'COMBINE-2': Real-world Evidence for Effectiveness of Two Drug Regimen, Antiretroviral Therapy With Integrase Inhibitors Plus a Reverse Transcriptase Inhibitor
Conditions: HIV Infections
Sponsor: ViiV Healthcare

Protocol 
Study ID:  207859
Official Title of Study: COMBINE-2: Real-world evidence for effectiveness of 
TwoDrug Regimen, Antiretroviral therapy with integrase inhibitors plus a reverse 
transcriptase inhibitor
Date of Document: 18 Jun 2018

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TITLE PAGE
Information Type: ViiV Healthcare Epidemiology Study Protocol
Title:
‘COMBINE-2’: Real-world evidence for effectiveness of Two
Drug Regimen, Antiretroviral therapy with integrase inhibitors 
plus a reverse transcriptase inhibitor 
Compound 
Number:
GSK3365791 (GSK1349572+GSK1329758, Juluca), GSK 
3515864 (GSK1349572+GR109714, D3)
Development Phase
IV
Effective Date:
[DD-MM-YYYY]
Subject:
Efficacy of integrase inhibitors plus a reverse transcriptase inhibitor ART.
Author(s):
1.
, MD; UNIMORE
2.
; NEAT ID statistician 
3.
, MBBS, MPH, PhD; ViiV Healthcare 
4.
 MD, FRCP; NEAT ID
Copyright 2016 ViiV Healthcare LLC and the GlaxoSmithKline group of companies. All 
rights reserved.  Unauthorised copying or use of this information is prohibited
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PASS information
Title
‘COMBINE-2’: Real-world evidence for effectiveness 
of Two Drug Regimen, Antiretroviral therapy with 
integrase inhibitors plus a reverse transcriptase inhibitor
Protocol version
identifier
v1.0
Date of last version of
protocol
EU PAS register number Study not yet registered
Active substance
dolutegravir/rilpivirine, dolutegravir/lamivudine 
Medicinal product
Invented name: JULUCA
Product reference
JULUCA: H0004427
dolutegravir/lamivudine: H0004909
Procedure number
JULUCA: EMEA/H/C/004427/0000
Marketing
authorisation
holder(s)
ViiV Healthcare UK Limited
Joint PASS
No
Research 
question and
objectives
Following
antiretroviral treatment with
the integrase 
inhibitor dolutegravir plus:
a.
Reverse transcriptase rilpivirine or;
b. Reverse transcriptase lamivudine
the study will aim to:
1. Assess the effectiveness of two-drug regimen (2DR 
– integrase inhibitor plus a reverse transcriptase 
inhibitor)
2. Collect information on the safety of 2DR in terms of 
drug related adverse events and serious adverse
events, and development of resistance

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Country(-ies) of study
Belgium, France, Germany, Italy, Spain, Poland and United 
Kingdom
Authors
 MBBS, MPH, PhD 
Global Head, Epidemiology & Real World Evidence
ViiV Healthcare
5 Moore Drive
Research Triangle Park, 
NC 27709, USA
Phone:
Dr 
, MD
Professor, University of Modena and Reggio Emilia 
Infectious Diseases Clinics 
via del Pozzo, 71
41124 Modena, 
Italy
Phone: 
 de l’Institut Pierre Louis d’Epidémiologie et 
de Santé Publique, 
Sorbonne Université, 
INSERM 56 Bd V Auriol, 
CS81393, 75646 
PARIS Cedex 13, 
France
Phone: 
Dr. 
NEAT-ID Foundation ‘’European AIDS Treatment 
Network Infectious Disease Foundation’’ 
PL709, 
Rue Haute 322 
1000 Brussels, 
Belgium
Phone: 
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MARKETING AUTHORISATION HOLDER 
Marketing authorisation
holder(s)
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS 
United Kingdom
MAH contact person
Dr. 
GlaxoSmithKline R&D Limited
Stockley Park West
Uxbridge
Middlesex
UB11 1BT
United Kingdom
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TABLE OF CONTENTS
PAGE
1. 
LIST OF ABBREVIATIONS......................................................................................7 
2. 
RESPONSIBLE PARTIES: SPONSOR INFORMATION PAGE................................9 
3. 
ABSTRACT............................................................................................................12 
4. 
AMENDMENTS AND UPDATES............................................................................13 
5. 
MILESTONES........................................................................................................13 
6. 
RATIONAL AND BACKGROUND ..........................................................................13 
7. 
RESEARCH QUESTION AND OBJECTIVE(S)......................................................14 
7.1. 
Primary Objective: ......................................................................................14 
7.2. 
Secondary Objective:..................................................................................14 
8. 
RESEARCH METHODS.........................................................................................14 
8.1. 
Study Design ..............................................................................................14 
8.2. 
Study Population and Setting......................................................................14 
8.2.1. 
Study Setting ...............................................................................14 
8.2.2. 
Inclusion Criteria..........................................................................15 
8.2.3. 
Patient Identification and Consent ...............................................15 
8.3. 
Variables.....................................................................................................15 
8.3.1. 
Exposure definitions ....................................................................15 
8.3.2. 
Outcome Definitions ....................................................................15 
8.3.2.1. 
Primary Outcomes......................................................15 
8.3.2.2. 
Secondary Outcomes.................................................16 
8.3.3. 
Confounders and Effect Modifier..................................................17 
8.4. 
Data Sources..............................................................................................17 
8.5. 
Study Size ..................................................................................................17 
8.6. 
Data Management ......................................................................................18 
8.6.1. 
Data Collection ............................................................................18 
8.6.1.1. 
Source Data ...............................................................18 
8.6.1.2. 
Source Documents.....................................................18 
8.6.1.3. 
Data Collection Methods ............................................19 
8.6.2. 
Data Handling Conventions .........................................................19 
8.6.3. 
Resourcing Needs .......................................................................19 
8.6.4. 
Timings of Assessment During Follow-up ....................................19 
8.7. 
Data Analysis..............................................................................................19 
8.7.1. 
Essential Analysis........................................................................19 
8.7.2. 
Exploratory Analysis ....................................................................20 
8.8. 
Quality Control and Quality Assurance .......................................................21 
8.9. 
Limitations of the Research Methods..........................................................21 
8.9.1. 
Study Closure/Uninterpretability of Results..................................21 
9. 
PROTECTION OF HUMAN SUBJECTS ................................................................22 
9.1. 
Ethical Approval..........................................................................................22 
9.2. 
Subject Confidentiality ................................................................................22 

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10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ..........................................................................................................22 
11. PLANS 
FOR 
DISSEMINATING 
AND 
COMMUNICATING 
STUDY 
RESULTS ..............................................................................................................25 
11.1. 
Target Audience .........................................................................................25 
11.2. 
Study Reporting and Publications ...............................................................26 
12. REFERENCES.......................................................................................................27 
ANNEX 1: DATA ASSESSMENT TABLE......................................................................28 
ANNEX 2: AIDS CLINICAL TRIAL GROUP (ACTG) GRADING SCALE........................29 

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1.
LIST 
OF 
ABBREVIATIONS
2DR
Two-drug regimen
ACTG
AIDS Clinical Trial Group
AE
Adverse Event
AR
Adverse Reaction
ART
Antiretroviral Therapy
CA
Competent Authority
CI
Chief Investigator
CRF
Case Report Form
CRO
Contract Research Organisation
CTA
Clinical Trial Authorisation
DMC
Data Monitoring Committee
DTG
Dolutegravir
EC
European Commission
EMEA
European Medicines Agency
EU
European Union
EUCTD
European Clinical Trials Directive
EudraVIGILANCE
European database for Pharmacovigilance
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice 
HIV
Human Immunodeficiency Virus
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of technical 
requirements for registration of pharmaceuticals for human use.
IDMC
Independent Data Monitoring Committee
IMP
Investigational Medicinal Product
IMPD
Investigational Medicinal Product Dossier
ISF
Investigator Site File
ISRCTN Number
International Standard Randomised Controlled Trials 
3TC
Lamivudine
MA
Marketing Authorisation
MHRA
Medicines and Healthcare products Regulatory Agency
MS
Member State
NHS R&D
National Health Service Research & Development  
NIMP
Non-Investigational Medicinal Product
PASS
Post-authorization Safety Study
PI
Principal Investigator
PIC
Participant Identification Centre
PIS
Participant Information Sheet
QA
Quality Assurance
QC
Quality Control
QP
Qualified Person 
RCT
Randomised Control Trial
REC
Research Ethics Committee
RNA
Ribonucleic acid
RPV
Rilpivirine

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SAE
Serious Adverse Event
SAR
Serious Adverse Reaction
SDV
Source Data Verification
SOP
Standard Operating Procedure 
SmPC
Summary of Product Characteristics 
SSI
Site Specific Information
SUSAR
Suspected Unexpected Serious Adverse Reaction 
TMG
Trial Management Group
TSC
Trial Steering Committee
TMF
Trial Master File
Trademark Information
Trademarks of ViiV Healthcare and the 
GlaxoSmithKline group of companies
Trademarks not owned by ViiV 
Healthcare and the GlaxoSmithKline 
group of companies
JULUCA
SAS
Stata
SPSS

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2.
RESPONSIBLE PARTIES:
SPONSOR
INFORMATION 
PAGE
MARKETING AUTHORISATION HOLDER
ViiV Healthcare UK Limited
Sponsor Legal Registered Address:
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS 
United Kingdom
Sponsor Medical Monitor Contact Information:
, MBChB, MRCP, MBA, DTM&H
, Dolutegravir Franchise
t: 
m: 
Email:
Sponsor Serious Adverse Events (SAE) Contact Information: 
Email for clinical safety mailbox = oax37649@gsk.com (preferred) 
Fax = +44 (0)20 8754 7822
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CHIEF INVESTIGATOR PROTOCOL AGREEMENT PAGE
x
I agree to conduct the study in compliance with the protocol.
x
I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described clinical study.
x
I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure that site staff receive the appropriate information throughout the 
study.
Investigator Name:  Dr. Cristina Mussini
6th June 2018
Investigator Signature
Date
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3.
ABSTRACT
The efficacy of two-drug regimen (2DR) therapy with an integrase inhibitor plus a 
reverse transcriptase inhibitor is being assessed in various pilot studies and clinical trials. 
In the PADDLE study, high rates of HIV RNA suppression were demonstrated after first-
line treatment with Dolutegravir (DTG) plus Lamivudine (3TC)1. Other studies have 
shown high rates of HIV RNA suppression after patients with HIV RNA suppression at 
baseline on triple therapy were switched to 2DR with DTG plus 3TC. Phase III, SWORD 
1 and SWORD 2 clinical trials for investigational 2DR of DTG and RPV for HIV 
treatment, achieved non-inferior viral suppression at 48 weeks compared with a three- or 
four-drug regimen2.
However, the pilot studies conducted to date and the Phase 3 programme all have strict 
inclusion/exclusion criteria. 
Thus, gathering real world evidence with less restrictive inclusion criteria to evaluate 
effectiveness of the 2DR with an integrase inhibitor such as DTG plus a reverse 
transcriptase inhibitor such as 3TC or RPV would further demonstrate the value of such 
regimen.
This multi-site observational study will assess the effectiveness of 2DR in approximately 
500 patients either as:
x
a first-line treatment for naïve patients,
x
a switching option for those with HIV RNA suppression on current treatment
(stable switch),
x
or a second-line treatment for those with virological failure (VF) on prior 
treatment.
The data collected for this study does not require any changes to the routine standard of 
care that patients receive. The study will aim to assess effectiveness of this regime with 
HIV RNA suppression below 50 copies/mL after 24 weeks of treatment, 48 weeks of 
treatment and a long term follow-up analysis at 96 weeks.

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4.
AMENDMENTS AND UPDATES
Amendment or 
update no
Date
Section of study 
protocol
Amendment or 
update
Reason
5.
MILESTONES
Milestone
Planned date
Start of data collection
Dec-2018
End of data collection
Dec-2021
Annual study progress reports
Yearly, within 30 days of the anniversary 
date of EC approvals.
Final report of study results
Nov-2022 or within 12 months after end of 
study
6.
RATIONAL AND BACKGROUND
The efficacy of two-drug regimen (2DR) therapy with an integrase inhibitor plus a 
reverse transcriptase inhibitor is being assessed in pilot studies and clinical trials. 
Dolutegravir (DTG) is a well tolerated 2nd generation integrase strand transfer inhibitor 
(INSTI); rilpivirine (RPV) is a well tolerated NNRTI and lamivudine (3TC) is an 
nucleoside reverse transcriptase inhibitors (NRTIs). In the PADDLE study, high rates of 
HIV RNA suppression were demonstrated after first-line treatment with DTG plus 3TC. 
Other studies have shown high rates of HIV RNA suppression after patients with HIV 
RNA suppression at baseline on triple therapy were switched to 2DR with DTG plus 
3TC. Other pilot studies are in progress: DOLBI in Spain, LAMIDOL in France and an 
ACTG-sponsored trial in the USA. In addition, the Phase 3 GEMINI 1 and 2 trials are in 
progress for DTG plus 3TC. These registrational, double-blinded trials randomise 
patients to receive first-line treatment with either triple therapy or DTG plus 3TC, with a 
combined sample size of over 1400 patients.  
SWORD 1 and SWORD 2 studies, the phase III clinical trials for investigational 2DR of 
DTG and RPV for HIV treatment, achieved non-inferior viral suppression at 48 weeks 
compared with a three- or four-drug regimen. This programme comprised of two studies 
with over 1000 patients who previously achieved viral suppression on a three- or four-
drug ART. These patients were randomised to either stay on their three- or four-drug 
regimen or switch to a DTG plus RPV regimen2.
The pilot studies conducted to date and the Phase 3 programme all have strict
inclusion/exclusion criteria. For example the PADDLE study excluded people who had 
screening HIV RNA levels above 100,000 copies/mL (although 3 patients had VL higher 
than this at baseline).

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Thus, gathering real world evidence in this multi-site observational study with less 
restrictive inclusion criteria to evaluate effectiveness of the 2DR would further 
demonstrate the value of such regimen.
7.
RESEARCH QUESTION AND OBJECTIVE(S)
The study will aim to assess the effectiveness of 2DR, following an Antiretroviral 
treatment with integrase inhibitors DTG plus a reverse transcriptase inhibitor RPV 
or 3TC; in patients either as a first-line treatment in naïve patients, a switching 
option for those with HIV RNA suppression on current treatment (stable switch), or 
a second-line treatment for those with VF on prior treatment.
7.1.
Primary Objective:
a) To assess the effectiveness of a 2DR (integrase inhibitor plus a reverse 
transcriptase inhibitor).
7.2.
Secondary Objective:
a) To collect information on the safety of a 2DR in terms of drug related AEs, SAEs
and development of resistance.
8.
RESEARCH METHODS
8.1.
Study Design
This is a multi-site observational study across Europe in patients who have started and/or 
who plan to initiate 2DR with an integrase inhibitor plus a reverse transcriptase inhibitor 
will be eligible for this study. We anticipate that the majority of these patients will be 
taking either DTG plus RPV, or DTG plus 3TC.  
The study does not require any changes to the routine standard of care that patients 
receive, and decisions on ARV treatment are made by the healthcare providers taking into 
account the treatment history, patient characteristics and local guideline or 
recommendations. Data will be collected every 6 months from participating sites for a 
period of 96 weeks for each potential patient.
8.2.
Study Population and Setting
8.2.1.
Study Setting
Potential NEAT-ID investigational sites across Europe will be contacted for feasibility
and if they already have patients taking dual combinations of an integrase inhibitor plus a 
reverse transcriptase inhibitor. Sites with at least 5 patients already taking this treatment 
(outside clinical trials) since January 2014 or who plan to initiate at least 5 patients in 
near future will be selected to participate in this study.

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NEAT ID Network team will perform site visits to assess protocol issues, consent, data 
quality and Study Management quality performance.
8.2.2.
Inclusion Criteria
The study population will consist of HIV positive male or female aged 18 years or over
and who have started 2DR with an integrase inhibitor plus a reverse transcriptase 
inhibitor from 2014 onwards as:
a) a first-line treatment among naïve patients, or
b) a switching option for those with HIV RNA suppression on current treatment
(stable switches), or 
c) a second-line treatment for those with virological failure (VF) on prior treatment.
8.2.3.
Patient Identification and Consent
The aim is to include at least 500 patients across Europe Once all relevant approvals are 
in place for the protocol, selected investigational sites will be contacted and asked to 
identify potential patients on 2DR either retrospectively and/or potential prospective 
pateints. Consent procedures will be undertaken as required by country specific 
regulations and local procedures for the collection of retrospective and/or prospective
data. These patients will not need to attend any additional visits or undergo any 
procedures above their routine standard of care. 
8.3.
Variables
8.3.1.
Exposure definitions
Any exposure to integrase inhibitors such as DTG and reverse transcriptase inhibitors 
such as 3TC or RPV is of interest. Exposure starts the first day ART of an integrase 
inhibitor plus a reverse transcriptase inhibitor are known to have taken. Person time 
exposed is defined as the number of days that the subject is known to have been exposed
to this dual combination regimen.
8.3.2.
Outcome Definitions
8.3.2.1.
Primary Outcomes
a) For treatment-naïve patients: the proportion of patients with HIV-RNA levels <50 
copies/mL at 24, 48, and 96 weeks, estimated using a Kaplan-Meier Method.
Participants with virologic rebound or virologic non-response will be considered 
as failure.
Virologic rebound will be defined as two consecutive measurements of >50 
copies/mL after suppression (one <50 copies/mL)
Virologic Non-response will be defined as two consecutive measurements of >50 
copies/mL after at least 24 weeks of treatment
b) For stable switch patients: the proportion of patients who lose virologic control (2
consecutive HIV RNA levels >50 copies/mL or HIV RNA >50c/mL followed by 

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study treatment discontinuation or missing value) within the first 24, 48 and 96
weeks after switching to a 2-DR, estimated using a Kaplan-Meier Method.
c) For treatment-experienced patients with VF on current treatment: the proportion 
of patients with HIV-RNA levels <50 copies/mL at 24, 48, and 96 weeks,
estimated using a Kaplan-Meier Method. Participants with virologic rebound or
virologic non-response will be considered as failure.
Virologic rebound will be defined as two consecutive measurements of >50 
copies/mL after suppression (one <50 copies/mL)
Virologic Non-response will be defined as two consecutive measurements of >50 
copies/mL after at least 24 weeks of treatment
Treatment effectiveness will also be assessed by using the following definition for 
virologic rebound and virologic non-response:
For naïve and switch with VF populations
a)
Virologic Rebound: two consecutive PHDVXUHPHQWVRIFRSLHVP/DIWHU
suppression (one <50) 
b) Virologic Non-response: tZRFRQVHFXWLYHPHDVXUHPHQWV RI  FRSLHVP/
after at least 24 weeks of treatment
For stable switch populaion
c) Virologic Rebound: 2 consecutive HIV RNA levels >200 copies/mL or HIV 
RNA >200c/mL followed by study treatment discontinuation or missing value
8.3.2.2.
Secondary Outcomes
In each population (naïve, stable switch, and treatment-experienced with VF):
a) Proportion of patients with HIV RNA >200 copies/mL after 24, 48 and 96 
weeks of treatment. (to analyse in real world and quantify the blips).
b) Proportion of patients with low level viremia (VL >50 and <200 copies/mL) 
at each time point for analysis.
c) Time to virologic suppression in the naïve and the switch with VF populations
(viral load < 50 copies/mL at the end of 6months/12months/18 months or as 
pre-specified. This allows for blips during the follow up period).  
d) Time to VF in the stable switch population
e) Resistance profile in case of virological failure
f)
Proportion of patients with:
1. Stable switch while virologically suppressed
2. Switch after Failure
3. Switching for tolerability, toxicity and other reasons 
g) Frequency of drug related AEs and SAEs
h) Evolution of CD4+, CD8+ T cells counts and CD4/CD8 ratio at each time 
point from D0.

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i)
Factors associated with plasma HIV-RNA > 50 copies/mL after 96 weeks if 
number of failures allows analysis
8.3.3.
Confounders and Effect Modifier
We will examine factors associated with VF.
8.4.
Data Sources
Data will be collected from all participating European sites. Following all relevant 
approvals, selected sites will be contacted and asked to identify patients currently on 2DR 
and collect data either retrospectively and/or identify prospective patients to start this 
treatment. Pseudo anonymised data will be collected by electronic transfer of  datasets 
from each site. 
The following data will be collected if available for each participant and updated 
information included in the 6 monthly data transfer / collection:
1. Baseline characteristics – age, gender, ethnicity, CD4 and CD8 count at time of 
first starting 2DR treatment, CD4 nadir, CDC disease stage. 
2. Duration of undetectability plasma HIV RNA levels at start of 2DR treatment,
where available
3. HIV RNA data – all available HIV RNA results since first starting antiretroviral 
treatment, with dates. Data on last viral load above 50 copies/mL.
4. Immunological data: all available CD4 and CD8 results since first starting 2DR 
treatment.
5. Antiretroviral treatment history – all antiretrovirals taken since first-line treatment
(if not naïve) started, with dates.  Reasons for stopping or switching each 
treatment and related toxicity data.
6. Resistance tests – results of all HIV resistance tests performed before and during 
antiretroviral treatment.
7. Co-morbidities and all co-medications
8. All available drug related AEs and SAEs since starting DTG+RPV or DTG+3TC.
8.5.
Study Size
The expected sample size for this study is 500 patients. 
a) In ARV naïve population, the expected success rate of a standard 3-drug regimen can 
be estimated at 90% at week 48 (based on SNGLE, SPRING-2 and FlAMINGO trials 
results) with a non-inferiority margin of 10% (see FDA guidelines). Therefore the 2-
DR will be considered acceptable if the percentage of patients in success (HIV RNA 
<50 copies/mL) at week 48 is significantly above 80%. Assuming a 90% response
rate, by including 90 individuals, we will have a 95 % probability to discard a 
combination for which efficacy is smaller than 80 % and we will select with a power 
of >80 % the strategy for which the efficacy is above or equal to 90%.

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b) In patients switching with HIV RNA suppression (Stable switch population), the 
expected VF rate of a standard 3-drug regimen can be estimated at 4% at week 48 
(based on NEAT22/SSAT60 trial result, IAS2017) with a non-inferiority margin of 
4%. Therefore, the 2-DR will be considered acceptable if the percentage of patients in 
VF at week 48 is significantly lower than 8%. Assuming a 4% VF , by including 320
individuals, we will have a 95% probability to discard a combination for which the 
rate of failure is greater than 8% and we will select with a power of >90% the strategy 
for which the rate of failure is less to 8%.
c) In a population of patients with a second line treatment due to VF on prior treatment, 
the expected success rate of a standard 3-drug regimen can be estimated at 90% at 
week 48 (based on the 24-week result (82%) of DTG-containing regimen in the 
DAWNING trial) with a non-inferiority margin of 10% (see FDA guidelines).
Therefore the 2-DR will be considered acceptable if the percentage of patients in 
success (FDA snapshot method) at week 48 is significantly above 80%. Assuming a 
90% response rate, by including 90 individuals, we will have a 95 % probability to 
discard a combination for which efficacy is smaller than 80 % and we will select with 
a power of >80 % the strategy for which the efficacy is above or equal to 90%.
For the above power calculations a total of at least 90 naïve, 320 stable switch patients 
and 90 second line treatment due to VF patients should be included. However, if the 
number of patients in naïve and VF cohorts are insufficient to fulfill the power 
calculations, these cohort data will be used for descriptive purposes only. 
8.6.
Data Management
8.6.1.
Data Collection
8.6.1.1.
Source Data
Source data are contained in source documents (original records or certified copies) 
maintained at site. No additional data will be collected for this study, data will be 
collected as part of routine standard of care data only.
8.6.1.2.
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 the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial) will be maintained at site in accordance with usual standard of care
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.  

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8.6.1.3.
Data Collection Methods
In order to maintain confidentiality, the subject will be identified only by subject number. 
Subject data will be collected via extraction from electronic source data by appropriately 
trained and authorised member(s) of the study team who must be identified and 
authorised in writing by the Principal Investigator (PI). A delegation of responsibility log 
will be updated accordingly.
Sites will provide / upload data every 6 months to the data management team who will 
store the data on a secure network drive with access to authorised personnel of the data 
management team only, maintained on a log of authorised personnel by the sponsor 
representative.
8.6.2.
Data Handling Conventions
Data will be handled in accordance with data handling guidelines provided to sites.
The Study Monitor and Data Manager will review data on an on-going basis and raise 
any discrepancies with site staff as required.
Identified only by subject number, the data are pseudo-anonymised at all times and are 
transferred securely. All transfers are fully documented.
8.6.3.
Resourcing Needs
The study will be overseen and managed by NEAT-ID. NEAT-ID will assign a Project 
Manager to the study who will oversee the day to day activities of the trial and manage 
the mutidiscpliary project team.
ViiV as sponsor will retain all repsonsibilities in relation to regulatory reporting.
8.6.4.
Timings of Assessment During Follow-up
Available data will be collected from enrolled participants every 6 months and transferred 
to the data coordinating centre.. Participant involvement in this study will end after week 
96 data collection.
8.7.
Data Analysis
The statistical analysis plan will be produced during the early stages of the study, after 
protocol finalization. This statistical analysis plan will describe the primary and 
secondary analysis and the format of the final tables, figures and listings to be generated.
Data will be analysed using SAS, SPSS or STATA.
8.7.1.
Essential Analysis
We ZLOOVHSDUDWHO\HYDOXDWHWKHHI¿FDF\RIthe 2DR according to prior treatment status;
first-line treatment for naïve patients, stable switching with HIV RNA suppression, or 
switching after VF. The primary effectiveness endpoint will be analysed with an 

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Intention-to-treat (ITT approach). The 95% two-sided confidence interval (CI) of the
observed proportion of patients reaching the effectiveness endpoint will be calculated.
In the treatment naïve and treatment experienced with VF individuals, the primary 
endpoint is the proportion of patients with HIV RNA suppression below 50 copies/mL
after 24, 48 and 96 weeks of treatment, estimated using Kaplan-Meier method standard.
2DR will be considered as an acceptable strategy in these populations if the lower bound
of the 95% CI is greater than 80%.
In the stable switch population, the primary endpoint is the proportion of patients with 
VF at weeks 24, 48 and 96 (defined as 2 consecutive plasma HIV RNA >50 copies/mL, 
or Plasma HIV RNA>50 c/mL followed by study treatment discontinuation or missing 
value). The 95% CI of the observed proportion of patients reaching the efficacy endpoint 
will be calculated with the Kaplan-Meier method, censoring at week 48 or last follow-up 
date if missing HIV RNA viral load values at week 48. 2DR will be considered as an 
acceptable strategy in this population if the upper bound of the 95% CI is lower than 8%.
Grade 3 and 4 adverse events, ART related adverse events (all grades), treatment-
modifying adverse events (all grades); AIDS defining event, death, study treatments 
discontinuation, as well as serious adverse events (SAE) will be described, between 0-24, 
24-48, and 48-96 weeks.
Changes from baseline in continuous endpoints in each population (naïve, stable switch, 
treatment-experienced with VF) between baseline and week 24, 48 and 96 will be
compared by using Wilcoxon’s paired test with the ITT population (last observation 
carried forward (LOCF) or other imputation method to be defined in the statistical 
analysis plan). We will use percentage and 95 % two-sided confidence interval to 
describe the qualitative endpoints, their change over time will be tested with a McNemar 
test with a 5 % Type I error. Linear mixed models will also be used to estimate and 
compare the evolution of CD4, CD8 count and CD4/CD8 ratio over time.
The number of included patients and the flowchart of the trial will be presented. The 
baseline patients’ eligibility and characteristics of the ITT population will be described. 
Quantitative variables will be described by their means, standard deviations, medians, 
Interquartile range (IQR), minimums and maximums. For qualitative variables, figures 
and percentages per class will be presented or method will be given. All protocol 
deviations and their reasons will be described. 
An interim analysis will be conducted after 24 weeks of treatment, the primary endpoint 
analysis will be conducted after 48 weeks of treatment and a long-term follow up analysis 
will be conducted after 96 weeks of treatment. 
Historical data from studies like STRIIVING, WAVES, DAWNING, FLAMINGO, 
SINGLE, SPRING I and II shall be used as a comparator for analysis.
CCI

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8.8.
Quality Control and Quality Assurance
Electronic data sets will provide an unmonitored subset of existing source data that will 
be subject to data validation. Site selection and training of site staff will ensure suitably 
qualified personnel are involved at every stage of the data gathering process.Data will be 
analysed by a Statistician skilled in population bases analysis using SAS, SPSS or 
STATA.
NEAT-ID may decide to include this study in the annual audit schedule. The audit 
conduct and reporting will be preformed by the independent QA personnel and in 
accordance with the GCP and the applicable NEAT-ID Standard Operating Procedures.
8.9.
Limitations of the Research Methods
Limitations of this study are common to non-randomized non-interventional study.
Selection bias may be present as the sites may elect to enroll participants that may have a 
better or worse health status compared to the general HIV positive treated population. 
Channeling bias may also be present.
8.9.1.
Study Closure/Uninterpretability of Results
Both the sponsor and the NEAT-ID collaboration reserve the right to terminate the study 
at any time. Should this be necessary, both parties will arrange discontinuation 
procedures and notify the appropriate regulatory agencies, IRBs, and IECs. In terminating 
the study, sponsor and the investigator will assure that adequate consideration is given to 
the protection of the subjects’interests.
Following completion of the study, any study documentation will be retained by the 
Investigator in accordance with Good Clinical Practice (GCP) and applicable regulatory 
requirements.
CCI

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9.
PROTECTION OF HUMAN SUBJECTS
9.1.
Ethical Approval 
Before the start of data collection, this protocol and any accompanying material to be 
provided to the patients (such as advertisements, subject information sheets, or 
descriptions of the study used to obtain informed consent) will be submitted to Ethics 
Committee (EC) in the relevant countries.  The investigator will not begin any study 
activities until approval from the EC has been documented and provided as a letter to the 
investigator.
Any subsequent amendments that require review by EC will not be implemented until the 
EC grants a favourable opinion for the study which will be disseminated to the 
investigator and sites (NOTE: amendments may also need to be reviewed and accepted 
by the regulatory agencies and/or local EC departments before they can be implemented 
in practice at sites)
An annual progress report will be submitted to the EC within 30 days of the anniversary 
date on which the favourable opinion was given, and annually until the trial is declared 
ended. NEAT ID will produce the annual reports as required.
NEAT ID  team will notify the EC of the end of the study. If the study is ended 
prematurely, NEAT ID  will notify the EC, including the reasons for the premature 
termination.
9.2.
Subject Confidentiality
All investigators and study site staff will comply with the requirements of the current 
Data Protection Regulations with regards to the collection, storage, processing and 
disclosure of personal information and will uphold the Regulation’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/storage 
media.
•
limiting access to the minimum number of individuals necessary for 
quality control, audit, and analysis.
10.
MANAGEMENT 
AND 
REPORTING 
OF 
ADVERSE 
EVENTS/ADVERSE REACTIONS
If during the study, a drug related adverse event (serious or non serious) is identified as 
being related to any ViiV Healthcare product (including products not covered in the 
specific study objective), this will be reported to the GSK Central Safety Department by 
email of fax. All drug related SAEs and pregnancy exposures will be reported within 24 

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hours (3 calendar days in case of a weekend) of first becoming aware of the event. Non-
serious drug related AEs related to any ViiV/GSK products will be reported within 5 
calendar days (7 calendar days in case of a weekend) of first becoming aware of the 
event.
All drug related serious and non-serious AEs, pregnancy exposures or incidents 
associated with  any ViiV Healthcare product will be collected and reported as described 
in the study-specific pharmacovigilance plan (sPVP).  This plan will include the 
following elements to ensure a comprehensive approach to safety event collection and 
reporting: 
x
Supplier/Vendor staff pharmacovigilance training (RAD-CDV-1281 - online training 
annually, on the collection and reporting of AEs through external version of 
myLearning).
x
Investigator and site staff pharmacovigilance training (RAD-CDV-1281 - online 
training annually, on the collection and reporting of AEs through external version of 
myLearning).
x
Safety-specific roles
x
ADRs, SAEs, pregnancy outcomes, and incident collection and reporting processes
x
Frequency of data review
x
Reporting process and timelines
x
Interim reports
x
Reconciliation process
x
Study-specific PVP monitoring process
x
Provision of final study report
10.1.
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.
An AE does not include the following:
x
Medical or surgical procedures such as surgery, endoscopy, 
tooth extraction, and transfusion. The condition that led to the 
procedure may be an AE.
x
Situations where an untoward medical occurrence has not 
occurred (e.g., hospitalization for elective surgery, social and/or 
convenience admissions)

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x
Any medical condition or clinically significant laboratory 
abnormality with an onset date before baseline are considered to 
be preexisting conditions and should be documented as medical 
history.
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 the drug 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 drug qualify as adverse reactions.
Serious Adverse Event 
(SAE)
A serious adverse event is any untoward medical occurrence that:
x
results in death
x
is life-threatening
x
requires inpatient hospitalisation or prolongation of existing 
hospitalisation unless hospitalization is for:
o
Routine treatment or monitoring of the studies 
indication, not associated with any deterioration in 
condition. 
o
Elective or pre-planned treatment for pre-existing 
condition that is unrelated to the indication under study 
and has not worsened since the start of the study drug.
o
Treatment on an emergency outpatient basis for an event 
not fulfilling any of the definitions of SAE given above 
and not resulting in hospital admission.
o
Social reasons and respite care in the absence of any 
deterioration in the patient’s general condition.
x
results in persistent or significant disability/incapacity
x
consists of a congenital anomaly or birth defect
x
Is medically significant, i.e. defines as an event that jeopardizes 
the patient or may require medical or surgical intervention to 
prevent one of the outcomes listed above.
x
All events of possible drug-induced liver injury with 
hyperbilirubinemia defined as ALT 3xULN and bilirubin 
2xULN (>35% direct*)
*Note: bilirubin fractionation is 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 subject meets the criterion of 
WRWDOELOLUXELQ[8/1WKHQWKHHYHQWLVVWLOOUHSRUWHGDVDQ6$(
INR elevations of >1.5 suggest severe liver injury.

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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.
 
 “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.
10.2.
Assessment of Adverse Events and Serious Adverse Events 
(SAE) 
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs 
for causality and for final review and confirmation of accuracy of event information and 
assessments.
10.3.
Assessment of Causality for Study Drugs
The relationship to study drug of each adverse event will be assessed taking into 
consideration the following:
•
A “reasonable possibility” is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.
•
The investigator/subinvestigator will use clinical judgment to determine the 
relationship.
•
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.
•
The approved Product Information (SmPC) for marketed each marketed product 
should be used in consideration of this assessment
A causality assessment should be provided on all AE/SAE forms reported to ViiV/GSK.
11.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
11.1.
Target Audience
The target audience includes healthcare providers, patient groups, regulatory and health 
authorities. 

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Interim and final study results will be presented at conferences such as but not limited to 
CROI and/or IAS, and followed by a  publication in relevant peer-reviewed medical 
scientific journal and relevant newsletters. 
11.2.
Study Reporting and Publications
Within one year after the end of the study, the Chief Investigator will submit a final 
report with the results, including any publications/abstracts, to the EC. ViiV Healthcare 
will submit the study report to the regulatory agencies.
A publication of the results will be prepared at week 24 data and 48 data outcome from 
first 200 patients and week 48 data outcome from at least 500 patients.

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12.
REFERENCES
1. Cahn P, Rolon MJ, et al. Dolutegravir-lamivudine as initial therapy in HIV-1
infected, ARV-naive patients, 48-week results of the PADDLE (Pilot 
Antiretroviral Design with Dolutegravir LamivudinE) study. J Int AIDS Soc.
(2017) May 9;20(1):21678.
2. Josep L, Chien-Ching H, 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), ISSN: 1474-547X, Vol: 391, Issue: 10123, Page: 839-849.

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ANNEX 1: Data Assessment Table
Data collected 
Timepoints 
Baseline (day0) 
Treatment (day1-
96weeks) 
Age 
X 
 
Gender 
X 
 
Ethnicity 
X 
 
Medical History: 
•
Nadir CD4 
•
HIV resistance tests 
•
ARV history 
X 
 
 
CD4 count1 
 
X 
X 
CD8 count1 
X 
X 
HIV RNA data 
X2 
X 
CDC disease stage 
X (Calculated assessment) 
 
Duration 
of 
undetectable 
plasma HIV RNA results  
X 
 
ARV treatment history  
 
X3 
HIV Resistance tests 
X7 
 
X4 
Co-morbidities 
 
X5 
Co-medications 
 
X5 
Side effects/toxicity 
 
X6 
Footnotes:
1.
Baseline before starting 2DR (DTG+RPV or DTG+3TC), and all available results after starting 2DR
2.
All data since first starting ARV with dates.
3.
Antiretroviral name and date of treatment, reasons for stopping, switching each treatment and related toxicity
4.
During the 2DR treatment , date of resistance test and test results
5.
Within 6-12 months of 2DR
6.
Only DTG+RPV and DTG+3TC related side effects and toxicity.
7.
Resistance tests will only be done if naive detectable or switch or VF.

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ANNEX 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