EXCLUSION CRITERIA ............................................................................................................................... 28 
6 
TRIAL PROCEDURES ....................................................................................................... 32 
6.1 
RECRUITMENT ........................................................................................................................................... 32 
6.2 
STUDY REGISTRATION ............................................................................................................................. 32 
6.3 
PATIENT IDENTIFICATION ......................................................................................................................... 32 
6.4 
SCREENING ................................................................................................................................................ 33 
6.5 
CONSENT ................................................................................................................................................... 34 
6.6 
RANDOMISATION ....................................................................................................................................... 35 
6.6.1 THE RANDOMISATION SCHEME .................................................................................................... 35 
6.6.2 METHOD OF IMPLEMENTING THE ALLOCATION SEQUENCE ..................................................... 35 
6.6.3 BLINDING ......................................................................................................................................... 35 
6.6.4 UNBLINDING .................................................................................................................................... 35 
6.7 
BASELINE DATA ......................................................................................................................................... 35 
6.8 
STUDY ON TREATMENT VISITS ................................................................................................................ 36 
6.9 
FOLLOW-UP ASSESSMENTS .................................................................................................................... 38 


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6.10 
EARLY TERMINATION VISIT ...................................................................................................................... 38 
6.11 
QUALITATIVE ASSESSMENTS – NESTED STUDIES ............................................................................... 39 
6.12 
WITHDRAWAL CRITERIA ........................................................................................................................... 39 
6.13 
LIVER CHEMISTRY STOPPING AND FOLLOW UP CRITERIA ................................................................ 42 
6.14 
SUICIDAL RISK MONITORING .................................................................................................................. 45 
6.15 
DECLINE IN RENAL FUNCTION ................................................................................................................ 46 
6.16 
PROTEINURIA............................................................................................................................................. 47 
6.17 
CREATINE PHOSPHOKINASE (CPK) ELEVATION ................................................................................. 47 
6.18 
STORAGE AND ANALYSIS OF SAMPLES .................................................................................................. 48 
6.19 
VIROLOGICAL FAILURE ............................................................................................................................. 48 
6.20 
END OF TRIAL ............................................................................................................................................ 48 
7 
TRIAL MEDICATION ........................................................................................................ 49 
7.1 
NAME AND DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT(S) ................................ 49 
7.2 
REFERENCE SAFETY INFORMATION ...................................................................................................... 49 
7.3 
DRUG STORAGE AND SUPPLY ................................................................................................................. 50 
7.4 
PREPARATION AND LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCT ................................. 50 
7.5 
DOSAGE SCHEDULES ............................................................................................................................... 51 
7.6 
DOSAGE MODIFICATIONS ......................................................................................................................... 51 
7.7 
KNOWN DRUG REACTIONS AND INTERACTION WITH OTHER THERAPIES ......................................... 51 
7.8 
CONCOMITANT MEDICATION ................................................................................................................... 52 
7.9 
PRIOR CONCOMITANT THERAPY ............................................................................................................ 52 
7.10 
TRIAL RESTRICTIONS................................................................................................................................ 52 
7.11 
ASSESSMENT OF COMPLIANCE ............................................................................................................... 53 
7.12 
PROVISION OF TREATMENT AFTER THE END OF THE TRIAL ............................................................... 53 
8 
PHARMACOVIGILANCE .................................................................................................. 53 
8.1 
DEFINITIONS .............................................................................................................................................. 53 
8.2 
OPERATIONAL DEFINITIONS FOR (S) AES ............................................................................................ 54 
8.2.1 ASSESSMENT OF INTENSITY ................................................................................................................... 55 
8.2.2 ASSESSMENT OF CAUSALITY .................................................................................................................. 56 
8.2.3 COLLECTION AND FOLLOW UP OF ADVERSE EVENTS ........................................................................ 56 
8.2.4 SERIOUS ADVERSE EVENTS (SAE) & REPORTABLE EVENTS ........................................................... 57 
8.3 
RECORDING AND REPORTING OF SAES AND SUSARS .................................................................. 58 
8.3.1 REPORTING REQUIREMENTS .................................................................................................................. 58 
8.4 
RESPONSIBILITIES .................................................................................................................................... 61 
8.5 
REPORTING URGENT SAFETY MEASURES ............................................................................................. 63 
8.6 
DEVELOPMENT SAFETY UPDATE REPORTS (DSUR) ........................................................... 63 
9 
STATISTICS AND DATA ANALYSIS ................................................................................... 63 
9.1 
SAMPLE SIZE .............................................................................................................................................. 63 
9.2 
STATISTICAL ANALYSIS PLAN .................................................................................................................. 64 
9.2.1 
Summary of baseline data and flow of patients ....................................................   65 
9.2.2 
Primary outcome analysis .....................................................................................   65 
9.2.3 
Secondary outcome analysis ................................................................................   66 
9.3 
SUBGROUP ANALYSES ............................................................................................................................. 66 
9.4 
ADJUSTED ANALYSIS ................................................................................................................................ 66 


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9.5 
INTERIM ANALYSIS .................................................................................................................................... 66 
9.6 
DSMB.............................................................................................................................. 67 
9.7 
SUBJECT POPULATION ............................................................................................................................. 67 
9.8 
PROCEDURE(S) TO ACCOUNT FOR MISSING OR SPURIOUS DATA ..................................................... 68 
9.9 
OTHER STATISTICAL CONSIDERATIONS ................................................................................................. 68 
9.10 
ECONOMIC EVALUATION .......................................................................................................................... 68 
10 
DATA HANDLING ............................................................................................................ 68 
10.1 
DATA COLLECTION TOOLS AND SOURCE DOCUMENT IDENTIFICATION ............................................. 68 
10.1.1 SOURCE DATA........................................................................................................................................... 68 
10.1.2 SOURCE DOCUMENTS ............................................................................................................................. 68 
10.1.3 CASE REPORT FORMS .............................................................................................................................. 69 
10.2 
DATA HANDLING AND RECORD KEEPING ............................................................................................... 70 
10.3 
ARCHIVING ................................................................................................................................................. 70 
11 
MONITORING, AUDIT & INSPECTION ............................................................................. 71 
12 
ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES/ GROUPS & 
 INDIVIDUALS.................................................................................................................72 
13 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................................. 73 
13.1 
ETHICS COMMITTEE (EC) REVIEW & REPORTS .................................................................................. 73 
13.2 
PEER REVIEW ............................................................................................................................................ 73 
13.3 
REGULATORY COMPLIANCE ................................................................................................................... 74 
13.4 
PROTOCOL COMPLIANCE ......................................................................................................................... 74 
13.5 
NOTIFICATION OF SERIOUS BREACHES TO GCP AND/OR THE PROTOCOL .................................... 74 
13.6 
DATA PROTECTION AND PATIENT CONFIDENTIALITY ........................................................................... 75 
13.7 
FINANCIAL AND OTHER COMPETING INTERESTS FOR THE CHIEF INVESTIGATOR, PIS AT EACH SITE AND 
COMMITTEE MEMBERS FOR THE OVERALL TRIAL MANAGEMENT ........................................................ 75 
13.8 
INDEMNITY .................................................................................................................................................. 75 
13.9 
AMENDMENTS ............................................................................................................................................ 75 
13.10 POST TRIAL CARE ..................................................................................................................................... 76 
13.11 ACCESS TO THE FINAL TRIAL DATASET ................................................................................................. 76 
14 
DISSEMINIATION POLICY................................................................................................ 76 
14.1 
DISSEMINATION POLICY ........................................................................................................................... 76 
15 
APPENDICES ................................................................................................................... 77 
APPENDIX 1: ASSESSMENT TABLE....................................................................................................................... 78 
APPENDIX 2: AIDS CLINICAL TRIAL GROUP (ACTG) GRADING SCALE, DAIDS GRADING SCALE ......... 83 
APPENDIX 3: HIGHLY EFFECTIVE METHODS FOR AVOIDING PREGNANCY IN FEMALES OF CHILD BEARING 
POTENTIAL ................................................................................................................................................. 84 
APPENDIX 4: THE CHILD-PUGH CLASSIFICATION SYSTEM .............................................................................. 85 
APPENDIX 5: DATA PROCESSING AGREEMENT ................................................................................................ 86 
APPENDIX 6: AMENDMENT HISTORY ................................................................................................................... 89 
 


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KEY TRIAL CONTACTS 
 
 
Chief Investigator 
Dr Graeme Moyle 
Chelsea and Westminster NHS Foundation Trust 
369 Fulham Rd 
London, SW10 9NH 
UK 
Sponsor 
NEAT ID Foundation 
CHU Saint Pierre 
PL 709 Rue Haute 322 
1000 Brussels 
Belgium 
Project Management 
WISARD Project Manager 
Research Organisation (KC) Ltd. (ROKC) 
27 Old Gloucester Street 
London, WC1N 3AX 
United Kingdom 
Data Management 
Biometrics Team 
Research Organisation (KC) Ltd. (ROKC) 
27 Old Gloucester Street 
London, WC1N 3AX 
United Kingdom 
Statistics 
Lambert Assoumou 
NEAT ID Foundation 
CHU Saint Pierre 
PL 709 Rue Haute 322 
1000 Brussels 
Belgium 
ANRS, Pierre Louis Institute of Epidemiology and Public Health, 
UMR-S 1136, 
INSERM 
 
Sorbonne Universités UPMC 
Paris Univ 06, 
France 
Peripheral Blood 
Monoclonal Cell (PBMC) 
Central Laboratory 
Prof. Bonaventura Clotet 
Institut de Recerca del Sida Irsi Caixa 
Hospital Germans Trias i Pujol 
2nd floor, Maternity building 
Ctra. de Canyet, s/n 
08916 Badalona (Barcelona) 
Spain 
PK Central Laboratory 
Prof Saye Khoo 
Liverpool Bioanalytical Facility 
Royal Liverpool University Hospital 
4th Floor UCD 
Prescot Street 
Liverpool, L69 3GA, UK 


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STUDY SYNOPSIS 
 
 
Full study Title 
An open-label, multi-centre, randomised, switch study to evaluate the virological 
efficacy over 96 weeks of 2-drug therapy with DTG/RPV FDC in antiretroviral 
treatment-experienced HIV-1 infected subjects virologically suppressed with NNRTIs 
resistance mutation K103N. 
Short title/Acronym 
WISARD: acronym of SWItch Study mutAtion Rilpivirine Dolutegravir. 
Clinical Phase 
3b 
Trial Design 
Open-label, 2 arm, phase 3b, multi-centre switch study 
Name of Investigational 
Product 
Dolutegravir & Rilpivirine 2 drug fixed dose combined therapy. 
“Juluca” is the brand name and will hereinafter be referred to as combined 
dolutegravir (DTG) and rilpivirine (RPV). Investigational product may be provided as 
commercial “Juluca” or unbranded supply of DTG + RPV. 
Boosted protease inhibitors or other ARV regimen (including Anatomical 
Therapeutic Chemical Classification System codes: JO5AB, JO5AE, JO5AF, JO5AG, 
JO5AR, JO5AX) 
Trial Participants 
population 
18years, male & female 
Planned Sample Size 
Up to 150 evaluable subjects. 
Eligibility Criteria 
HIV-1 infected adults aged 18 years or over, virologically suppressed with NNRTIs 
resistance mutation K103N. (Subjects who at any time have had the mutations 100I, 
101E/P, 106A/M, 138K/G/Q, 181C/I/V, 188L, 190A/S/E/Q, 230L mutations are to be 
excluded. Other NNRTI region variants can be included). 
Treatment duration 
96 weeks 
Follow up duration 
30 days 
Formulation, Dose, 
Route of Administration 
Experimental arm (Baseline visit switch group): One combined Dolutegravir 50mg 
/Rilpivirine 25mg FDC tablet taken orally once daily for 96 weeks. 
Control arm (deferred week 48 switch group): patients will continue their current 
boosted PI regimen (or other antiretroviral combination) for 48 weeks. Patients will 
then be switched to one combined Dolutegravir/Rilpivirine FDC tablet taken orally 
once daily for 48 weeks. 
Indication 
HIV-1 infected patients with a history of virological failure to NNRTIs and having the 
K103N mutation. 
Methodology 
Eligible consented patients will be randomised 2:1 to switch to the experimental 
arm or continue on their current therapy and switch at week 48(control arm). 
Efficacy will be assessed by maintenance of virological success. 
Number of sites 
36 sites in 7 countries 
(United Kingdom, France, Belgium, Germany, Spain, Italy & Ireland) 


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Objectives 
(See also section 2.4 for 
exploratory objectives) 
Primary 
1. 
To compare viral load 
outcomes on DTG/RPV FDC 
regimen (experimental arm) to 
continued ART regimen (control 
arm) at 48 weeks as measured 
by HIV-1 RNA below or 
confirmed above 50 copies/Ml. 
Secondary 
1. To investigate whether 
switching patients to DTG/RPV 
FDC is associated with 
improvement of lipid profile, 
patient satisfaction, quality of 
life and potential for drug-drug 
interactions. Investigated over 
96 weeks with evaluation at 
week 24, 48 & 96. 
2. To evaluate DTG & RPV trough 
concentrations 
3. Changes in cell associated virus 
(using PBMC analysis) 
Outcome Measures 
Primary 
a. Virological suppression (<50 copies/ml 
HIV RNA) at week 48 in individuals 
with previous NNRTIs virological 
failure and/or baseline transmitted 
resistance with the k103N resistance 
mutation, switching to DTG/RPV FDC. 
(Analysed in line with FDA snapshot) 
b. Virological failure will be 2 
consecutive viral loads >50 copies at 
least 2 weeks apart, investigated over 
48 weeks. 
Secondary 
a. Proportion of participants with 
plasma HIV-1 RNA <50 c/mL at 
week 24, 48 and 96. 
b. Changes in laboratory parameter 
from baseline 
c. Changes in renal markers, bone 
markers, and fasting lipids from 
baseline, week 24, 48 and 96. 
d. Resistance in failures (descriptive 
analysis) and baseline factors 
associated with failures. 
e. Changes in QoL and patient 
satisfaction from baseline. 
f. Number of participants with 
adverse events (AEs), Severity of 
AEs, and treatment 
discontinuations due to AEs. 
g. Number of potential DDIs avoided. 
h. Virological suppression (<200 
copies/ml HIV RNA) at week 24, 48, 
96 in individuals with previous 
NNRTIs virological failure and/or 
baseline transmitted resistance 
with the k103N resistance 
mutation, switching to DTG/RPV 
FDC. Analysed in line with FDA 
Snapshot method. 
i. Pre-dose plasma concentrations of 
DTG and RPV at week 4 
(experimental arm only), 48 
(experimental arm only) &96. Plus 
pre/post-dose (as appropriate) at 
early termination visit and /or in 
the event of virological failure, a 
post dose sample will be taken 
within 20-28 hours. 
j. Changes in cell associated virus 
using PBMC Illumina MiSeq 
sequencing at week 48 and week 
96. 


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FUNDING AND SUPPORT 
 
 
FUNDER (& COLLABORATOR) 
ViiV Healthcare Ltd (herein after known as “ViiV”) 
980 Great West Road, 
Brentford, Middlesex, 
TW8 9GS 
 
KEY CONTRIBUTORS 
 
 
 
 
 
Dr Marta Boffito 
Chelsea and Westminster Hospital, 
369 Fulham Road, 
Chelsea, 
London, 
SW10 9NH 
Michael Aboud  
ViiV Healthcare Ltd 
980 Great West Road, 
Brentford, Middlesex, 
TW8 9GS 
Jim Demarest 
ViiV Healthcare Ltd 
980 Great West Road, 
Brentford, Middlesex, 
TW8 9GS 


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LIST OF ABBREVIATIONS 
 
 
 
Acronym 
Description 
ABC 
Abacavir 
ACR 
Albumin: Creatinine Ratio 
ACTG 
AIDS Clinical Trial Group 
AE 
Adverse Event 
ALT 
Alanine Amino Transferase 
ALT (SGPT) 
Alanine transaminase (serum glutamic-pyruvic transaminase) 
APR 
Annual Progress Report 
AR 
Adverse Reaction 
ART 
Anti Retroviral 
AST 
Aspartate aminotransferase 
AST (SGOT) 
Aspartate Aminotransferase (serum glutamic-oxaloacetic transaminase) 
AV Block 
Atrioventricular Block 
BL 
Baseline 
BMD 
Bone Mineral Density 
CA 
Competent Authority 
CAR 
Current Antiretroviral Therapy 
CD4 
Cluster of Differentiation 4 
CD8 
Cluster of Differentiation 8 
CI 
Chief Investigator 
CNS 
Central Nervous System 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine Phospohokinase 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CSR 
Clinical Study Report 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
cTnI 
Cardiac Troponin I 
cTnT 
Cardiac Troponin T 
CVA 
Cerebral Vascular Accident 
DAIDS 
The Division of AIDS 
DDI 
Drug-Drug Interaction 
DILI 
Drug Induced Liver Injury 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 


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DSUR 
Development Safety Update Report 
DTG 
Dolutegravir 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EFV 
Efavirenz 
EMEA 
European Medicines Agency 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
EVG 
Elvitegravir 
FCBP 
Females of Childbearing Potential 
FDA 
Food and Drug Administration (United States of America) 
FDC 
Fixed-Dose Combination 
FEV1 
Forced Expiratory Volume in the first second 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GMP 
Good Manufacturing Practice 
GSK 
GlaxoSmithKline 
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
HIV RNA 
Human Immunodeficiency Virus Ribonucleic Acid 
HLA 
Human Leukocyte Antigen 
HS CRP 
High-Sensitivity C-reactive protein 
HSR 
Hyper Sensitivity Reaction 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical requirements for 
registration of pharmaceuticals for human use. 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
INI 
Integrase Inhibitors 
INR 
International Normalised Ratio (for blood clotting time) 


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INSTI 
Integrase Strand Transfer Inhibitor 
ISF 
Investigator Site File 
ISRCTN Number 
International Standard Randomised Controlled Trials 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone Releasing System 
LDL 
Low Density Lipoprotein 
LLN 
Lower limit of Normal 
MA 
Marketing Authorisation 
MCH 
Mean Cell Haemoglobin 
MCV 
Mean Cell Volume 
MDRD 
Modified Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MS 
Member State 
NEAT ID 
The European treatment network for HIV, hepatitis and global infectious diseases 
NHS 
National Health Service 
NIMP 
Non-Investigational Medicinal Product 
NNRTIs 
Non-Nucleoside Reverse Transcriptase Inhibitors 
NRTIs 
Nucleoside Reverse Transcriptase Inhibitors 
NVP 
Nevirapine 
OCT-2 
Organic Cation Transporter 
OD 
Once daily 
PBMC 
Peripheral Blood Monoclonal Cell layer 
PCR 
Protein: Creatinine Ratio 
pH 
Power of hydrogen 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PK 
Pharmacokinetics 
PRTD 
Proximal Renal Tubule Dysfunction 
PSRAEs 
Suicidality-related adverse events 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QA 
Quality Assurance 
QC 
Quality Control 
QoL 
Quality of Life 
QoL Q 
Quality of Life Questionnaire 
QP 
Qualified Person 
RAL 
Raltegravir 
RBC 
Red Blood Cell 


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RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
RNA 
Ribonucleic Acid 
ROKC 
Research Organsiation (KC) Ltd 
RPV 
Rilpivirine 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SERF 
Safety Event Reporting Form 
SJS 
Stevens-Johnson Syndrome 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TDR 
Drug Transmitted Resistance 
TEN 
Toxic Epidermal Necrolysis 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TPN 
Total Parental Nutrition 
TSC 
Trial Steering Committee 
ULN 
Upper limit of Normal 
USM 
Urgent Safety Measure 
VL 
Viral Load 
WBC 
White Blood Cell 
WK 
Week 
WOCBP 
Women of Child-Bearing Potential 


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1. BACKGROUND & RATIONALE 
 
 
HIV-1 infected patients that experience virological failure while on NNRTIs (EFV or NVP) with 
development of K103N mutation (+/- other NNRTIs and/or NRTIs mutations) are usually switched to a 
boosted PI-based regimen or other complex ARV combinations. The same is true for patients who need 
to start antiretroviral therapy and have acquired virus that is already resistant to antiretrovirals (drug 
transmitted resistance, TDR). These “second line” combinations are often associated with numerous 
issues that can have a potential impact on the quality of life (QoL) of these patients: high pill burden, 
high potential for drug-drug interactions (DDIs), persistent side effects and metabolic toxicity. Therefore, 
a simpler and better tolerated alternative 2nd line treatment option would be a useful tool for the clinical 
management of these patients. 
Dolutegravir (DTG) is a well-tolerated 2nd generation integrase strand transfer inhibitor (INSTI) with a 
low metabolic impact and low DDI potential; rilpivirine (RPV) is a well-tolerated NNRTI not affected by 
the presence of the K103N mutation, characterised by a lower DDI potential and metabolic impact 
compared to other NNRTIs. Neither requires a PK boosting agent. The aim of this study is to assess the 
efficacy and tolerability of a dual combined therapy with DTG 50 mg OD + RPV 25 mg OD in virologically 
suppressed patients with previous virological failure with NNRTIs and having the clinically significant 
mutation K103N. Secondary objective of the study is to assess whether a simplification of the treatment 
in term of pill burden, long term metabolic toxicity and potential of DDI improves the QoL of the 
participants. The study will also evaluate DTG & RPV trough concentrations plus changes in cell 
associated virus. 
 
1.1. 
Assessment and management of risk 
Summaries of findings from both clinical and non-clinical studies conducted with DTG or RPV can be 
found in the IBs and product labels for each individual drug. 
The following section outlines the risk assessment and mitigation strategy for DTG and RPV in this 
protocol. Where available, the approved country product label should be referenced. For other ART 
regimens the approved country product labels should be referenced. See section 7.2 for RSI details. 


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Table 1.0 : Outline of the risk assessment and mitigation strategy for this protocol 
 
Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [DTG/RPV FDC] 
Refer to individual IBs for DTG and RPV and the Juluca SmPC for additional information 
DTG: 
Hypersensitivity 
reaction (HSR) 
and rash 
RPV: Rash 
DTG: Hypersensitivity is a recognised risk 
with integrase inhibitors, including DTG. 
HSR were characterised by rash, 
constitutional findings, and sometimes 
organ dysfunction, including severe liver 
injury. Hypersensitivity has been observed 
uncommonly with DTG in clinical trials. 
Rash was commonly reported in DTG 
Phase IIb/III clinical trials; episodes were 
generally mild to moderate in intensity; no 
episodes of severe rash, such as Stevens- 
Johnson Syndrome (SJS), Toxic Epidermal 
Necrolysis (TEN) and erythema multiforme 
were reported. 
RPV: Based on the association between 
other NNRTIs (such as EFV and NVP) and 
severe rash, and some observations of 
grade 1 and 2 rashes with RPV in clinical 
studies, severe skin reactions are also 
considered a potential risk for RPV. 
In clinical trials with DTG/RPV FDC, the risk 
of HSR was low. Serious skin reactions 
have not been seen with DTG+RPV FDC in 
clinical trials. 
Subjects with history of 
allergy/sensitivity to any of the study 
drugs are excluded (Section 5.2). 
 
Specific/detailed toxicity management 
guidance is provided for HSR and rash 
(Section 6.12). 
 
The subject informed consent form 
includes information on this risk and the 
actions subjects should take in the event 
of: 1) a HSR or associated signs and 
symptoms; or 2) developing any type of 
rash or skin abnormality. For Grade 3/4 
rash, except where the etiology is clear 
and not associated with study drug or 
where there is a definitive diagnosis 
clearly attributable to a concomitant 
medication (and not to study drug) or to 
a concomitant infection, subjects must 
permanently discontinue study drug and 
be withdrawn from the study. 
DTG & RPV: Drug 
induced liver 
injury (DILI) and 
other clinically 
significant liver 
chemistry 
elevations 
DTG: Non-clinical data suggested a 
possible, albeit low, risk for hepatobiliary 
toxicity with DTG. Drug-related hepatitis is 
considered an uncommon risk for ART 
containing DTG regardless of dose or 
treatment population. For subjects with 
hepatitis B virus (HBV) and/or hepatitis C 
virus (HCV) co-infection, improvements in 
immunosuppression as a result of HIV 
virologic and immunologic responses to 
DTG- containing ART, along with 
Subjects meeting either of the following 
criteria during the screening period are 
excluded from participating. 
 
 Alanine aminotransferase (ALT) 5 
times the upper limit of normal (ULN) 
or ALT 3xULN and bilirubin 1.5x 
ULN (with >35% direct bilirubin) 
 Subjects with acute viral hepatitis 
 Subjects positive for Hepatitis B 
surface antigen (+HBsAg) at screening 


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Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [DTG/RPV FDC] 
Refer to individual IBs for DTG and RPV and the Juluca SmPC for additional information 
 
inadequate therapy for HBV co-infected 
subjects, are likely contributed to 
significant elevations in liver chemistries. 
RPV: Hepatic events have been reported in 
patients receiving a RPV containing 
regimen. Patients with underlying HBV, 
HCV, or marked elevations in 
transaminases prior to treatment may be 
at increased risk for worsening or 
development of transaminase elevations 
with use of RPV. A few cases of hepatic 
toxicity have been reported in patients 
receiving a RPV containing regimen who 
had no pre-existing hepatic disease or 
other identifiable risk factors. 
Hepatotoxicity is considered a risk for both 
DTG and RPV. Based on clinical trial data, 
synergistic or additive hepatotoxicity is not 
expected with DTG + RPV FDC. 
 Subjects with an anticipated need for 
HCV therapy during the study. 
 
Specific detailed liver stopping criteria 
and toxicity management guidance is 
provided for suspected DILI or other 
clinically significant liver chemistry 
elevations (Section 6.13). 
DTG & RPV: 
Psychiatric 
disorders 
Psychiatric disorders including suicidal 
ideation and behaviours are common in 
HIV-infected patients. Depression including 
suicidal ideation and behaviours is a 
recognised risk for both the DTG and RPV 
components of the DTG/RPV FDC. 
DTG: Depression, including suicidal 
ideation and behaviours, has been 
reported with DTG, particularly in patients 
with a pre-existing history of depression or 
psychiatric illness. A possible class effect 
has been suspected for INI drugs as the 
other two marketed INIs (RAL and EVG) 
have suicidal ideation/behaviours as 
adverse reactions in their product labels. 
The psychiatric profile for DTG (including 
suicidality, depression, bipolar and 
Subjects who in the investigator’s 
judgment, pose a significant suicidality 
risk, are excluded from participating. 
As a result of the elevated risk in the 
HIV- infected population, subjects should 
be monitored closely for suicidal ideation 
and behaviour or any other unusual 
changes in behaviour. Investigators are 
advised to consider mental health 
consultation or referral for subjects who 
experience signs of suicidal ideation or 
behaviour. 


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Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [DTG/RPV FDC] 
Refer to individual IBs for DTG and RPV and the Juluca SmPC for additional information 
 
hypomania, anxiety and abnormal dreams) 
was similar to RAL- or favourable 
compared with EFV- based regimens in 
clinical trials. The reporting rate for 
insomnia was statistically higher for 
blinded DTG+ abacavir/lamivudine 
(ABC/3TC) compared to EFV/TDF/FTC in 
study ING114467; however, this was not 
duplicated in any other Phase IIb/III study 
conducted with DTG. 
RPV: Depression, including suicidal 
ideation and behaviours, has also been 
reported with RPV. As with DTG, RPV 
insomnia and abnormal dreams have been 
commonly reported with RPV. 
No synergistic or additive effect on the risk 
of depression or suicidal behaviours is 
expected from the co-administration of 
DTG and RPV based on available clinical 
trial data. Although the incidence of 
depression or suicidal behaviour is 
expected to be higher in those with a 
previous history, the majority of patients 
with such a history are not expected to 
have a recurrence when treated with DTG 
+ RPV FDC. 
 
DTG & RPV: 
Increased rates of 
virologic failure/ 
Observed 
Resistance 
Virologically suppressed subjects switching 
from stable CAR to DTG + RPV may 
experience virologic failure/breakthrough 
and development of resistance. All 
antivirals are prone to the development of 
resistance in the setting of inadequate 
combination therapy and/or incomplete 
adherence to therapy. DTG + RPV FDC is 
also a new dual antiretroviral regimen 
which is different from current standard 
Subjects will have HIV-1 RNA measured 
at each study visit. Management of 
subjects experiencing an increase in viral 
load is described in Section 6.16. 
 
DSMB review of data may be triggered 
as a result of continuous monitoring of 
protocol-defined virological withdrawal. 


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Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [DTG/RPV FDC] 
Refer to individual IBs for DTG and RPV and the Juluca SmPC for additional information 
 
treatment regimens that contain three 
antiretroviral components. 
DTG: Week 96 and Week 144 analyses for 
the Phase III/IIIb clinical studies supported 
the efficacy findings from earlier analyses 
and demonstrated robust maintenance of 
viral suppression with no finding of HIV-1 
resistance in treatment-naïve subjects. 
RPV: In Phase III clinical trials (pooled 
Week 96 analyses), 3.2% of patients in the 
RPV arm experienced virologic failure 
between Week 48 and Week 96 (2.3 % on 
EFV). 
DTG + RPV dual therapy has not been 
studied in patients with known or 
suspected resistance to integrase 
inhibitors or NNRTIs. 
 
DTG: Theoretical 
serious drug 
interaction with 
dofetilide and 
pilsicainide 
Co-administration of DTG may increase 
dofetilide/pilsicainide plasma 
concentration via inhibition of organic 
cation transporter (OCT-2), resulting in 
potentially life-threatening toxicity. 
The co-administration of DTG with 
dofetilide or pilsicainide is prohibited in 
the study (Section 7.7 & 7.8). 
DTG: Renal 
function 
Mild elevations of creatinine have been 
observed with DTG which are related to a 
likely benign effect on creatinine secretion 
with blockade of OCT-2. DTG has been 
shown to have no significant effect on 
glomerular filtration rate (GFR) or effective 
renal plasma flow. There has been no 
indication of an increased risk of renal 
dysfunction in clinical trials with the 
combination of DTG + RPV. 
Specific detailed toxicity management 
guidance is provided for subjects who 
develop a decline in renal function or 
proteinuria (Section 6.15 & 6.16). 
DTG: Creatine 
Phosphokinase 
(CPK) elevations 
Grade 3 to 4 creatine phosphokinase (CPK) 
elevations were observed with DTG in 
clinical trials. Elevations were usually 
explained by exercise and were transient 
Specific toxicity management guidance is 
provided for subjects who develop grade 
3 or 4 elevations in CPK (see section 6). 


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Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [DTG/RPV FDC] 
Refer to individual IBs for DTG and RPV and the Juluca SmPC for additional information 
and 
rhabdomyolysis 
and asymptomatic. However, as 
rhabdomyolysis and myositis are labelled 
for raltegravir, this is considered a 
potential risk for DTG. Arthralgia and 
myalgia are labelled for DTG. No cases of 
rhabdomyolysis were reported in clinical 
trials with DTG +RPV FDC. 
 
DTG: Neural tube 
defects 
In a birth surveillance study conducted in 
Botswana (the Tsepamo study), 
preliminary results showed that in babies 
born to women who were taking DTG 
when they became pregnant there was an 
increased risk of neural tube defects 
compared with the background rate. Later 
data from the study has shown a 
numerically higher rate of neural tube 
defects with exposure to DTG (0.19%) 
compared to non-DTG-containing 
antiretroviral regimens at the time of 
conception (0.11%), however, the 
difference was not statistically significant. 
A causal relationship of these events to 
the use of dolutegravir has not been 
established. No increased risk of these 
defects was reported in babies born to 
mothers who started dolutegravir 
containing regimen later in pregnancy. 
Dolutegravir was tested in a complete 
package of reproductive toxicology 
studies, including embryofoetal 
development studies. No adverse 
development outcomes, including neural 
tube defects, were identified. In 
reproductive toxicity studies in animals, 
DTG was shown to cross the placenta. 
Data analysed to date from other sources 
including the Antiretroviral Pregnancy  
1. A female subject is eligible to 
participate if she is not pregnant, not 
lactating, and, if she is a female of 
reproductive potential, agrees to 
follow one of the options listed in 
the Modified List of Highly Effective 
Methods for Avoiding Pregnancy in 
Females of Reproductive Potential 
(FRP) (see Appendix 9, Section 
12.9.1) from 30 days prior to the first 
dose of study medication and until 
the last dose of study medication 
and completion of the Follow-up 
visit. 
2. Women who are breastfeeding or 
plan to become pregnant or 
breastfeed during the study are 
excluded; 
3. Women who become pregnant, or 
who desire to be pregnant while in 
the study will have study treatment 
discontinued and will be withdrawn 
from the study. 
4. Females of reproductive potential 
are reminded re: pregnancy 
avoidance and adherence to 
contraception requirements at every 
study visit. 
Pregnancy status is monitored every 4 
weeks throughout the study. 


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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [DTG/RPV FDC] 
Refer to individual IBs for DTG and RPV and the Juluca SmPC for additional information
 
Registry, clinical trials, and post-marketing 
data are insufficient to address the risk of 
neural tube defects with DTG. 
 
RPV: QT interval 
(QTc) 
prolongation and 
overdose 
In healthy subjects, supratherapeutic doses 
of RPV (75 mg once daily and 300 mg once 
daily) have been shown to prolong the QTc 
interval of the electrocardiogram (ECG). 
RPV at the recommended dose of 25 mg 
administered once daily is not associated 
with a clinically relevant effect on QTc and 
accidental overdose would not be 
expected to have a significant effect. 
However, there is a potential that 
intentional overdose of large quantities of 
DTG + FTC FDC could lead to a clinically 
significant prolongation of the QT interval.
Subjects who use medications which are 
associated with a known risk of Torsade 
de Pointes are excluded. 
 
Screening ECG performed to identify 
those with pre-existing prolonged QT 
interval. 
DTG: 
Pancreatitis 
DTG: Pancreatitis is considered a potential 
risk for the DTG component of the DTG+ 
RPV FDC. Lipase elevations are seen in HIV 
patients, with and without ART, and were 
noted in ART naive subjects from the Phase 
IIb and III studies with DTG. In clinical 
studies with DTG + RPV, one patient was 
reported as having acute pancreatitis. 
However, this was a grade 4 increase in 
lipase with no evidence of clinical 
pancreatitis, which resolved within 3 days 
and did not lead to withdrawal. There were 
no cases of pancreatitis in the CAR group. 
 
Lipase elevations may occur in patients 
treated with DTG + RPV FDC but are 
expected to be transient and not result in a 
diagnosis of pancreatitis. 
Patients should be managed as routine 
standard of care. 
 
 
 
 


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2. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 
 
2.1 Primary objective 
 
 
 
To compare viral load outcomes on DTG/RPV FDC regimen (experimental arm) to continued ART 
regimen (control arm) at 48 weeks as measured by HIV-1 RNA below or confirmed above 50 
copies/Ml. 
 
 
2.2 Secondary objectives 
 
 
 
To investigate whether switching patients to DTG/RPV FDC is associated with improvement of lipid 
profile, patient satisfaction, quality of life and potential for drug-drug interactions, investigated over 
time through 96 weeks with evaluation (and comparison to control arm) at week 24, 48 and 96. 
 
To evaluate DTG & RPV trough concentrations 
 
Changes in cell associated virus (using Peripheral Blood Monoclonal Cell (PBMC) analysis) 
 
 
2.3 Outcome measures/endpoints 
 
2.3.1 
Primary endpoint/outcome 
 
 
 
Virological suppression (<50 copies/ml HIV RNA) at week 48 in individuals with previous NNRTIs 
virological failure and/or baseline transmitted resistance with the K103N resistance mutation, 
switching to DTG/RPV FDC. Analysed with FDA snapshot. 
 
Virological failure will be 2 consecutive viral loads >50 copies at least 2 weeks apart, investigated 
over 48 weeks. 
 
 
2.3.2 
Secondary endpoints/outcomes 
 
 
 
Proportion of participants with plasma HIV-1 RNA <50 c/mL at week 24, 48 and 96. 
 
Changes in laboratory parameter from baseline. 
 
Changes in renal markers, bone markers, and fasting lipids from baseline at week 24, 48 and 96. 


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Resistant outcomes in failures (descriptive analysis) and baseline factors associated with failure i.e. 
treatment emergent mutations (NRTI, NNRTI, PI and II regions) as compared with previous 
resistance tests. 
 
Changes in QoL and patient satisfaction from baseline. 
 
Number of participants with adverse events (AEs), severity of AEs, and treatment discontinuations 
due to AEs. 
 
Number of potential DDIs avoided (This will be measured by comparing the drug interaction 
outcomes between antiretroviral therapy and co-medications before and after the switch by using 
the www.hiv-druginteractions.org/ website (within the same study arm and between study arms). 
The grading will be done by looking at how many interactions graded amber or red will be graded 
green after the switch. For example, if a patient on atorvastatin as a co-medication and on two NRTIs 
and darunavir/cobicistat he would score “one amber and two green” and when switched to 
rilpivirine/dolutegravir, he would score “all green”, showing the latter regimen is more favourable 
in terms of drug-drug interactions). 
 
Virological suppression (<200 copies/ml HIV RNA) at week 24, 48, 96 in individuals with previous 
NNRTIs virological failure and/or baseline transmitted resistance with the k103N resistance 
mutation, switching to DTG/RPV FDV. Analysed in line with FDA Snapshot method. 
 
Pre-dose plasma concentrations of DTG and RPV at week 4 (experimental arm only), 48 
(experimental arm only) & 96. Plus pre/post-dose (as appropriate) at early termination visit and /or 
in the event of virological failure (see section 6.12) a post dose sample will be taken within 20-28 
hours. 
 
Changes in cell associated virus using PBMC Illumina MiSeq sequencing at week 48 and week 96. 
 
2.4 Exploratory endpoints/outcomes 
 
 
 
Changes in HsCRP over 96 weeks with evaluation at week 24, 48 & 96. 
 
 
Changes in CD4/CD8 over 96 weeks with evaluation at week 24, 48 & 96. 


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3 TRIAL DESIGN 
 
 
Open-label, randomised, 2 arm, multicentre trial over 96 weeks with early or delayed switch from an ARV 
regimen containing a boosted PI (and/or other antiretroviral combinations) to Dolutegravir (DTG) & 
Rilpivirine (RPV) combination therapy in patients with a history of virological failure with NNRTIs or baseline 
drug transmitted resistance and having developed a K103N mutation. 
Patients will be randomised to switch at baseline or at 48 weeks. 
Study visits will take place at screening, baseline, weeks 4, 12, 24, 48, 52, 72, 96, and either a follow-up visit 
(30 days (+/- 7 days) after week 96 visit) or an early termination visit. An optional visit at week 60 may be 
performed for subjects on the control arm (3 months after therapeutic modification) as required per national 
guidelines 
 
Routine investigations will include viral load, CD4 & CD8, haematology (including haemoglobin, white cell 
count and differential, platelets), biochemistry (including sodium, potassium, creatinine, albumin, glucose, 
ALT, AST, ALP, total bilirubin, total cholesterol, HDL, LDL, triglycerides), PK, PBMC, quality of life 
questionnaires (EuroQoL), patient satisfaction questionnaire, Pittsburgh sleep questionnaire, DDI 
assessment & urine sample (for haematuria, proteinuria, glycosuria, leukocytes) for full list of investigations 
please see appendix 1. 


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3.1 Study Schema
Control Arm
Experimental Arm
Figure 1.0
4
STUDY SETTING
This study will be conducted within the NEAT ID network and include sites in 7 countries that have an 
excellent track record in clinical research. A full feasibility assessment will be undertaken for all potential 
sites. A Trial Management Team will facilitate the project. See section9 & 12 for details of DSMB composition 
and responsibilities.
The sponsor will perform site visits to assess protocol issues, consent, project management, data quality, 
drug dispensing, and trial management quality performance.


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5 ELIGIBILITY CRITERIA 
 
 
 
5.1 Inclusion criteria 
Patient volunteers who meet all of the following criteria are eligible for this trial: 
 
1. Is male or female aged 18 years or over. 
 
2. Has documented HIV-1 infection. 
 
3. Is capable of giving informed consent. 
 
4. Is willing to comply with the protocol requirements. 
 
5. Virologically suppressed (plasma HIV-RNA <50 copies/mL) and on a stable regimen for >24 weeks. 
6. Subjects are required to have a history of the K103N mutation (acquired or selected). Subjects who at any 
time have had the mutations 100I, 101E/P, 106A/M, 138K/G/Q, 181C/I/V, 188L, 190A/S/E/Q, 230L 
mutations are to be excluded. Other NNRTI region variants can be included. All PI and NRTI mutations are 
acceptable. Study sites may ask the coordinating centre for advice as required. 
7. Subjects must have never failed INSTI (2 x VL >200 >2 weeks apart) but current regimen can include INSTI. 
8. A female, may be eligible to enter and participate in the study if she: 
is of non-child-bearing potential defined as post-menopausal (12 months of spontaneous 
hormone (FSH) level consistent with postmenopausal status may be used to confirm a post- 
menopausal state in women who are not using hormonal contraception) or hormonal replacement 
therapy at the discretion of the PI. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement alone is insufficient. 
OR is physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or 
bilateral oophorectomy or, 
OR is of child-bearing potential with a negative pregnancy test at Screening (& baseline visit) and 
agrees to use one of the following methods of contraception to avoid pregnancy: 
o True abstinence from penile-vaginal intercourse from 2 weeks prior to administration of IP, 
throughout the study, and for at least 2 weeks after discontinuation of all study medications 
(When this is in line with the preferred and usual lifestyle of the subject.) (Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), and 


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withdrawal are not acceptable methods of contraception]; 
o Any intrauterine device (IUD) with published data showing that the expected failure rate is 
<1% per year (not all IUDs meet this criterion, see Appendix 3 for an example listing of 
approved IUDs); 
o Male partner sterilisation confirmed prior to the female subject’s entry into the study, and 
this male is the sole partner for that subject; 
o Approved hormonal contraception (see appendix 4 for a listing of examples of approved 
hormonal contraception); 
o Any other method with published data showing that the expected failure rate is <1% per 
year; 
o Any contraceptive method must be used consistently and for at least 2 weeks after 
discontinuation of IP. 
9. If a heterosexually active male, he is using effective birth control methods and is willing to continue 
practising these birth control methods during the trial and until follow-up visit. 
10. Subjects currently receiving DTG or RPV, but not both, can be included. 
 
5.2 Exclusion criteria 
Patients meeting 1 or more of the following criteria cannot be selected: 
 
1. 
Infected with HIV-2. 
 
2. 
Detectable HIV-1 RNA at screening (HIV-1 RNA measurement >=50 c/mL). 
 
3. 
 Subjects requiring regular dosing doing with H2 or PPI antacid medications or a history of achlorhidria 
or drug known to interact with RPV or DTG. 
4. 
Use of medications that are associated with Torsades de Pointes. 
 
5. 
Corrected QT interval (QTc [Bazett]) >450 milliseconds or QTc (Bazett) >480 milliseconds for participants 
with bundle branch block. The QTc is the QT interval corrected for heart rate according to Bazett's 
formula (QTcB). 
6. 
Unstable health conditions (i.e. opportunistic infections, cancers, unstable liver disease etc). 
 
7. 
Any evidence of an active Centres for Disease Control and Prevention Category C disease. Exceptions 
include cutaneous Kaposi's sarcoma not requiring systemic therapy and historic CD4+ lymphocyte 
counts of <200 cells/millimeter^3. 


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8. 
History or presence of allergy to the study drugs or their components or drugs of their class. 
 
9. 
Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non- 
invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localised 
malignancies require agreement between the investigator and the Study medical monitor for inclusion 
of the subject prior to randomisation. 
10. Any pre-existing physical or mental condition which, in the opinion of the Investigator, may interfere 
with the subject's ability to comply with the dosing schedule and/or protocol evaluations or which may 
compromise the safety of the participants. Subjects considered to pose a significant risk of suicide 
should be excluded. 
11. Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, 
metabolism or excretion of the study drugs or render the subject unable to take oral medication. 
12. Using any concomitant therapy disallowed as per the reference safety information and product labelling 
for the study drugs. Specifically, co-administration with the following medicinal products is not allowed: 
- dofetilide or pilsicainide; 
 
- fampridine (also known as dalfampridine); 
- carbamazepine, oxcarbazepine, phenobarbital, phenytoin; 
 
- rifampicin, rifapentine; 
 
-  proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, 
rabeprazole; 
- systemic dexamethasone, except as a single dose treatment; 
 
- St John's wort (Hypericum perforatum). 
 
13. Has acute viral hepatitis including, but not limited to, A, B, or C. 
 
14. Active hepatitis B/ Hep B non-immune subjects who have failed vaccination (antibody concentration < 
10 international units). (If local practice does not include vaccination of low risk patients, then the 
patients without HBsAb are not excluded – this must be clearly documented in the medical records and 
eCRF). Note: subjects can be re screened if they receive vaccination and subsequently meet eligibility 
criteria. 
15. Evidence of Hepatitis B virus (HBV) infection based on the results of testing at Screening for Hepatitis B 
surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), and Hepatitis B surface antibody (HBsAb) 


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as follows: Participants positive for HBsAg are excluded; Participants positive for anti-HBc (negative 
HBsAg status) and negative for HBsAb are excluded (if local practice does not include vaccination of low 
risk patients, then the patients without HBsAb are not excluded – this must be clearly documented in 
the medical records and eCRF). Note: Subject positive for anti-HBc (negative HBsAg status) and positive 
for HBsAb are immune to HBV and are not excluded. 
16. Participants with an anticipated need for any Hepatitis C virus (HCV) therapy during the Early Switch 
Phase and for interferon-based therapy for HCV throughout the entire study period. 
17. Any investigational drug within 30 days prior to the trial drug administration. 
 
18. Any evidence of viral resistance different to the one described in the inclusion criteria i.e. not meeting 
inclusion criteria or having different mutation at K103. 
19. Dialysis or renal insufficiency (creatinine clearance < 50ml/min). 
 
20. 
 bilirubin). 
21. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). 
22. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification (see 
appendix 4). 
23. Opportunistic infection within 4 weeks prior to first dose of DTG plus RPV. 
 
24. Clinical decision that a switch of antiretroviral therapy should be immediate. 
 
25. Screening blood result with any grade 3/4 toxicity according to Division of AIDS (DAIDS) grading scale, 
except: asymptomatic grade 3 glucose, amylase or lipid elevation, asymptomatic grade 4 triglyceride 
elevation (re-test allowed) or unconjugated hyperbilirubinaemia due to atanazavir exposure. 
26. Any condition (including illicit drug use or alcohol abuse) or laboratory results which, in the 
investigator’s opinion, interfere with assessments or completion of the trial. 
 
27. Women planning pregnancy or who are pregnant or breast feeding. (NB: See section 6.12 Withdrawal 
Criteria for guidance if pregnancy does occur). 
28. Females of childbearing potential and males must be willing to use a highly effective (acceptable 
effective contraceptive measures are only acceptable for IMP’s with unlikely human teratogenicity / 


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fetotoxicity in early pregnancy) method of contraception (hormonal method of birth control; true 
abstinence). Contraceptive methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods (see Appendix 4). 
Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
 oral 
 intravaginal 
 transdermal 
• progesteron-only hormonal contraception associated with inhibition of ovulation 
 oral 
 injectable 
 implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system ( IUS) 
• bilateral tubal occlusion 
• vasectomised partner 
• true sexual abstinence 
(NB: See section 6.12 Withdrawal Criteria for guidance if pregnancy does occur). 
29. Hypersensitivity to the active substances or to any of the excipients listed below: 
List of excipients 
Tablet core 
 
Mannitol (E421) 
 
Magnesium stearate 
 
Microcrystalline cellulose 
 
Povidone (K29/32) 
 
Sodium starch glycolate 
 
Sodium stearyl fumarate 
 
Lactose monohydrate 
 
Croscarmellose sodium 
 
Povidone (K30) 
 
Polysorbate 20 
 
Silicified microcrystalline cellulose 
Tablet coating 
 
Polyvinyl alcohol- part hydrolysed 
 
Titanium dioxide (E171) 
 
Macrogol 
 
Talc 
 
Iron oxide yellow (E172) 
Iron oxide red (E172) 


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6 TRIAL PROCEDURES 
 
 
The schedule of assessments is summarised in the study flow chart in Appendix 1. From the Baseline visit 
through to follow up, visits may take place +/- 7 days from that specified at the discretion of the Investigator. 
 
Please note that if additional tests / procedures are required in accordance with local practice then these 
should still be performed (no usual tests / procedures should be withheld from the patients during the study). 
 
6.1 Recruitment 
 
 
Following full written informed consent, sites must keep a record of all screening and enrolled participants 
using screening and enrolment logs. Diagnostic tests/procedures may be used in determining eligibility 
however, written informed consent must be obtained prior to any study specific procedures. All information 
collected for eligible participants will be completely anonymised and recorded in the Investigator Site File 
(ISF). 
 
6.2 Study Registration 
All eligible consented participants will be given a unique study identifier via an electronic study database. 
Anonymised information that will be collected are: 
• 
age,
• 
gender,
• 
ethnicity
• 
whether the patient is enrolled or not enrolled,
• 
the reason not eligible for trial participation, or if they are eligible but declined (where available) 
Reason for subject wishing to participate
6.3 Patient identification 
Patients will be identified through clinic visits by their direct study medical care team and visits will be 
captured on a participant screening log. 


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6.4 Screening 
Written informed consent must be obtained from the subject prior to performing any study related 
evaluations or procedures. 
 
Subjects will be provided with written information about the study in the form of a Participant Information 
Sheet (PIS) and will be allowed adequate time for questions and to consider the study before agreeing to 
participate. It will be the responsibility of the investigator or co-investigator to obtain written informed 
consent prior to undertaking any procedures detailed in the protocol. This responsibility may be delegated 
to other suitably trained personnel if allowed according to country-specific regulations and approved by the 
local ethics committee. 
 
The investigator or designee must provide adequate explanation of the aims, methods, objectives, and 
potential hazards of the study. It must also be explained to the subject that they are free to refuse or 
withdraw from the study for any reason without detriment to their future care or treatment. 
 
The following evaluations must be performed within 28 days prior to study randomisation: 
• 
Assessment of subject eligibility according to the inclusion and exclusion criteria
• 
Demographics
• 
Medical and social history (past and current), including HIV-associated conditions (see 
Appendix 1)
• 
Full antiretroviral history (including resistance history i.e. record all resistance history by 
major mutations in NRTI, NNRTI, PI and II regions).
• 
Review of non-antiretroviral medication (any medication taken within the last 30 days)
• 
Concomitant medication check
• 
Physical examination including height and weight
• 
Vital signs (pulse, blood pressure): after 10 minutes resting
• 
Urinalysis (see Appendix 1) and pregnancy test for WOCBP -HCG).
• 
Laboratory evaluations (non-fasting): haematology and biochemistry (Appendix 1)
• 
Total cholesterol and lipids (HDL, LDL and triglycerides)
• 
HIV RNA viral load


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• 
HBV antigen test (including HbsAG, anti-HBc and HBsAb , if done as per standard practice) 
and HCV antibodies test (if test positive for HCV antibodies, test for HCV RNA, if positive and 
chronic for either HBV or HCV, add AST test to the biochemistry panel at screening visit. Hep 
B surface antibodies post vaccination levels to be included in assessment, if this is part of 
local practice)
• 
ECG
• 
CD4 & CD8 count / % and ratio
 
6.5 Consent 
 
 
The Principal Investigator (PI) retains overall responsibility for the informed consent of participants at their 
site and must ensure that any person delegated responsibility to participate in the informed consent process 
is duly authorised, trained and competent to participate according to the ethically approved protocol, 
principles of Good Clinical Practice (GCP) and Declaration of Helsinki. If delegation of consent is acceptable 
then details should be provided. 
Informed consent must be obtained prior to the participant undergoing procedures that are specifically for 
the purposes of the trial and are out-side standard routine care at the participating site (including the 
collection of identifiable participant data unless the trial has prior approval from the Ethics Committee (EC). 
The right of a participant to refuse participation without giving reasons must be respected. 
The participant must remain free to withdraw at any time from the trial without giving reasons and without 
prejudicing his/her further treatment and must be provided with a contact point where he/she may obtain 
further information about the trial. Where a participant is required to re-consent or new information is 
required to be provided to a participant it is the responsibility of the PI to ensure this is done in a timely 
manner. 
 
 
The Principal Investigator takes responsibility for ensuring that all vulnerable subjects are protected and 
participate voluntarily in an environment free from coercion or undue influence. 
Where the participant population is likely to include a significant proportion of participants who cannot read 
or write, require translators or have cognitive impairment, appropriate alternative methods for supporting 
the informed consent process should be employed. This may include allowing a witness to sign on a 


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participant’s behalf (in the case of problems with reading or writing), or allowing someone to date the form 
on behalf of the participant, or providing PIS in other languages or in a format easily understood by the 
participant population (in the case of cognitive impairment). 
 
6.6 Randomisation 
 
6.6.1 The randomisation scheme 
 
 
This study is open label and patients will be randomised to switch at baseline or after 48 weeks. Full details of 
randomisation scheme will be included in the study randomisation plan. 
 
6.6.2 Method of implementing the allocation sequence 
 
 
Method will be detailed in the randomisation plan. 
 
6.6.3 Blinding 
This section is not applicable. 
 
6.6.4 Unblinding 
This section is not applicable. 
 
6.7 Baseline data 
The following evaluations and procedures are to be completed pre dose. 
• 
Smoking history
• 
Alcohol intake
• 
Recreational drug use
• 
Symptoms review and adverse events
• 
Review of concomitant medications
• 
Physical examination (symptom directed)
• 
Weight
• 
Vital signs (pulse, blood pressure: after 10 minutes resting)
• 
Urinalysis (see Appendix 1)
• 
Laboratory evaluations: haematology and biochemistry (fasted) (Appendix 1)


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• 
Total cholesterol and lipids (HDL, LDL and triglycerides) (fasted)
• 
HIV RNA viral load as per local laboratory standard method.
Note. In event of viral load failure follow section 6.18 viral failure, resistance assessment & 
pharmacokinetic assessment procedures. 
• 
Blood sampling for PBMC isolation
(Required unless exemption documented in site contract i.e. if site does not have capacity 
to process PBMC samples) 
• 
CD4 & CD8 count / % and ratio.
• 
Quality of life questionnaire (EuroQoL)
• 
Pittsburgh sleep questionnaire
• 
Patient treatment satisfaction questionnaire
• 
DDI assessment
• 
Drug dispensing
• 
Adherence assessment
• 
Pregnancy test for WOCBP -HCG).
Note: Investigators to remind females of reproductive potential of the need to avoid 
pregnancy while in study and adherence to the study’s contraception requirements. As a 
reminder, females of reproductive potential who changed their minds and desire to be 
pregnant should be withdrawn from the study. 
Note: all subjects should be reminded to take precautions to prevent transmission of HIV in 
accordance with national guidelines. 
See Appendix 1 for details of assessments required. 
 
6.8 Study on treatment visits 
 
 
Study Visits: weeks 4, 12, 24, 48, 52, 72 and 96 (all visits +/- 7 days visit window). An optional visit at week 
60 may be performed for subjects on the control arm (3 months after therapeutic modification) as required 
per national guidelines. The following evaluations and procedures are to be performed pre dose: 
• 
Symptoms review and adverse events
• 
Review of concomitant medications
• 
Physical examination (symptom directed)


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• 
Weight
• 
Vital signs (pulse, blood pressure: after 10 minutes resting)
• 
Viral load
• 
Alcohol intake, smoking habit and recreational drug use (week 24, 48 and 96)
• 
Adherence assessment (including date/time of last dose on PK days including ETV visit 
and/or in the event of virological failure)
• 
Urinalysis (see Appendix 1) (week 24, 48 and 96)
• 
Week 48 (and screening) only: HBV antigen test (including HbsAG, anti-HBc and HBsAb, if 
done as per standard practice) and HCV antibodies test (if test positive for HCV antibodies, 
test for HCV RNA, if positive and chronic for either HBV or HCV, add AST test to the 
biochemistry panel at screening visit. Hep B surface antibodies post vaccination levels to be 
included in assessment, if this is done as per local practice)
• 
Laboratory evaluations: haematology and biochemistry (fasting)
• 
Total cholesterol and lipids (HDL, LDL and triglycerides) (fasted)
• 
PBMC (BL & week 48, 96 & ETV only)
(Required unless exemption documented in site contract i.e. if site does not have capacity 
to process) 
• 
Pre-dose blood sampling for measurement of DTG & RPV (PK assessment) (week 4 & 48 
(experimental arm), week 52 (deferred switch patients) and week 96 (both arms)). Plus pre- 
or post-dose (as appropriate) at early termination visit and/or in the event of virological 
failure (see section 6.12). A post dose sample will be taken within 20-28 hours
• 
HIV RNA viral load
Note. In event of viral load failure follow section 6.18 viral failure & resistance assessment 
procedures. 
• 
CD4 & CD8 count / % (week 24, 48, 72 and 96)
• 
EuroQoL questionnaire (week 24, 48 and 96)
• 
Pittsburgh sleep questionnaire (week 24, 48 and 96)
• 
Patient treatment satisfaction questionnaire (week 24, 48 and 96)
• 
DDI assessment (week 24, 48 and 96)
• 
Adherence assessment
• 
Drug Dispensing (not at week 96)


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• 
Pregnancy test for WOCBP -HCG).
Note: Investigators to remind females of reproductive potential of the need to avoid 
pregnancy while in study and adherence to the study’s contraception requirements. As a 
reminder, females of reproductive potential who changed their minds and desire to be 
pregnant should be withdrawn from the study. 
Note: all subjects should be reminded to take precautions to prevent transmission of HIV in 
accordance with national guidelines 
• 
In addition urine home pregnancy tests for WOCBP should be performed by the patient every 4 
weeks. The results should be communicated via a telephone call visit and recorded in the patient 
records and in the eCRF.
 
All subjects should return unused DTG+RPV tablets at next clinic visits for drug accountability purposes. The 
investigator or designee is responsible for keeping accurate up-to-date accountability documentation for the 
study drugs (as per pharmacy manual) such as dispending, returns, and supply. 
See Appendix 1 for details of assessment and specific visit requirements. 
 
6.9 Follow-up assessments 
This visit will be conducted by phone 30 days post the week 96 visit (+/- 7 day window). The following 
evaluations are to be performed: 
• 
Symptoms review and adverse events
• 
Urine home pregnancy test for WOCBP. The result should be communicated via a telephone call 
visit and recorded in the patient records and in the eCRF.
A follow-up visit is not required if a patient withdraws from IMP prior to week 96. In this case, an early 
termination visit should be conducted instead. See section 6.10. 
 
6.10 
Early Termination visit 
In the case of early termination, every attempt will be made to ensure the subject has a termination visit. At this 
visit, the following evaluations and procedures are to be performed: 
 
• 
Symptoms review and adverse events
• 
Alcohol intake, smoking habit and recreational drug use
• 
Total cholesterol and lipids (HDL, LDL and triglycerides) (fasted)


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• 
PBMC (Required unless exemption documented in site contract i.e. if site does not have 
capacity to process). 
• 
Blood sampling for measurement of DTG & RPV (PK assessment). (Pre- or post-dose (as 
appropriate) at early termination visit and/or in the event of virological failure (see section 
6.18). A post dose sample will be taken within 20-28 hours.
• 
Vital signs (pulse, blood pressure: after 10 minutes resting)
• 
Physical examination (symptom-directed)
• 
Weight
• 
Review of concomitant medications
• 
Laboratory evaluations: haematology and biochemistry (fasting) (Appendix 1)
• 
HIV RNA viral load
- Note: In event of viral load failure follow section 6.18 viral failure & resistance assessment 
procedures. 
• 
CD4 & CD8 count / %
• 
EuroQoL questionnaire
• 
Pittsburgh sleep questionnaire
• 
Patient treatment satisfaction questionnaire
• 
DDI assessment
• 
Adherence assessment (including date/time of last dose on PK days including ETV visit and/or in the 
event of virological failure) 
• 
Pregnancy test for WOCBP -HCG). 
 
 
Patients will be requested to attend for remaining visits and complete study assessments to week 96 even if 
they are no longer taking study medication. 
See Appendix 1 for details of assessments. 
 
6.11 
Qualitative assessments – Nested studies 
This section is not applicable 
 
6.12 
Withdrawal criteria 
A subject is free to withdraw from the study at any time. In addition, the Investigator may decide, for reasons 


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of medical prudence, to stop study medication. 15% lost to follow-up rate expected. 
 
All patients who discontinue study medication will be followed up and requested to attend for study 
visits up until week 96. 
 
 
If this is not possible or acceptable to the subject or Investigator, the subject may be withdrawn from the 
study and the reason for withdrawal recorded in the Case Report Form. 
If any participants experience virological failure (two consecutive HIV-RNA more than 50 copies/ml), the 
study medication must be stopped and participants should be managed in accordance with local processes, 
participants will be followed up and asked to attend all study visits. 
 
Study medication may also be discontinued in the following instances: 
1. If the subject withdraws their consent. 
 
2. If the investigator considers in the interest of the subject (i.e. intercurrent illness, unacceptable toxicity) 
that it is best for them to stop study medication. 
3. The subject fails to comply with the protocol requirements or fails to cooperate with investigator. 
 
The date and reasons for stopping medication will be clearly stated on the subject’s CRF and source 
document. Every attempt should be made to arrange follow up visits for subjects who are withdrawn from 
study medication. This visit should involve assessments as outlined in section 6. 
 
A female subject receiving dolutegravir/rilpivirine who becomes pregnant during the study should remain 
on study for the purpose of follow-up but must immediately have their dolutegravir/rilpivirine withdrawn 
and replaced by triple standard ARV therapy to avoid suboptimal drug exposure during pregnancy. 
Exceptions may be discussed with ViiV in situations where the benefits of continuing the pregnant woman 
on dolutegravir plus rilpivirine outweigh the risks. For reporting requirements for pregnancies see section 
8.3. 
 
Note: Investigators must remind females of reproductive potential of the need to avoid pregnancy while in 
study and adherence to the study’s contraception requirements. Females of reproductive potential who 
changed their minds and desire to be pregnant should be withdrawn from the study. 


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Allergic reactions 
 
Subjects may continue study drug for Grade 1 or 2 allergic reactions at the discretion of the Investigator. The 
subject should be advised to contact the Investigator immediately if there is any worsening of symptoms or 
if further systemic signs or symptoms develop. Antihistamines, topical corticosteroids, or antipruritic agents 
may be prescribed. 
 
investigational product(s) should permanently discontinue the investigational product regimen and the 
subject should be withdrawn from the study. Subjects should be treated as clinically appropriate and 
followed until resolution of the adverse event. 
 
Subjects in the CAR arm who are receiving ABC as part of their NRTI background regimen should be evaluated 
for the possibility of a clinically suspected ABC hypersensitivity reaction (HSR) and managed appropriately as 
outlined in the local prescribing information for ABC. 
 
 
Rash 
 
Mild to moderate rash is an expected adverse reaction for both DTG and RPV containing ART. Episodes 
generally occur within the first ten weeks of treatment, rarely require interruptions or discontinuations of 
therapy and tend to resolve within two to three weeks. The index case of hypersensitivity with DTG involved 
a profuse, purpuric and coalescing leukocytoclastic vasculitis as well as clinically significant liver chemistry 
elevations. Other than this case, no other instances of serious skin reaction, including Stevens - Johnson 
syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and erythema multiform, have been reported for DTG, RPV 
or DTG/RPV FDC in clinical trials. 
 
Subjects with an isolated Grade 1 rash may continue study drug at the Investigator’s discretion. The subject 
should be advised to contact the Investigator immediately if there is any worsening of the rash, if any 
systemic signs or symptoms worsen, or if mucosal involvement develops. 
 
 


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Subjects may continue study drug for an isolated Grade 2 rash. However, study drug (and all other concurrent 
medication(s) suspected in the Investigators causality assessment) should be permanently discontinued for 
physician immediately if rash fails to resolve (after more than two weeks), if there is any worsening of the 
rash, if any systemic signs or allergic symptoms develop, or if mucosal involvement develops. 
Subjects should permanently discontinue study drug (and all other concurrent medication(s) suspected in 
the Investigators causality assessment) for an isolated Grade 3 or 4 rash, and the subject should be 
withdrawn from the study. Subjects should be treated as clinically appropriate and followed until resolution 
of the AE. 
 
The rash and any associated symptoms should be reported as adverse events (see section 8) and appropriate 
toxicity ratings should be used to grade the events (based on DAIDS toxicity gradings). 
If the etiology of the rash can be definitely diagnosed as being unrelated to IP and due to a specific medical 
event or a concomitant non-study medication, routine management should be performed and 
documentation of the diagnosis provided. 
 
Subjects in the CAR arm who are receiving ABC as part of their NRTI background regimen should be evaluated 
for the possibility of a clinically suspected ABC hypersensitivity reaction (HSR) and managed appropriately as 
outlined in the local prescribing information for ABC. 
 
Subjects withdrawing from the trial may be replaced if considered necessary by the Chief investigator. 
 
 
 
6.13 
Liver Chemistry Stopping and Follow up Criteria 
 
 
Liver chemistry threshold stopping criteria have been designed to assure subject safety and to evaluate liver 
event etiology during administration of study drug and the follow-up period. Study drug must be stopped if 
any of the following liver chemistry criteria are met: 
• 
 required)
 
NOTE: serum bilirubin fractionation should be performed if testing is available. If testing 
is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 


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direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin  2xULN, then the event meets liver stopping criteria and should 
be reported as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 suggest severe 
liver injury. 
• 
ALT 
 
• 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, or eosinophilia, OR;
• 
ALT 
 baseline ALT with symptoms or worsening of acute hepatitis or hypersensitivity such as
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia; 
 
• 
ALT 
 and <8 xULN that persists > 2 weeks (with bilirubin <2xULN and no signs or symptoms 
of acute hepatitis or hypersensitivity);
• 
weekly for >2 weeks;
 
 
on 2 consecutive evaluations). 
 
When liver chemistry stopping criterion is met, the following procedures must be followed: 
 
• 
Immediately hold dolutegravir and rilpivirine. If a causal relationship between the liver event and 
dolutegravir and rilpivirine cannot be ruled out, then doluetgravir and rilpivirine must be 
permanently discontinued and the Subject not rechallenged due to the risk of a recurrent reaction. 
If the liver event has a clear underlying alternative cause, other than drug-induced liver injury, then 
Drug Restart may be considered (see below).
• 
Report the event to the study sponsor pharmacovigilance team within 24 hours of learning its 
occurrence (see section 8.3)
• 
Events of possible drug-induced liver injury (DILI) with hyperbilirubinemia defined as ALT 3xULN 
and bilirubin 2xULN (>35% direct) will be reported to the Sponsor as SAEs using the SAE reporting 
form Complete the liver event CRF for all events meeting liver stopping criteria.


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• 
Perform liver event follow up assessments (described below), and monitor the subject until liver 
chemistries resolve, stabilise, or return to baseline values as described below;
• 
Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat liver 
chemistries, liver event follow up assessments (see below), and close monitoring;
• 
A specialist or hepatology consultation is recommended;
 
• 
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) 
resolve, stabilise or return to within baseline values;
Consider the following additional tests to further evaluate the liver event: 
 
• 
Viral hepatitis serology including:
 
- 
Hepatitis A IgM antibody; 
 
- 
HBsAg and Hepatitis B Core Antibody (IgM); 
 
- 
Hepatitis C RNA; 
 
- 
Hepatitis E IgM antibody; 
 
• 
Cytomegalovirus IgM antibody;
 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing);
• 
Syphilis screening
 
• 
Drugs of abuse screen including alcohol
 
• 
Serum acetaminophen test (APAP adduct test)
 
• 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH);
 
• 
Fractionate bilirubin, if total bilirubin is greater than 1.5xULN;
 
• 
Obtain complete blood count with differential to assess eosinophilia;
 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal 
antibodies;
• 
Liver imaging (ultrasound, magnetic resonance, or computerised tomography) to evaluate liver 
disease;


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• 
Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, fatigue, 
decreased appetite, nausea, vomiting, abdominal pain, jaundice, fever, or rash as relevant on the 
AE report form;
• 
Record use of concomitant medications, acetaminophen, herbal remedies, other
 
over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form. 
 
Restarting Study Drug 
If a causal relationship between the liver event and DTG/RPV FDC cannot be ruled out, then DTG/RPV FDC 
must be permanently discontinued and the Subject not rechallenged. 
 
Drug Restart Following Transient Resolving Liver Events Not Related to Study Drug 
Restart can be considered when liver chemistries improve to within 1.5x baseline and ALT<3xULN) where: 
 
Liver chemistries have a clear underlying cause other than drug-induced liver injury (e.g. biliary, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no evidence of 
alcoholic hepatitis or hypersensitivity, and the drug should not be associated with HLA markers of liver 
injury. 
 
The subject is receiving compelling benefit and benefit of drug restart exceeds risk 
 
Approval from the Chief Investigator plus Ethics Committee/IRB & ViiV Healthcare (as appropriate) for 
the drug restart has been obtained. 
 
The subject has been provided with a clear description of the possible benefits and risks of drug restart, 
including the possibility of recurrent, more severe liver injury or death. 
 
The subject has also provided signed informed consent specifically for the restart. Documentation of 
informed consent must be recorded in the study file. 
• 
Following drug restart, the Subject will return to the clinic once a week for liver chemistry tests for one 
month or for as long as clinically indicated and then laboratory monitoring may resume as per protocol. 
If protocol defined stopping criteria for liver chemistry elevations are met, study drug must be stopped. 
 
 
6.14 
Suicidal Risk Monitoring 
Subjects with HIV infection may occasionally present with symptoms of depression and/or suicidality 
(suicidal ideation or behaviour). In addition, there have been some reports of depression, suicidal ideation 


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and behaviour (particularly in patients with a pre-existing history of depression or psychiatric illness) in some 
patients being treated with integrase inhibitors, including DTG. Therefore, it is appropriate to monitor 
subjects for suicidality before and during treatment. 
Subjects should be monitored appropriately and observed closely for suicidal ideation and behaviour or any 
other unusual changes in behaviour. It is recommended that the investigator consider mental health 
consultation or referral for subjects who experience signs of suicidal ideation or behaviour. 
 
See section 8 for reporting details. 
 
 
6.15 
Decline in Renal Function 
Subjects who experience an increase in creatinine from Baseline of 45 mMol/L (or 0.5 mg/dL) without 
associated evidence for proteinuria should return for a confirmatory assessment within 2 to 4 weeks. A 
urinalysis and urine microalbumin/creatinine ratio should be done at this confirmatory visit. If the creatinine 
increase is confirmed, the investigator should contact the sponsor to discuss additional follow-up and 
medical management. 
 
Subjects who have a decline in creatinine clearance of >50% must return for a confirmatory assessment as 
soon as possible. A urinalysis and urine microalbumin/creatinine ratio should be done at this confirmatory 
visit. If the estimated creatinine clearance has declined by >50% (confirmed), then study medication should 
be withheld and the investigator should contact the sponsor to discuss the rationale for restarting study 
drugs (if appropriate). Consideration for confounding factors (e.g. NRTI background therapy, other 
medications, dehydration, concurrent conditions) should be taken into account, and a nephrology consult 
may be obtained. If a subject in the control group is also receiving TDF, then a switch to an alternative fully 
active NRTI should be considered if restarting study medication. Current local prescribing information should 
be consulted for additional details on dosing background therapy in renally impaired subjects. If study 
medication is reinitiated, it should have been withheld for no more than 4 weeks. If IP is not reinitiated the 
subject must be withdrawn. 
 
Proximal Renal Tubule Dysfunction (PRTD) is defined as: 
• 
 <2.0mg/dL;
 
• Either of the above accompanied by any two of the following:
 


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• 
 non-diabetic;
• Low serum potassium (<3mEq/L);
 
• Low serum bicarbonate (<19mEq/L).
 
Subjects meeting criteria for PRTD must return for a confirmatory assessment within 2 weeks. A urinalysis 
should be done at the time of the confirmatory assessment. If PRTD is confirmed the drugs should be 
terminated and the sponsor should be contacted to discuss the rationale for restarting study drugs (if 
appropriate). If a subject is also receiving TDF/FTC, then a switch to an alternative NRTI combination should 
be considered if restarting study medication. If re initiation of study medication is planned, study medication 
should be withheld for no more than 4 weeks. Subjects on ABC/3TC FDC may switch to the individual 
components dose adjusted for renal dysfunction according to approved prescribing information, or switch 
to alternative nucleosides at the discretion of the Investigator. 
 
6.16 
Proteinuria 
Subjects with an abnormal urine microalbumin/creatinine ratio (>0.3mg/mg, >300mg/g or 
>34mg/mmol) that represents a change from baseline and no associated increase in creatinine, should have 
a repeat spot urine microalbumin/creatinine ratio performed within 2-4 weeks. If confirmed, then 
consideration should be made for additional evaluation after consultation with the sponsor. Additional 
evaluation may include a creatinine measurement and nephrology referral. 
 
Subjects with an abnormal urine albumin/creatinine ratio (>0.3mg/mg, 300 mg/g or>34mg/mmol and 
representing a change from baseline) and a serum creatinine increase >45 mMol/L (or 0.5 mg/dL) should 
have confirmation of both results within 2 weeks. If confirmed, the study sponsor should be immediately 
contacted. Agreement on further management should be agreed between the investigator and study 
sponsor. 
 
6.17 
Creatine Phosphokinase (CPK) Elevation 
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2 to 4 weeks to ensure the 
result is transient or due to exercise and will not require a change in study treatment. A history regarding use of 
drugs known to cause increase of CPK (such as statins) physical activity or exercise preceding the CPK evaluation 
should be obtained. Grade 4 elevations in CPK should have a repeat assessment after the subject has abstained 
from exercise for >24 hours. For persistent Grade 4 CPK elevations that are considered possibly or probably 
related to the study drug, study drug should be discontinued and the subject withdrawn from the study. 


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6.18 
Storage and analysis of samples 
 
 
See appendix 1 for details of assessments required. 
 
 
All samples (with the exception of PK & PMBC samples) will be analysed at each local site laboratories and 
destroyed after analysis. PK samples will be shipped and analysed by a central laboratory in the UK. PBMC 
samples will be shipped and analysed by a central laboratory in Spain. 
 
Collection and processing and storage instructions for all samples will be detailed in a separate Laboratory 
Manual. 
 
6.19 
Virological failure 
 
 
Virological failure is defined as two consecutive measurements of plasma viral load above 50 copies/ml separated 
by at least 14 days during the assigned treatment. Note: If the initial sample analysis returns result of >50c/mL, 
the remainder of the sample should be re-analysed, if possible. Only if the repeat analysis produces a second 
result of >50c/mL, or if re-analysis is not possible, the patients should be recalled for retesting. The remainder of 
the retesting sample should be analysed if the retesting analysis produces a result of >50c/mL. In case of 
virological failure a resistance study will be conducted in the local lab of each centre. Note: resistance test should 
be performed from the suspect virological failure visit sample and from the confirmatory visit when available. 
 
Pharmacokinetic testing should also be carried out in the event of viral failure. 
 
Patients should discontinue study medication and receive rescue medication at investigators discretion. 
 
Therapeutic failure includes virological failure, change in treatment for any reason, consent withdrawal, loss to 
follow-up or death. 
 
6.20 
End of trial 
 
The end of the trial is defined as the date of the last visit (i.e. Follow-up visit) of the last subjects undergoing 
the trial. 


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The sponsor must notify the Competent Authority and main REC of the end of a clinical trial within 90 days 
of its completion. 
Note: The DSMB will elect stopping criteria as defined in the DSMB charter. If the study ends early by 
recommendation from the DSMB or for any other reason, the sponsor will notify the Competent Authorities 
and Ethics Committees of the reasons for the premature termination. 
 
 
 7    TRIAL MEDICATION 
 
 
7.1 Name and description of investigational medicinal product(s) 
Subjects will discontinue their usual boosted protease inhibitor or other ARV regimen (including Anatomical 
Therapeutic Chemical Classification System codes: JO5AB, JO5AE, JO5AF, JO5AG, JO5AR, JO5AX) and will 
switch to DTG plus RPV at baseline or week 48. 
 
 
ViiV will supply Dolutegravir 50mg / Rilpivirine 25mg FDC tablets in the form of “Juluca”(which will be labelled 
in accordance with annex 13 requirements). 
 
From baseline to week 96 or from week 48 to week 96, as randomised, participants will take a DTG/ RPV 
combined tablet once a day orally. Participants in the deferred group will continue to take their usual ARV 
regimen from baseline to week 48 until they switch to DTG/ RPV combined tablet. 
 
The early switch group will be dispensed a supply of DTG/RPV combined tablets at baseline, week 4, 12 and 
24. Both the early switch group and deferred switch group will be dispensed supply of DTG/RPV combined 
tablets at week 48, 52 and 72. Please refer to the study specific pharmacy manual for more information. 
Note, dispensing weeks may be modified with sponsor’s approval and in line with local regulations (if 
required). Prior to switch subjects will continue to be dispensed standard care boosted protease inhibitor or 
other ARV regimen. 
 
7.2 Reference Safety Information 
 
 
The Reference Safety Information (RSI) for the DTG/RPV FDC is the Juluca Summary of Product 
Characteristics (section 4.8 Undesirable effects). Please refer to this for further information on 
contraindicated treatments, drug interactions and adverse events expectedness. For pre-switch reference 


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safety information, investigators are to refer to the SmPC (per ATC code) for information on expectedness, 
contraindicated treatments, drug interactions and adverse events. 
 
7.3 Drug storage and supply 
 
 
Investigators are to ensure that the investigational product will only be used in accordance with the protocol. 
Drug supplies will be kept in a secure, limited access storage area under the recommended storage 
conditions (see pharmacy manual) accessible only to those authorised by the investigator to dispense to 
eligible subjects. 
 
The investigator will ensure that records are maintained showing the receipt and disposition of all study 
supplies. A drug accountability log will be kept with the investigational supplies for reconciliation purposes. 
This should be used to record the trial identification of the subject to whom the investigational product was 
dispensed, the date and quantity of investigational product dispensed, and the quantity of investigational 
product unused/returned by the subject. This will be verified by the study monitor. 
 
Partially used or empty containers may be destroyed by pharmacy/designee at local site after the study 
monitor has completed a final inventory to verify the quantity returned. The pharmacy/designee are 
required to document destruction for verification by the sponsor. 
 
 
7.4 Preparation and labelling of Investigational Medicinal Product 
 
 
Dolutegravir & Rilpivirine combined therapy tablets will be labelled with Annex 13 compliant labels and QP 
certified by Almac Group Ltd who will provide supply directly to each site on request of the sponsor. 
 
Boosted PIs (or other antiretroviral combination regimen) will be sourced from usual commercial supply as 
per standard practice. 
 
Further information can be found in the pharmacy manual. 


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7.5 Dosage schedules 
 
 
Experimental arm (Baseline visit switch group): One combined Dolutegravir 50mg /Rilpivirine 25mg tablet 
taken orally once daily (at the same time) for up to 96 weeks with a meal. NB: A high protein drink is not 
suitable substitute for a meal. 
Control arm (deferred week 48 switch group): patients will continue their current boosted PI regimen (or 
other antiretroviral combination regimen) for 48 weeks. Patients will then be switched to one combined 
Dolutegravir 50mg /Rilpivirine 25mg tablet taken orally once daily for up to 48 weeks with a meal. 
 
7.6 Dosage modifications 
 
 
There are no dose modifications for this trial. Please refer to section 6 for withdrawal and stopping rules. 
 
7.7 Known drug reactions and interaction with other therapies 
 
 
 Dolutegravir 
 
 
See section 8.3 and reference safety information. 
Dofetilide is prohibited as DTG may inhibit its renal tubular secretion resulting in increased dofetilide 
concentrations and potential for toxicity. Strong inducers of DTG metabolism such as carbamazepine must 
be avoided. 
 
 Rilpivirine 
 
 
See section 8.3 and reference safety information. 
Medications that affect rilpivirine and that are affected by the use of rilpivirine accordingly must be reviewed 
by the investigator and/or avoided. 


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7.8 Concomitant medication 
DTG/RPV FDC is contraindicated in combination with the following: 
 
 
antiarrhythmic agents dofetilide or pilsicainide (DTG may inhibit its renal tubular secretion resulting in 
increased dofetilide concentrations and potential for toxicity) 
 
fampridine (also known as dalfampridine) 
 
anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin 
 
antimycobacterials rifampicin, rifapentine 
 
proton pump inhibitors (such as omeprazole, esomeprazole, lansoprazole, pantoprazole, and 
rabeprazole) 
 
systemic dexamethasone (except as a single dose treatment) 
 
St John’s wort (Hypericum perforatum) 
7.9 Prior Concomitant Therapy 
 
 
All medications (prescriptions or over-the-counter medications, herbal and naturopathic products) continued 
at the start of the treatment or started during the treatment must be documented (dose, frequency, stop 
and start dates). Unnecessary changes or additions to any concomitant medication should be avoided. 
 
Warnings and precautions regarding contraindicated concomitant medications, AE and drug interactions can 
be found above or within reference safety information. 
NOTE! Caution must also be applied when patients take medications that inhibit CYP3A as this may lead to 
excessive exposure of rilpivirine. 
 
Any medications excluded in the Exclusion criteria will not be permitted in this study.  However, if there is a 
clinical need for the use of any of these medications then the participant may need to be discontinued from 
the study. If this is the case, then the investigator should discuss with the CI or Sponsor trials team, but the 
final decision remains that of the site investigator. 
All concomitant medication information will be captured in the participant’s Case Report Forms. 
 
7.10 
Trial restrictions 
Please refer to inclusion & exclusion criteria listed in sections 5.1 & 5.2. 


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7.11 
Assessment of compliance 
Adherence during the trial will be monitored by subject questioning regarding missed tablets at each visit. If 
poor adherence is suspected based on tablet counts, this will be discussed with the subject to confirm lack of 
adherence i.e. via subject interview. The outcome of this questioning should be documented in the patient 
notes. If the subject misses a significant number of tablets, this should be reported to the study monitor 
All subjects should return unused medication and containers at weeks 72 and 96 (plus at weeks 4, 12, 24 and 
48 for the experimental arm) for pharmacy accountability purposes (see section 7.3). 
 
 
7.12 
Provision of treatment after the end of the trial 
No post trial medication will be provided to patients. Following study completion, patients are to receive 
treatment as per local standard of care. 
 
 
8 PHARMACOVIGILANCE 
 
 
 
8.1 Definitions 
 
Term 
Definition 
Adverse Event (AE)
Any untoward medical occurrence in a participant to whom a medicinal
product has been administered, including occurrences which are not 
necessarily caused by or related to that product. 
Adverse Reaction (AR)
An untoward and unintended response in a participant to an investigational
medicinal product which is related to any dose administered to that 
participant. 
 
The phrase “response to an investigational medicinal product” means that a 
causal relationship between a trial medication and an AE is at least a 
reasonable possibility, i.e. the relationship cannot be ruled out. 
 
All cases judged by either the reporting medically qualified professional or 
the Sponsor as having a reasonable suspected causal relationship to the trial 
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Serious Adverse Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
 
 
results in death 
 
is life-threatening 
 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
results in persistent or significant disability/incapacity 
 
consists of a congenital anomaly or birth defect 
 
Other ‘important medical events’ may also be considered serious if they 
jeopardise the participant or require an intervention to prevent one of the 
above consequences. 
NOTE: For the purposes of this study, all AEs meeting liver stopping criteria 
(as defined in section 6.13) associated with dolutegravir and all events of 
possible drug-induced liver injury (DILI) with hyperbilirubinemia defined as 
and must be reported (see Section 8.3) 
NOTE: The term “life-threatening” in the definition of “serious” refers to an 
event in which the participant was at risk of death at the time of the event; 
it does not refer to an event which hypothetically might have caused death 
if it were more severe. 
Serious Adverse Reaction 
(SAR) 
An adverse event that is both serious and, in the opinion of the reporting 
Investigator, believed with reasonable probability to be due to one of the 
trial treatments, based on the information provided. 
Suspected Unexpected 
Serious Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not consistent 
with the information about the medicinal product in question set out: 
 
The reference safety information for the DTG/RPV FDC is contained within 
Juluca Summary of Product Characteristics (SmPC) at section 4.8 Undesirable 
effects, please refer to this document for further information on 
contraindicated treatments, drug interactions and adverse events 
expectedness. 
 
“Severe” is often used to describe intensity of a specific event, which may be of relatively minor medical 
significance. “Seriousness” is the regulatory definition supplied above. 
 
8.2 Operational definitions for (S) AEs 
 
 
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with the study treatments. An adverse event (AE) 
can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
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not considered related to the medicinal (investigational) product. 
 
Adverse events observed by the Investigator, or reported by the subject, and any remedial action taken, will 
be recorded in the subject’s CRF and should be verifiable in the subject’s notes throughout the study. The 
nature of each event, time of onset after drug administration, duration and severity will be documented  
together with the Investigator’s opinion of the causal relationship to the investigational product (unrelated, 
unlikely, possible, probable, and definite). 
All subjects experiencing adverse events, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline, or until there is a satisfactory explanation for the changes 
observed. 
Procedures such as surgery should not be reported as adverse events. However, the medical condition for 
which the procedure was performed should be reported if it meets the definition of an adverse event. For 
example, an acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event and the resulting appendectomy noted on the CRF. 
Planned procedures such as surgery pre planned prior to the subject’s enrolment into the study do not need 
to be reported as adverse events if these are documented as planned at the screening visit. 
 
Clinically significant changes in physical examination and blood safety profiles should also be recorded as 
adverse events. 
 
 
8.2.1 
Assessment of Intensity 
Severity should be recorded and graded according to the AIDS Clinical Trial Group (ACTG) Grading Scale 
(appendix 2). 
 
Note: There is a distinction between the seriousness and the intensity of an adverse event. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious adverse event. For example, a 
headache may be severe in intensity but would not be classified as serious unless it meets one of the 
seriousness criteria for serious events. 
 
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routinely reported as a serious adverse event. However, there may be occasions where in the investigator’s 
clinical judgement they do not consider the event to be life threatening therefore they do not consider the 
event to meet the definition of an SAE. In these cases, the investigator must document clearly in the 
participants source documentation that the Grade 4 event has been assessed and why in their clinical 
judgement they do not consider the event to be life threatening. 
 
 
 
8.2.2 
Assessment of Causality 
The relationship to study drug of each adverse event will be assessed using the following definitions: 
DEFINITE: 
distinct temporal relationship with drug treatment. Known reaction to agent or chemical 
group or predicted by known pharmacology. Event cannot be explained by subject’s clinical state or other 
factors. 
PROBABLE:  reasonable temporal relationship with drug treatment. Likely to be known reaction to agent or 
chemical group or predicted by known pharmacology. Event cannot easily be explained by subject’s clinical 
state or other factors. 
POSSIBLE: 
reasonable temporal relationship with drug treatment. Event could be explained by 
subject’s clinical state or other factors. 
UNLIKELY: poor temporal relationship with drug treatment. Event easily explained by subject’s clinical 
state or other factors. 
UNRELATED: the event occurs prior to dosing. Event or intercurrent illness is due wholly to factors other 
than drug treatment. 
 
8.2.3 
Collection and follow up of Adverse Events 
 
 
All adverse events, however minor, will be documented in the CRF whether or not the Investigator considers 
the event to be treatment related. 
 
The adverse event reporting period will be from consent until the subject’s final study visit (I.e. follow-up visit or 
end of trial visit). In addition, any untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as possibly, probably or definitely related to the study drug medication should also be 
reported as an Adverse Event. 
 


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Adverse events may be directly observed, reported spontaneously by the subject or by questioning the subject 
at each study visit. 
 
All adverse events should be followed up until they are resolved or the subject’s participation in the study ends 
(i.e. until the final CRF is completed for that subject). In addition, all serious and non-serious adverse events 
assessed by the Investigator as possibly related to the investigational medication should continue to be followed 
until resolution, or until no further change can reasonably be expected. 
 
Rash and any associated symptoms should be reported as adverse events (see section 6.12) 
 
 
 
8.2.4 
Serious Adverse Events (SAE) & reportable events 
 
 
See SAE definition within section 8.1. 
 
Liver stopping criteria & clinically significant liver chemistry evaluation adverse events. 
All AEs meeting liver stopping criteria, clinically significant liver chemistry elevations (as defined in section 
6.13) associated with dolutegravir and all events of possible drug-induced liver injury (DILI) with 
hyperbilirubinemia defined as ALT  3Xuln and bilirubin  2Xuln (>35% direct) are considered serious for the 
purposes of this clinical trial and must be reported. See section 8.4 for reporting guidelines. NOTE: bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick indicating direct bilirubin elevations and suggesting liver injury. If 
testing is unavailable and a 
be reported as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 suggest severe 
liver injury. 
 
Suicidality-related adverse event 
If any subject experiences a possible suicidality-related adverse event (PSRAE) while participating in this 
study that is considered by the Investigator to meet above described definitions, this should be reported to 
the Sponsor. See section 8.4 for reporting format & timeline. A PSRAE may include, but is not limited to, an 
event that involves suicidal ideation, a preparatory act toward imminent suicidal behaviour, a suicide 
attempt, or a completed suicide. The investigator should exercise his or her medical and scientific judgment 
in deciding whether an event is possibly suicide related. 


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 Pregnancy 
 
There is no requirement to report pregnancies in female partners of male participants. Please see risk section 
1.1 for further details. 
 
Trial subject pregnancies should be reported as per table 2 
 
Overdose 
 
All participants should be counselled about the importance of taking the medications as prescribed and they 
should understand the quantity of medicine they should be taking. Participants must be told to contact the 
clinic immediately if they take too much medication. If the overdose fits the criteria of an SAE (see Section 
8) it should be reported appropriately. See table 2 for SAE reporting format and timelines. 
 
 
 
Deaths 
 
Any AE, adverse reaction or unexpected adverse reaction that results in death should be reported as an SAE. 
See table 2 for SAE reporting format and timelines. 
Deaths occurring more than 28 days after the final dose, which are considered to be unrelated to the study 
medication, should not be reported as a Serious Adverse Event. 
 
 
 
8.3 Recording and reporting of SAEs AND SUSARs 
 
8.3.1 
Reporting requirements 
 
 
All SAEs occurring from consent to 28 days post cessation of trial treatment must be recorded & reported 
by site (see table 2 for forms to be used and reporting timeline). 
 
The investigator must immediately and not later than in 24 hours, report to the sponsor; all serious adverse 
events by emailing safety@rokcservices.com or by sending a fax to +44 (0) 203 905 2575.   
 
For each SAEs / SUSARs the following information will be collected in a dedicated safety event 
reporting form (SERF): 


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full details in medical terms and case description 
 
 
event duration (start and end dates, if applicable) 
 
 
action taken 
 
 
outcome 
 
 
seriousness criteria 
 
 
causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator 
 
 
whether the event would be considered expected or unexpected. 
 
 
Any change of condition or other follow-up information should be provided to the Sponsor as soon 
as it is available or at least within 24 hours of the information becoming available. Query responses 
should be also provided to the Sponsor within the requested timelines. Follow-up information and 
Query Response must be sent emailing safety@rokcservices.com or by sending a fax to +44 (0) 203 
905 2575. Events will be followed up until the event has been resolved or a final outcome has been 
reached. 
 
 
All SAEs assigned by the PI or delegate (or following central review) as both suspected to be related 
to IMP-treatment and unexpected, will be classified as SUSARs and will be subject to expedited 
reporting to the Competent Authority. The Sponsor will inform CAs, ECs and ViiV of SUSARs within 
the required expedited reporting timescales. 
 
 
Table 2: Safety Reporting Format & Timelines 
 
Safety Data 
Reporting Format 
Timeline 
All SAEs arising during the 
Clinical Trial, regardless of 
Investigator/designee 
causality assessments against 
IMP(s) 
SERF 
Site to report to sponsor 
within 24 hours of first 
becoming aware of the event. 


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Pregnancy information for all 
female Clinical Trial Subjects 
who become pregnant while 
participating in the Clinical 
Trial and following exposure to 
an IMP. 
SERF 
Site to send to sponsor within 
24 hours of first becoming 
aware of the pregnancy or the 
pregnancy outcome. 
The subject will also be 
followed to determine the 
outcome of the pregnancy 
(including information on the 
status of the mother and 
child), which will also be 
reported to sponsor. 
 
 
All liver events meeting the 
criteria for an SAE, including all 
events of possible drug- 
induced liver injury (DILI) with 
hyperbilirubinemia defined as 
2Xuln (>35% direct) 
SERF 
 
 
 
 
 
 
 
The SAE form must be 
completed and reported to 
the sponsor within 24 hours. 
 
 
 
 
 
All Liver Chemistry Elevations 
that meet Liver Stopping 
Criteria (as defined in the 
Protocol), regardless of 
Investigator/designee 
causality assessments against 
IMP(s); and whether or not 
the event and/or associated 
signs and symptoms meet 
definitions of seriousness as 
outlined above 
Liver Event CRF Modules i.e. 
VHL liver event CRF, liver 
imaging and/or liver biopsy 
CRFs 
Site to complete the Liver 
event CRF modules and send 
to sponsor within one week of 
first becoming aware of the 
event 
 
 
 


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Suicidality-related adverse 
events (PSRAEs) (as defined in 
the Protocol) that met the 
criteria for an SAE. 
SERF 
PSRAE CRF Module 
The SAE form must be 
completed and reported to 
the sponsor within 24 hours. 
The PSRAE CRF Module 
should be completed and 
reported to the sponsor 
within one week of the 
investigator diagnosing a 
possible suicidality-related 
adverse event 
Deaths 
Any AE, adverse reaction or 
unexpected adverse reaction 
that results in death should be 
reported as an SAE on an SERF 
Site to report to sponsor 
within 24 hours of first 
becoming aware of the event. 
Overdose 
If the overdose fits the criteria 
of an SAE (see Section 8) it 
should be reported 
appropriately on an SERF 
Site to report to sponsor 
within 24 hours of first 
becoming aware of the event. 
 
 
 
All safety reports and reportable events listed on the above table (including Investigator causality) 
assessment should be reported in English to the sponsor. 
 
 
Reporting Period 
 
The SAEs, and pregnancy reports that are subject to the above reporting provisions are those that occur 
following the consent through to 28 days post cessation of trial treatment. 
 
8.4 Responsibilities 
Principal Investigator (PI): 
 
Checking for AEs and ARs when participants attend for treatment / follow-up. 
 
1. Using medical judgement in assigning seriousness, causality and expectedness using the 
Reference Safety Information approved for the trial. 
2. Ensuring that all SAEs and SARs (including SUSARs) are recorded and reported to the Sponsor 
within 24 hours of becoming aware of the event and provide further follow-up information 
as soon as available. Ensuring that SAEs and SARs (including SUSARs) are chased with Sponsor 


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if a record of receipt is not received. 
3. Ensuring that AEs and ARs are recorded and reported to the Sponsor in line with the 
requirements of the protocol. 
 
Chief Investigator (CI) / delegate or independent clinical reviewer: 
 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
2. Using medical judgement in assigning seriousness, causality and expectedness of SAEs where 
it has not been possible to obtain local medical assessment. 
3. Using medical judgement in assigning expectedness 
4. Immediate review of all SUSARs. 
5. Review of specific SAEs and SARs in accordance with the trial risk assessment and protocol 
 
Sponsor: 
 
1. Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs according to the 
trial protocol. 
2. Reporting safety information to the CI, delegate or independent clinical reviewer for the 
ongoing assessment of the risk / benefit. 
3. Reporting safety information to the Data Safety Monitoring Board (DSMB) according to 
committee charter documents. 
4. Expedited reporting of SUSARs to the Competent Authorities and ECs within required 
timelines in accordance with the applicable country legislations. 
5. Notifying Investigators of SUSARs that occur within the trial. 
6. Checking for and notifying PIs of updates to the Reference Safety Information for the trial. 
7. See section 8.3.1 for details of reporting requirements to ViiV. 
 
 
 
Data Safety Monitoring Board (DSMB): 
 
In accordance with the DSMB Charter, periodically reviewing overall safety data to determine 
patterns and trends of events, or to identify safety issues, which would not be apparent on an 
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8.5 Reporting urgent safety measures 
 
 
It is the responsibility of the investigator to apply the appropriate level of Urgent Safety Measure (USM) for 
the safety and protection of each participant in this study in order to prevent harm. USMs may be applied 
without prior approval from the sponsor, Competent Authority (CA) or Ethics Committee but must be 
reported to the sponsor immediately who will then inform the CA and EC according to local regulation. 
Please have full details including the action taken. 
 
8.6 Development Safety Update Reports (DSUR) 
The sponsor will be responsible for the production of DSURs once a year throughout the clinical trial, or on 
request, and their submission to relevant Competent Authorities and Ethics Committees as required within 
applicable timeframes. 
 
9 
STATISTICS AND DATA ANALYSIS 
 
 
 
9.1 Sample size 
 
This is a pilot proof of concept study to investigate whether complex regimens taken by patients with 
resistance mutations can be replaced by a simple two class single pill regimen safely in terms of viral load 
and adverse events. 
No formal sample size calculation is performed. It is anticipated that data from 150 participants is adequate 
to meet the trial objectives (100 in the DTG/RPV arm and 50 in the control arm). The expected success rate 
is 95% based on the data reported by the SWORD 1 & 2 studies. If the observed success rate is 95% in the 
DTG/RPV arm at week 48 and varies from 95% to 100% in the control arm, with 150 participants (100 in the 
DTG/RPV arm and 50 in the control arm), the lower bound of the confidence interval of the difference in the 
success rate between the 2 arms (DTG/RPV – control) would varied from -9.3% to -7.4% (see table below). 
 
Success rate 
95% Confidence Interval 
DTG/RPV 
(n=100) 
Control 
(n=50) 
Difference 
lower 
upper 
95% 
95% 
0.0% 
-7.4% 
7.4% 
95% 
96% 
-1.0% 
-7.9% 
5.9% 


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95% 
97% 
-2.0% 
-8.4% 
4.4% 
95% 
98% 
-3.0% 
-8.8% 
2.8% 
95% 
99% 
-4.0% 
-9.1% 
1.1% 
95% 
100% 
-5.0% 
-9.3% 
-0.1% 
 
In addition,  we would like to show whether the observed success rate in the DTG/RPV arm is above 95%. 
Therefore, we estimated power for a one-sample proportion test (Binomial test) by varying the external 
threshold from 80% to 90% to detect the minimum effect size at which we will have 80% power to achieve 
the goal (see table below). 
Ho (null hypothesis): p = p0 versus Ha (alternative hypothesis): p > p0 
N 
alpha 
p 
p0 
delta 
power 
100 
5% 
95% 
80% 
15% 
100% 
100 
5%
95% 
81% 
14% 
99.9% 
100 
5% 
95% 
82% 
13% 
99.6% 
100 
5% 
95% 
83% 
12% 
98.9% 
100 
5%
95% 
84% 
11% 
97.2% 
100 
5% 
95% 
85% 
10% 
93.7% 
100 
5% 
95% 
86% 
9% 
93.7% 
100 
5%
95% 
87% 
8% 
87.2% 
100 
5% 
95% 
88% 
7% 
76.6% 
100 
5% 
95% 
89% 
6% 
61.6% 
100 
5%
95% 
90% 
5% 
43.6% 
We show that, with 100 individuals in the DTG/RPV arm, we will have a 95% probability to discard a 
combination for which efficacy is smaller than 87% and we will select with a power of 80% the strategy for 
which the efficacy is above or equal to 95%. 
The power calculation was made using the statistical software package nQuery Advanced, using the exact 
test for single proportion module (Version 8.5.2.0). 
 
9.2 Statistical analysis plan 
 
The statistical analysis plan will be produced during the early stages of the clinical trial before the database 
has been locked for the first statistical analysis. This statistical analysis plan will describe the rules used for 
classification of the efficacy and safety data, the primary and secondary analyses and the format of the final 
tables, figures, and listings to be generated. The statistical analysis plan will be finalised and approved in line 
with applicable SOPs   before any analysis is conducted. 


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9.2.1 
Summary of baseline data and flow of patients 
The final analysis will be performed at the end of trial. A flow diagram will be produced, according to 
CONSORT standards, to show the disposition of all randomised patients up to the end of the trial. 
Baseline data will be described according to the treatment arms: age, sex, ethnicity, length of prior ARV 
therapy and presence of NRTI and NNRTI mutations in historical resistance samples. 
 
 
9.2.2 
Primary outcome analysis 
 
The primary endpoint will be a comparison of the percentage of participants with undetectable plasma HIV 
RNA levels at Week 48. 
 
Undetectable will be defined as plasma RNA levels of <50 copies/Ml. Participants with missing data at 
analysis time points will be considered as having lost undetectable plasma HIV-1 RNA levels. Any patient with 
HIV RNA levels >50 copies/Ml at analysis time points will have a repeat test (see section 6.18 for repeat testing 
process). If the result from the repeat test is below 50 copies/Ml, the patient will be classified as a responder. 
This is to prevent false positive HIV RNA results being classified as treatment failures. 
 
The analysis will be performed using the FDA Snapshot method. The primary population for analysis will be 
Intent to Treat, including all randomised patients who have received at least one dose of study medication. 
Participants will be categorised as follows, based on their HIV RNA results and disposition up to the end of 
the trial. 
 
HIV RNA <50 copies/Ml at Week 48 
 
HIV RNA confirmed >50 copies/Ml at Week 48 (virological failure) 
 
Missing HIV RNA data – discontinued randomised treatment for adverse events 
Missing HIV RNA data – discontinued randomised treatment for other reasons 
The intention of this study is to be a comparative pilot study. All analysis details will be included in Statistical 
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9.2.3 
Secondary outcome analysis 
 
Primary efficacy analysis repeated with (<200 copies/ml HIV RNA) at 24, 48, 96. 
 
The primary efficacy analysis will be repeated for the Per Protocol population, excluding participants with 
serious protocol violations which could interfere with the reliability of the efficacy outcome. Examples would 
include taking other antiretroviral treatment within the first 48 weeks of treatment, incorrect randomisation 
or early discontinuation from the study for reasons unconnected to efficacy or safety. This analysis will be 
conducted to check the reliability of the results from the primary efficacy analysis. 
 
In addition, a “Switch Included” analysis will be conducted, to check the outcomes of participants who 
discontinued randomised treatment for any reason. This analysis will follow the same methods as FDA 
Snapshot, but will include HIV RNA data from all participants with results available at Week 48, whether they 
are on or off randomised treatment. There will be no formal non inferiority outcome analysis as this is a pilot 
study. 
 
All analysis details will be included in Statistical Analysis Plan. 
 
 
9.3 Subgroup analyses 
 
The sample size of 150 participants is too small to allow meaningful subgroup analyses. The two analyses 
described above (Per Protocol and Switch Included) will assess the reliability of the results from the primary 
efficacy analysis. 
 
9.4 Adjusted analysis 
 
The primary efficacy analysis will be by multiple logistic regression. This analysis will be adjusted for two 
baseline categorical variables which might influence the 48-week outcome: presence of M184V mutation at 
baseline and CD4 count at baseline (above versus below 350 cells/Ul).  
 
9.5 Interim analysis 
An interim analysis will be performed when 120 participants reach the week 24 visit (corresponding to 80 


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participants in the DTG/RPV arm and 40 participants in the control arm). This will include a primary efficacy 
analysis for the Per Protocol population, excluding participants with serious protocol violations which could 
interfere with the reliability of the efficacy outcome. This analysis will be conducted to check the reliability 
of the results from the primary efficacy analysis and will also include the number of patients that 
discontinued the study due to adverse event or death, and discontinued the study for other reasons.   
 
In the ANRS 163 ETRAL trial (Katlama et al., JAC 2019), in which 10% of participants harboured viruses with 
K103N mutation, the proportion of participants in success at week 24 with a dual therapy with etravirine and 
raltegravir was estimated at 96.4% (95%CI 92.3 to 98.7). Therefore, for this interim analysis at week 24: The 
expected level of efficacy is 96%, and the unacceptable level of efficacy (p0) is 87%. With alpha = 5% 
(unilateral) and 80% power, if we include 80 participants in the DTG/RPV arm, we will consider that the 
treatment is effective to be continued if there are no more than 4 failures. We test the null hypothesis Ho: 
confidence interval would exclude 87% if the true success rate (p) is 96%. This gives a 5% chance of continuing 
if p = p0 and an 80% chance of contin
 
 
 
9.6 DSMB 
A DSMB will be appointed to monitor this study and draw up their own charter and decide when they will 
meet based on the protocol. The DSMB will meet when 80% of patients have reached 24 weeks to look at 
efficacy and safety, DSMB may also want to meet before or after that. 
Decisions on stopping the study will be based on a combined evaluation of the efficacy and safety results. 
Additional issues could include treatment- emergent drug resistance, serious adverse events or high rates of 
discontinuation for adverse events. 
 
9.7 Subject population 
The primary population for analysis will be Intent to Treat exposed, including all randomised participants 
who have received at least one dose of study medication. The analyses of safety will also be conducted on 
the Intent to Treat exposed population. 
The primary efficacy analysis will be repeated for the Per Protocol population, excluding participants with 
serious protocol violations which could interfere with the reliability of the efficacy outcome. Examples would 
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or early discontinuation from the study for reasons unconnected to efficacy or safety. This analysis will be 
conducted to check the reliability of the results from the primary efficacy analysis. 
 
9.8 Procedure(s) to account for missing or spurious data 
In the primary efficacy analysis (FDA Snapshot), participants with missing data at analysis time points will be 
considered as having lost undetectable plasma HIV-1 RNA levels. 
The analyses of overall participants disposition will show the number of participants who did not attend 
each protocol-defined visit. 
 
9.9 Other statistical considerations. 
  
All deviations from the statistical analysis plan will be recorded during the conduct of all analyses. If there is 
a decision for major modifications to the statistical analysis while the clinical trial is in progress, this will be 
part of a protocol amendment. 
 
9.10 
Economic evaluation 
 
There are no plans for an economic evaluation of this trial. 
 
 
10 DATA HANDLING 
 
 
 
10.1 
Data collection tools and source document identification 
 
10.1.1 Source Data 
All information in original records and certified copies of original records or clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data 
are contained in source documents (original records or certified copies) maintained at site. 
10.1.2 Source Documents 
Original documents, data and records (e.g., hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries of evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 


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the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial) will be 
maintained at site. 
The subject’s number and date of entry into the study, along with a study identifier, should be recorded in 
the subject’s study records. The following should also be recorded in the study records; confirmation of 
written and oral consent, the subject’s clinical status, date of every study visit, date study medication was 
started and stopped, concomitant medications, copies of all relevant reports and laboratory tests, comments 
on results and reference to any adverse events. 
 
Source documents include, but are not limited to participant medical records, serious adverse events (SAE) 
& reportable event forms (see section 8), questionnaires, laboratory reports, participant progress notes, 
pharmacy records and any other reports or records of procedures performed in accordance with the 
protocol. 
 
10.1.3 Case report forms 
Subject data collected during the study will be recorded in the study specific case report forms (CRFs). In 
order to maintain confidentiality, the subject will be identified only by subject number. 
 
The design of CRFs will ensure that: 
 
 adequate collection of data has been performed 
 
 proper paper trails can be kept to demonstrate the validity of the trial (both during and after the 
trial) 
 only the data required by the protocol are captured in the CRF (using the CRF to capture 
secondary data not required for the study may be a criminal beach of the Data Protection Act, 
makes the CRF unnecessarily complicated, and can make it more difficult to extract the primary 
data for analysis) 
Data required for the study will be recorded in a web-based electronic CRF (eCRF) collection tool by 
appropriately trained and authorised member(s) of the study team who must be identified and authorised 
in writing by the Principal Investigator before they conduct any study related tasks. A delegation of 
responsibility log identifying who can enter data and/or sign off a CRF will be maintained by the Principal 
Investigator. 
 


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The eCRF should be kept current by entering data within two weeks of collection to enable the study monitor 
to review the subject status throughout the course of the study. 
 
The data will be reviewed and approved by the Investigator following subject completion. 
 
10.2 Data handling and record keeping 
 
 
The Study Monitor and Data Manager will review data on an on-going basis and raise any discrepancies 
with site staff as required. 
At the end of the study, the site will be provided with copies of their CRFs before the eCRF is 
decommissioned, ensuring site access to their data at all times. 
Data extracted from the eCRF will be kept on a secure network drive of NEAT ID with access to authorised 
personnel only. 
Identified only by subject number, the data are pseudo-anonymised at all times and are transferred securely 
using the NEAT ID file share process. All transfers are fully documented. 
 
10.3 Archiving 
Following completion of the study, subject records, CRF and other study documentation will be retained by 
the Investigator in accordance with Good Clinical Practice (GCP) and applicable regulatory requirements. 
 
 
Following closure of the study, the investigator or the head of the medical institution (where applicable) 
must maintain all site study records (except for those required by local regulations to be maintained 
elsewhere), in a safe and secure location. 
 
The records must be maintained to allow easy and timely retrieval, when needed (e.g. for sponsor or 
regulatory inspection) and must be available for review in conjunction with assessment of the facility, 
supporting systems, and relevant site staff. 
 
Where permitted by local laws/regulations or institutional policy, some or all of these records can be 
maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution 
needs to be exercised before such action is taken. 
 
The investigator must ensure that all reproductions are legible and are a true and accurate copy of the 
original and meet accessibility and retrieval standards, including re-generating a hard copy, if required. 


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Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and 
that an acceptable quality control process exists for making these reproductions. 
 
The Investigator’s Site Files must be retained for 25 years from the date of the final study report. Sponsor 
will inform the investigator of the retention period due date at the time when the final study report (or 
equivalent) is issued to the site. 
 
The investigator must notify sponsor of any changes in the archival arrangements, including, but not 
limited to, archival at an off-site facility or transfer of ownership of the records in the event the 
investigator is no longer associated with the site. 
 
Archiving will be authorised by the Sponsor following submission of the end of study report. 
 
The sponsor will be responsible for archiving the TMF. The Investigators at site(s) will be responsible for 
retention/archiving subject records, CRF, ISF and other study documentation (as applicable) in accordance 
with Good Clinical Practice (GCP) and applicable regulatory requirements. 
Destruction of essential documents will require authorisation from the Sponsor. 
 
 
The trial database will be maintained and stored in accordance with Good Clinical Practice (GCP). 
 
 
11 MONITORING, AUDIT & INSPECTION 
 
 
 
A trial monitoring plan will be followed for this study based on the trial risk assessment. The plan will detail 
monitoring frequency, requirements, and processes. The purpose of monitoring is to verify the rights and 
wellbeing of human subjects are protected; that trial data is accurate, complete and verifiable with source 
data; that the trial is conducted in compliance with the protocol, GCP and the applicable regulatory 
requirements. 
 
A monitor will conduct regular site visits for the purpose of monitoring various aspects of the study. The 
Investigator must agree to allow the study monitor and authorised representatives of the Sponsor, to inspect 
all CRF and corresponding source documents, e.g. original medical records, subject records and laboratory 
raw data, access to the clinical supplies, dispensing and storage areas and agree to assist with their activities 
if requested. The Investigator should provide adequate time and space for monitoring visits. 
 


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The monitor will query any missing or spurious data with the Investigator, which should be resolved in a 
timely manner. A monitoring log will be maintained recording each visit, the reason for the visit, the 
monitor’s signature and Investigator’s or designee’s confirmation signature. 
 
For the purpose of compliance with GCP and regulatory agency guidelines, it may be necessary for sponsor 
authorised Quality Assurance personnel and/or authorised personnel from an external regulatory agency to 
conduct an audit/inspection of an Investigational site. The purpose of an audit is to assess the quality of data 
with regard to accuracy, adequacy and consistency, and to assure that studies are in accordance with Good 
Clinical Practices, and Regulatory Agency guidelines. Having the highest quality data from studies is an 
essential aspect of drug development. 
 
The Investigator will be given sufficient notice to prepare for such visits, which are planned to take usually 
between one and three days and may be conducted at any stage during the study. The audit will involve the 
review of all study related documentation, which is required by GCP to be maintained by each site, review 
of drug storage, dispensing and return, review of all study related supplies and review of source documents 
against the CRF to assure the adequacy and accuracy of the information which has been recorded, including 
the verification of any AE which have occurred. 
12 ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES/ GROUPS & INDIVIDUALS 
 
 
 
Trial Management Committees 
 
 The only trial management committee involved in the set up and management of the clinical trial will be the DSMB. 
 
 
Data Safety Monitoring Board (DSMB) 
The Data Safety Monitoring Board (DSMB) is to monitor the main safety and efficacy outcome measures, any 
analysis, and the overall conduct of the trial, with the aim of protecting the safety and interests of the trial 
participants. DSMB charter to be followed. DSMB will be composed of a statistician and medical experts. 
 
 
 
 
 
 


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13 ETHICAL AND REGULATORY CONSIDERATIONS 
 
 
13.1 
Ethics Committee (EC) review & reports 
The study will comply with the following requirements 
 
 
Before the start of the trial, approval will be sought from a EC for the trial protocol, informed 
consent forms and other relevant documents e.g. advertisements and GP information letters 
 
Substantial amendments that require review by EC will not be implemented until the EC grants a 
favourable opinion for the study (note that amendments may also need to be reviewed and 
accepted by the regulatory authority before they can be implemented in practice at sites) 
 
All correspondence with the EC will be retained in the Trial Master File/Investigator Site File 
 
 
An annual progress report (APR) will be submitted (if required) to the EC as per country 
requirements. 
 
The Chief Investigator will notify the EC of the end of the study 
 
 
If the study is ended prematurely, the Chief Investigator will notify the EC, including the reasons 
for the premature termination 
 
Within one year after the end of the study, the sponsor will submit a final report with the results, 
including any publications/abstracts, to the EC 
 
13.2 
Peer review 
The high-quality peer review process (initiated by study sponsor) for the trial protocol will meet the 
following review criteria: 
 
 
a) Independent: At least two individual experts will review the study. Reviewers are external to the 
investigators’ host institution and not involved in the study in any way. 
 
b) Expert: Reviewers have knowledge of the relevant discipline to consider the clinical and/or service 
based aspects of the protocol, and/or have the expertise to assess the methodological and statistical 
aspects of the study. 
c) Proportionate: Peer review commensurate with the size and complexity of the study. 
 
 


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13.3 
Regulatory Compliance 
 
This study will comply with the following: 
 
 
the trial will not commence until a Clinical Trial Authorisation (CTA) is obtained as required by 
local regulations 
 
the protocol and trial conduct will comply with the Medicines for Human Use (Clinical Trials) 
Regulations 2004 and any relevant amendments 
 
13.4 
Protocol Compliance 
 
Prospective, planned deviations or waivers to the protocol are not allowed under the UK & EU regulations 
on Clinical Trials and must not be used e.g. it is not acceptable to enrol a subject if they do not meet the 
eligibility criteria or restrictions specified in the trial protocol. 
Accidental protocol deviations can happen at any time. They must be adequately documented on the 
relevant forms and reported to the Chief Investigator and Sponsor immediately. 
Deviations from the protocol which are found to frequently recur are not acceptable, will require immediate 
action and could be classified as a serious breach. 
 
13.5 
Notification of Serious Breaches to GCP and/or the protocol 
 
A “serious breach” is a breach which is likely to effect to a significant degree – 
 
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial 
 
Sponsor will be notified immediately of any case where the above definition applies during the trial conduct 
phase. 
The sponsor will notify the licensing authority in writing of any serious breach of 
 
(a) the conditions and principles of GCP in connection with that trial; or 
(b) the protocol relating to that trial, as amended from time to time, within 7 days of becoming 
aware of that breach 
 
 
 
 


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13.6 
Data protection and patient confidentiality 
 
 
All investigators and trial site staff will comply with the requirements of current Data Protection Regulations 
with regards to the collection, storage, processing and disclosure of personal information and will uphold 
the Act’s core principles. 
Personal information is to be collected, kept secure, and maintained in line with the following requirements: 
 
 
the creation of coded, depersonalised data where the participant’s identifying information is 
replaced by an unrelated sequence of characters. 
 
 
secure maintenance of the data and the linking code in separate locations using encrypted digital 
files within password protected folders and storage media. 
 
limiting access to the minimum number of individuals necessary for quality control, audit, and 
analysis. 
 
13.7 
Financial and other competing interests for the chief investigator, PIs at each site and committee 
members for the overall trial management 
 
The sponsor will identify and collect the following disclosure information: 
 
 
ownership interests that may be related to products, services, or interventions considered for use 
in the trial or that may be significantly affected by the trial 
 
commercial ties requiring disclosure include, but are not restricted to, any pharmaceutical, 
behaviour modification, and/or technology company 
 
any non-commercial potential conflicts e.g. professional collaborations that may impact on 
academic promotion. 
 
13.8 
Indemnity 
The sponsor will take out appropriate insurance cover for this trial. 
 
13.9 
Amendments 
 
Under the Medicines for Human Use (Clinical Trials) Regulations 2004, the sponsor may make a non- 
substantial or substantial amendment at any time during a trial. If the sponsor wishes to make a substantial 


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amendment to the CTA or the documents that supported the original application for the CTA, the sponsor 
will submit a valid notice of amendment to the appropriate EC, trial registries, regulatory agencies. It is the 
sponsor’s responsibility to decide whether an amendment is substantial or non-substantial. 
 
13.10 Post trial care 
 
Post study medication will not be provided following completion of the trial. Investigators are to ensure 
patients have access to medication for their HIV treatment following study end. 
 
13.11 Access to the final trial dataset 
The investigators will be provided reasonable access to statistical tables, figures, and relevant reports. 
 
Sponsor will also provide the investigators with the full summary of the study results. The investigator is 
encouraged to share the summary results with the study subjects, as appropriate. 
 
The procedures and timing for public disclosure of the results summary and for development of a manuscript 
for publication will be in accordance with sponsor policies. 
 
14 DISSEMINIATION POLICY 
 
 
14.1 
Dissemination policy 
 
A whole or part of this study results will be communicated, orally presented, and/or published in appropriate 
scientific journals. Full anonymity of subject’s details will be maintained throughout. Subjects wanting to see 
the results of the trial can request a copy of the article from the investigators once it has been published. 


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15 APPENDICES 
 
Appendix 1: 
Assessment Table 
Appendix 2: 
AIDS Clinical Trial Group (ACTG) Grading Scale 
Appendix 3: 
Highly Effective Methods for Avoiding Pregnancy in Females of Child Bearing 
Potential 
Appendix 4: 
The Child-Pugh Classification System 
Appendix 5: 
Data Processing Agreement 
Appendix 6: 
Amendment History 


 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 


 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 


 
 
 
 
 


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Appendix 2: AIDS Clinical Trial Group (ACTG) Grading Scale
DAIDS AE Grading Table Corrected Version 2.1-July 2017 
Attached as a separate document and available online at:
https://rsc.tech-res.com/docs/default-source/safety/daidsgradingcorrecetedv21.pdf?sfvrsn=6


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Appendix 3: Highly Effective Methods for Avoiding Pregnancy in Females of Child Bearing 
Potential 
 
The following is the all inclusive list of the highly effective methods for avoiding pregnancy (i.e., have a 
failure rate of less than 1% per year when used consistently and correctly and, when applicable, in 
accordance with the product label). 
The list does not apply to Females of Child Bearing Potential (FCBP) with same sex partners or for subjects 
who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
1. Contraceptive subdermal implant 
 
2. Intrauterine device or intrauterine system 
 
3. Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]) 
 
4. Injectable progestogen [Hatcher, 2011] 
 
5. Contraceptive vaginal ring [Hatcher, 2011] 
 
6. Percutaneous contraceptive patches [Hatcher, 2011] 
 
7. Male partner sterilisation with documentation of azoospermia prior to the female subject's entry into 
the study, and this male is the sole partner for that subject [Hatcher, 2011]. The documentation on male 
sterility can come from the site personnel’s: review of subject’s medical records, medical examination 
and/or semen analysis, or medical history interview provided by her or her partner. 
 
These methods of contraception are only effective when used consistently, correctly and in accordance 
with the product label. The investigator is responsible for ensuring that subjects understand how to 
properly use these methods of contraception. 
References 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. Contraceptive 
Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3 2. 
 
 


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Appendix 4: The Child-Pugh classification system 
 
The Child-Pugh classification is a scoring system used to determine the prognosis with cirrhosis. 
Scoring is based upon several factors: albumin, ascites, total bilirubin, prothrombin time, and 
encephalopathy, as follows: 
 
 
 
Score: 
1 point 
Score: 
2 points 
Score: 
3 points 
Serum Albumin (g/dL) 
>3.5 
3.0 - 3.5 
<3.0 
Serum Bilirubin (mg/dL) 
<2.0 
2.0 - 3.0 
>3.0 
Prothrombin time (seconds) 
1 - 4 
4 - 6 
>6 
Ascites 
none 
moderate 
severe 
Encephalopathy 
none 
mild 
severe 
 
 
 
The three classes and their scores are: 
 
 
Class A is score 5 - 6 
 
Class B is score 7 - 9 
 
Class C is score >9 
 
Patients with a score of 10 or more (in the Class C category) have a prognosis with 1-year survival being about 50%. 
Patients with Class A or B have a better prognosis of 5-years, with a survival rate of 70%- 80%. 
 


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Appendix 5: Data Processing Agreement 
 
Definitions: 
 
• 
“Protocol” means the document entitled “The effect of switching to Dolutegravir and Rilpivirine 
combination therapy in patients with HIV-1 and the K103N mutation” containing the details of the study as 
developed by the Lead Sponsor and approved by the relevant Ethics Committee(s). 
• 
“Sponsor” means “NEAT ID” 
• 
Participating site acts as a data processor as defined under article 4, 8) of the Regulation (EU) 
2016/679 (“Data Processor”) for the Lead Sponsor who acts as data controller as defined under article 4, 7) 
of the Regulation (EU) 2016/679 (“Data Controller”). 
• 
“Applicable Law” means any applicable data protection or privacy laws, including: 
a) 
the Regulation (EU) 2016/679 also referred as the General Data Protection Regulation ("GDPR"); 
b) 
other applicable laws that are similar or equivalent to or that are intended to or implement the 
laws that are identified in (a) of this definition; 
• 
"Personal Data" means any information relating to an identified or identifiable natural person 
(”Data Participant”), including without limitation pseudonymised information, as defined in Applicable Law 
and described in the Protocol. 
Rights and obligations: 
1. 
The Data Processor is instructed to process the Personal Data for the term of the Trial and only for 
the purposes of providing the data processing tasks set out in the Protocol. The Data Processor may not 
process or use Personal Data for any purpose other than a Data Participant’s medical records, or other 
than provided in the instructions of the Trial protocol, including with regard to transfers of personal data to 
a third country or an international organisation, unless the Data Processor is required to do so according to 
Union or Member State law. 
2. 
Data Processor shall at all times maintain a record of processing of Personal Data in accordance 
with Applicable Law and if the Data Processor considers an instruction from the Data Controller to be in 
violation of the Applicable Law, the Data Processor shall promptly inform the Data Controller in writing 
about this. 
3. 
The Data Processor must ensure that persons authorized to process the Personal Data have 
committed themselves to confidentiality or are under an appropriate statutory obligation of 
confidentiality. 
4. 
The Data Processor shall implement appropriate technical and organisational measures to prevent 
that the Personal Data processed is: 
(i) 
accidentally or unlawfully destroyed, lost or altered, 
(ii) 
disclosed or made available without authorization, or 
(iii) 
otherwise processed in violation of Applicable Law. 
 
 


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5. 
The appropriate technical and organisational security measures must be determined with due 
regard for: 
(i) 
the current state of the art, 
(ii) 
the cost of their implementation, and 
(iii) 
the nature, scope, context and purposes of processing as well as the risk of varying likelihood and 
severity for the rights and freedoms of natural persons. 
6. 
Taking into account the nature of the processing, the Data Processor shall assist the Data 
Controller, by means of appropriate technical and organisational measures, insofar as this is possible, in 
fulfilling its obligation to respond to requests from Data Participants pursuant to laws and regulations in 
the area of privacy and data protection (such as, the right of access, the right to rectification, the right to 
erasure, the right to restrict the processing, the right to data portability and the right to object) 
7. 
The Data Processor shall upon request provide the Data Controller with sufficient information to 
enable the Data Controller to ensure that the Data Processor's obligations under this DPA are complied 
with, including ensuring that the appropriate technical and organisational security measures have been 
implemented. 
8. 
The Data Controller is entitled to appoint at its own cost an independent expert, reasonably 
acceptable to the Data Processor, who shall have access to the Data Processor's data processing facilities 
and receive the necessary information for the sole purpose of auditing whether the Data Processor has 
implemented and maintained said technical and organisational security measures. The expert shall upon 
the Data Processor's request sign a non-disclosure agreement provided by the Data Processor, and treat all 
information obtained or received from the Data Processor confidentially, and may only pass on, after 
conferral with the Data Processor, the findings as described under 10) (ii) below to the Data Controller. 
9. 
The Data Processor must give authorities who by Union or Member State law have a right to enter 
the Data Controller's or the Data Controller's processors’ facilities, or representatives of the authorities, 
access to the Data Processor's physical facilities against proper proof of identity and mandate, during 
normal business hours and upon reasonable prior written notice. 
10. 
The Data Processor must without undue delay in writing notify the Data Controller about: 
(i) 
any request for disclosure of Personal Data processed under the Protocol by authorities, unless 
expressly prohibited under Union or Member State law, 
(ii) 
any finding of (a) breach of security that results in accidental or unlawful destruction, loss, 
alteration, unauthorised disclosure of, or access to, Personal Data stored or otherwise processed by the 
Data Processor under the Protocol, or (b) other failure to comply with the Data Processor's obligations, or 
(iii) 
any request for access to the Personal Data (with the exception of medical records for which the 
Data Processor is considered data controller) received directly from the Data Participants or from third 
parties. 
11. 
Such a notification from the Data Processor to the Data Controller with regard to a breach of 
security as meant in 10) (ii)(a) above will contain at least the following information: 
(i) 
the nature of the Personal Data breach, stating the categories and (by approximation) the number 


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of Data Participants concerned, and stating the categories and (by approximation) the number of the 
personal data registers affected (datasets); 
(ii) 
the likely consequences of the Personal Data breach; 
(iii) 
a proposal for measures to be taken to address the Personal Data breach, including (where 
appropriate) measures to mitigate any possible adverse effects of such breach. 
12. 
The Data Processor shall document (and shall keep such documentation available for the Data 
Controller) any Personal Data breaches, including the facts related to the Personal Data breach, its effects 
and the corrective measures taken. After consulting with the Data Controller, the Data Processor shall take 
any measures needed to limit the (possible) adverse effects of Personal Data breaches (unless such 
consultation cannot be awaited due to the nature of the Personal Data breach). 
13. 
The Data Processor must promptly and reasonably assist the Data Controller (with the handling of 
(a) responses to any breach of security as described in 10) (ii) above and (b) any requests from Data 
Participants under Chapter III of the GDPR, including requests for access, rectification, blocking or deletion. 
The Data Processor must also reasonably assist the Data Controller by implementing appropriate technical 
and organisational measures for the fulfilment of the Data Controller's obligation to respond to such 
requests. 
14. 
The Data Processor must reasonably assist the Data Controller with meeting the other obligations 
that may be incumbent on the Data Controller according to Union or Member State law where the 
assistance of the Data Processor is implied, and where the assistance of the Data Processor is necessary for 
the Data Controller to comply with its obligations. This includes, but is not limited to, at the request to 
provide the Data Controller with all necessary information about an incident under 10) (ii), and all 
necessary information for an impact assessment in accordance with Article 35 and Article 36 of the GDPR. 
Subprocessor: 
15. 
The Data Processor may only engage a subprocessor, with prior specific or general written consent 
from the Data Controller. The Data Processor undertakes to inform the Data Controller of any intended 
changes concerning the addition or replacement of a subprocessor by providing a reasonable prior written 
notice to the Data Controller. The Data Controller may reasonably and in a duly substantiated manner 
object to the use of a subprocessor. The Data Processor must inform the Data Controller in writing of the 
discontinued use of a subprocessor. 
16. 
Prior to the engagement of a subprocessor, the Data Processor shall conclude a written agreement 
with the subprocessor, in which at least the same data protection obligations as set out in this DPA shall be 
imposed on the subprocessor, including obligations to implement appropriate technical and organisational 
measures and to ensure that the transfer of Personal Data is done in such a manner that the processing 
will meet the requirements of the Applicable Law. 
The Data Controller has the right to receive a copy of the relevant provisions of Data Processor's agreement with 
the subprocessor related to data protection obligations. The Data Processor shall remain fully liable to the Data 
Controller for the performance of the subprocessor obligations under this DPA. The fact that the Data Controller 
has given consent to the Data Processor's use of a subprocessor is without prejudice for the Data Processor's duty 
to comply with this DPA 
 


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Appendix 6: Amendment History 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
1 
1.0 to 2.0 
23 March 2018 
Emily Hutton. 
Project Manager 
Formatting and minor edit to text to ensure 
consistency. 
Version 1.0 not submitted & not approved. 
2 
2.0 to 3.0 
11 July 2018 
Barbara Gastl, 
Project Director 
1. St Stephens Clinical Research removed as 
study sponsor and responsible party for 
Project Management & Biometrics and Data 
Management. 
2. Introduction of NEAT ID as the sole sponsor 
for the trial and ROKC as CRO for Project 
Management, Data Management and 
Statistics. 
3. Inclusion criteria No. 3 updated in line with 
UK REC comments as follows “Is capable 
of giving informed consent, or if 
appropriate, subjects having an 
acceptable individual 
 capable of giving consent on the subject’s 
 behalf.”. 
4. Additional risk/safety information added to 
address emerging NTD safety information. 
Pregnancy testing also added to all visits 
from baseline to ETV. 
5. Clarification to Reference Safety Information, 
cautioning on the use of concomitant 
medicines that inhibit CYP3A and effects to 
exposure of rilpivirine. 
6. Addition of pregnancy tests for WOCBP at 
every study visit and home testing every 4 
weeks throughout the trial 
7. Clarification of applicable Reference Safety 
Information in section 8.1
3 
3.0 to 4.0 
01Jul2020 
Zainib Shabir, 
Project Manager 
1. Align all protocols for all territories following 
initial approval 
2. Updated RSI information to SmPC of Juluca in-
line with previously submitted amendments 
3. Correct minor admin errors and minor 
inconsistencies 
4. Addition of interim analysis at week 24 
5. Updated exclusion criteria 14 and 15 to include 
an exemption based on local practice for 
vaccination of patients at low-risk of acquiring 
Hepatitis B 
6. Updated exclusion criteria 25 to include an 
exemption for hyperbilirubinaemia due to 
atazanavir exposure 
7. Removed the requirement for the screening 
pregnancy test to be performed in serum to 


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allow for different standard practices at sites 
8. Addition of Week 52 PK sampling for deferred 
switch patients to match the Week 4 PK 
sampling for immediate switch patients 
9. Replaced Appendix 2 AE grading table with an 
external link to the most up-to-date version 
10. Added a Data Processing Agreement as 
Appendix 5 
 
4 
4.0 to 5.0  
30Oct2020  
Jacob Lowman, 
Project Manager 
1. Expanded section 9 on statistical analysis 
with more information concerning the 
analysis and powering of the study, 
including the addition of a Week 24 interim 
analysis 
2. Corrected conditions of virological failure to 
correctly state repeat test should be at least 
14 days from initial detectable test 
3. Correction of primary outcome measure b. to 
be investigated over 48 weeks rather than 96 
weeks 
4. Updated risk wording concerning pregnancy in 
women taking dolutegravir as provided by the 
IMP manufacturer 
5. Removed incorrect mentions of Trial Steering 
Committee and Trial Management Group in 
various section 
6. Numerous minor administrative changes 
 
 
 
 
 


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