An Open Label Study Evaluating the Safety and Efficacy of Switching From Rilpivirine/Emtricitabine/Tenofovir Alafenamide in Combination With Dolutegravir, to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Combination With Doravirine, in Male HIV+ Subjects > 45 Years With Multi-drug Resistant Virus and Virologic Suppression (Documented With at Least One Viral Load Result < 50 Copies Per mL) During the Last 6 Months on Current Therapy
Phase: PHASE4
Conditions: HIV-1-infection
Sponsor: Quest Clinical Research

 
 
Bictegravir/emtricitabine/tenofovir alafenamide plus 
doravirine in highly treatment-experienced men with 
mulƟdrug-resistant HIV 
 
 
 
 
 
NCT04538040 
2023 

Protocol No. BETD-001 
Version 3 / Date (25-Jun-2021) 
Quest Clinical Research 
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Protocol Title: 
An open label study evaluating the safety and efficacy of switching 
from 
rilpivirine/emtricitabine/tenofovir 
alafenamide 
in 
combination 
with 
dolutegravir, 
to 
bictegravir/emtricitabine/tenofovir alafenamide in combination 
with doravirine, in male HIV+ subjects > 45 years with multi-drug 
resistant virus and virologic suppression (documented with at least 
one viral load result < 50 copies per mL) during the last 6 months on 
current therapy. 
 
Switch Therapy: 
Bictegravir/emtricitabine/tenofovir alafenide plus doravirine: 
Investigator: 
F. Lisa Sterman MD, MPH 
Phase: 
IV 
Protocol Number: 
BETD-001 
Version No.: 
3.0 
Date: 
06-25-2021 
 
 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
The information contained in this protocol is confidential and is intended for the use of clinical Investigators. It is the 
property of Quest Clinical Research and should not be copied or distributed to persons not involved in the clinical 
investigation, unless such persons are bound by a confidentiality agreement with Quest Clinical Research. 

Protocol No.: BETD-001 
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PROTOCOL APPROVAL – SPONSOR SIGNATURE PAGE 
 
This study protocol entitled: 
 
An 
open 
label 
study 
evaluating 
the 
safety 
and 
efficacy 
of 
switching 
from 
rilpivirine/emtricitabine/tenofovir alafenamide in combination with dolutegravir, to 
bictegravir/emtricitabine/tenofovir alafenamide in combination with doravirine, in male HIV+ 
subjects > 45 years with multi-drug resistant virus and HIV virologic suppression ( documented 
with at least one viral load result < 50 copies per mL) during the last 6 months on current 
therapy. 
 
The information this protocol contains is consistent with the current risk/benefit evaluation of the 
study drug as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki and the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP). 
 
This protocol is approved by: 
 
Name:     
 
 
 
 
Signature:    
 
 
 
Date: 
/ 
/ 
(DD/MMM/YYYY) 

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TABLE OF CONTENTS 
1.0 
GLOSSARY ............................................................................................................................... 7 
2.0 
PROTOCOL SYNOPSIS ............................................................................................................... 9 
3.0 
BACKGROUND INFORMATION ............................................................................................... 12 
3.1 
Study Rationale ......................................................................................................... 12 
3.2 
Anticipated Risks and Safety concerns for the switch ................................................. 12 
4.0 
STUDY OBJECTIVES ................................................................................................................ 13 
5.0 
INVESTIGATIONAL PLAN ........................................................................................................ 13 
5.1 
Overall Study Design and Plan ................................................................................... 13 
5.2 
Duration of Study Participation ................................................................................. 14 
5.2.1 
Study Procedures ................................................................................................. 14 
5.2.2 
Screening/Baseline ............................................................................................... 14 
5.2.3 
28 Days (+/- 14 days) ........................................................................................... 15 
5.2.4 
Week 12 (+/- 14 days) .......................................................................................... 15 
5.2.5 
Week 24 (+/- 14 days) .......................................................................................... 15 
5.2.6 
Week 36 (+/- 14 days) .......................................................................................... 15 
5.2.7 
Week 48/End-of-treatment (EOT)/Early Termination Visit +/- 14 days) ............. 16 
5.3 
Randomisation and Blinding ...................................................................................... 16 
5.4 
Source Data ............................................................................................................... 16 
6.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ......................................................................... 17 
6.1 
Subject Inclusion Criteria ........................................................................................... 17 
6.2 
Subject Exclusion Criteria .......................................................................................... 17 
7.0 
SUBJECT WITHDRAWAL CRITERIA .......................................................................................... 17 
7.1 
Removal of Subjects from Assessment ....................................................................... 17 
7.2 
Handling of Withdrawals ........................................................................................... 18 
7.3 
Termination of Study ................................................................................................. 18 
7.3.1 
Regular Termination of Study .............................................................................. 19 
7.3.2 
Premature Termination of Study ......................................................................... 19 
8.0 
TREATMENT OF SUBJECTS ...................................................................................................... 19 
8.1 
Treatments Administered .......................................................................................... 19 
8.2 
Assessment of Compliance and procedures ............................................................... 20 
9.0 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............................................. 20 

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9.1 
Pharmacokinetic Analyses ......................................................................................... 20 
10.0 
ASSESSMENT OF SAFETY ........................................................................................................ 20 
10.1 
Safety Parameters ..................................................................................................... 20 
10.1.1 Adverse Events ..................................................................................................... 20 
10.1.2 Adverse Event Definition ...................................................................................... 20 
10.1.3 Laboratory investigations criteria for AE ............................................................. 21 
10.1.4 Intensity of Adverse Events .................................................................................. 23 
10.1.5 Treatment-Emergent Adverse Events .................................................................. 23 
10.1.6 Serious Adverse Events ......................................................................................... 23 
10.1.7 AE or SAE Exceptions ............................................................................................ 24 
10.1.8 Laboratory Evaluation .......................................................................................... 24 
10.1.8.1 
Safety Laboratory Parameters ............................................................ 24 
10.1.9 Other Safety Parameters ..................................................................................... 24 
10.1.9.1 
Vital Signs ............................................................................................ 24 
10.1.9.2 
Physical Examination .......................................................................... 24 
10.2 
Recording and Reporting Adverse Event/Intercurrent Illnesses .................................. 25 
10.3 
Adverse Event Follow-up Procedures ......................................................................... 25 
11.0 
STATISTICAL METHODS .......................................................................................................... 25 
11.1 
General Methods ...................................................................................................... 25 
11.2 
Demographics and baseline characteristics ................................................................ 26 
11.3 
Analysis of Primary endpoints ................................................................................... 26 
11.3.1 Safety and Tolerability ......................................................................................... 26 
11.3.1.1 
Adverse Events ................................................................................... 26 
11.3.1.2 
Clinical Laboratory Tests ..................................................................... 27 
11.3.1.3 
Vital Signs ............................................................................................ 27 
11.3.1.4 
Physical Examination .......................................................................... 27 
11.3.1.5 
Tolerability .......................................................................................... 27 
11.3.1.6 
Pharmacokinetic Analyses .................................................................. 27 
11.3.2 Safety and Tolerability ......................................................................................... 28 
11.3.3 Pharmacokinetics Analyses .................................................................................. 28 
11.3.4 Preliminary Assessment of Clinical Activity .......................................................... 28 
11.5 
Interim analysis ......................................................................................................... 29 
11.6 
Statistical Considerations .......................................................................................... 29 
11.7 
Procedure For Accounting for Missing, Unused, and Spurious Data ............................ 29 
11.8 
Derived And Transformed Data ................................................................................. 29 
11.9 
Deviations From The Original Statistical Plan ............................................................. 30 

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11.10 Subject Selection For Analyses ................................................................................... 30 
12.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................... 30 
12.1 
Source Data ............................................................................................................... 31 
12.2 
Source Documents ..................................................................................................... 31 
12.3 
Direct Access ............................................................................................................. 31 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 31 
13.1 
Quality Control .......................................................................................................... 31 
13.2 
Quality Assurance...................................................................................................... 32 
13.2.1 Inspection ............................................................................................................. 32 
13.2.2 Audit ..................................................................................................................... 32 
14.0 
ETHICS ................................................................................................................................... 32 
14.1 
Ethical Conduct of the Study ...................................................................................... 32 
14.2 
Institutional Review Board/Independent Ethics Committee Approval ........................ 33 
14.3 
Informed Consent ...................................................................................................... 33 
14.4 
Modification of Protocol ............................................................................................ 34 
15.0 
INVESTIGATOR OBLIGATIONS ................................................................................................ 35 
15.1 
Confidentiality ........................................................................................................... 35 
15.2 
Investigator Documentation ...................................................................................... 35 
15.3 
Study Conduct ........................................................................................................... 36 
15.4 
Adherence to Protocol ............................................................................................... 36 
15.5 
Adverse Events and Study Report Requirements ....................................................... 36 
15.6 
Investigator’s Final Report ............................................................................................... 36 
16.0 
DATA HANDLING AND RECORD KEEPING ............................................................................... 36 
16.1 
Completion of Case Report Forms .............................................................................. 36 
16.2 
Archiving ................................................................................................................... 37 
17.0 
FINANCING AND INSURANCE ................................................................................................. 37 
18.0 
PUBLICATION POLICY ............................................................................................................. 37 
19.0 
REFERENCES .......................................................................................................................... 37 
APPENDICES ....................................................................................................................................... 40 
APPENDIX 1: STUDY SCHEDULE OF EVENTS ........................................................................................ 41 
APPENDIX 2: INVESTIGATOR SIGNATURE PAGE .................................................................................. 43 
APPENDIX 3: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) .............................. 44 

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APPENDIX 4: DATA SHEET FOR BICTEGRAVIR/EMTRICITABINE/TENOFOVIR ALAFENAMIDE (BIKTARVY®) 
45 
APPENDIX 5: DATA SHEET FOR DORAVIRINE (PIFELTRO ®) .................................................................. 46 
APPENDIX 6: PITTSBURGH SLEEP QUALITY INDEX ............................................................................... 47 
APPENDIX 7: WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT QUESTIONNAIRE ............................ 48 

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1.0 
GLOSSARY 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC0-inf 
Area under the plasma concentration curve from time 0 to infinity 
AUClast 
Area under the plasma concentration curve from time 0 to the last
observable concentration 
AUC0-t 
Area under the plasma concentration versus time curve, from time 0 
to the last measurable concentration 
BLQ 
Below the limit of quantification 
BIC/FTC/TAF + DOR 
Bictegravir/emtricitabine/tenofovir alafenamide in combination with 
doravirine 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CK 
Creatine kinase 
CL 
Total clearance 
Cmax 
Maximum plasma concentration 
CRF 
Case report form 
CV 
Coefficient of variation 
EOT 
End-of-treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GLP 
Good Laboratory Practices 
h 
Hour 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IRB 
Institutional review board 
kel 
First-order rate constant for elimination of drug 

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LDH 
Lactate dehydrogenase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic 
RBC 
Red blood cell (count) 
RNA 
Ribonucleic Acid 
RPV/FTC/TAF + DTG 
Rilpivirine/emtricitabine/tenofovir alafenamide in combination with 
dolutegravir 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOP 
Standard operating procedure 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
TRAE 
Treatment-related adverse event 
tlag 
Time between drug administration and first observed concentration 
above lower limit if quantitation in plasma 
tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
US 
United States 
Vd 
Volume of distribution 
WBC 
White blood cell (count) 
WHO 
World Health Organization 

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2.0 
PROTOCOL SYNOPSIS 
 
 
 
 
Title 
An open label study evaluating the safety and efficacy of switching 
from rilpivirine/emtricitabine/tenofovir alafenamide in combination 
with dolutegravir, to bictegravir/emtricitabine/tenofovir alafenamide 
in combination with doravirine, in male HIV+ subjects > 45 years with 
multi-drug resistant virus and virologic suppression (documented with 
at least one viral load result < 50 copies per mL) during the last 6 
months on current therapy. 
Protocol Number 
BETD-001 
Switch therapy 
Bictegravir/emtricitabine/tenofovir alafenide plus doravirine 
Number of Sites and 
Countries 
One site, US 
Phase 
Phase IV 
 
 
Indication 
Male HIV+ subjects over 45 years old with prior multidrug resistance 
to HIV therapy, with a prior positive response to 
rilpivirine/emtricitabine/tenofovir alafenamide in combination with 
dolutegravir, and switching to bictegravir/emtricitabine/ tenofovir 
alafenamide in combination with doravirine. 
Study Design 
The current study proposal is an open label observational trial for 
maintenance of virologic suppression, and is designed as a non- 
inferiority switch trial. The study will involve approximately 30 patients, 
which includes a PK arm of approximately 10 patients. The study will 
also include secondary outcomes of quality of life (QOL) and weight 
changes 
Hypothesis: 
Patients with prior NUC or NNRTI resistance (but not to rilpivirine or 
doravirine) will maintain their virologic suppression after a drug 
regimen switch from rilpivirine/emtricitabine/tenofovir alafenamide in 
combination with dolutegravir, to bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine. The switch therapy will 
avoid food interactions, and will be well tolerated by subjects. 
Primary Endpoint 
1. Percentage of patients with viral HIV load (VL) <50 and <200 
copies/mL at 48 weeks 
Secondary 
Endpoints 
1. Tolerability 
2. Changes in body mass index (BMI) from baseline to 48 weeks 

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3. Provide data on heavily treatment experienced (HTE) patients, 
switching to a bictegravir/emtricitabine/tenofovir alafenamide in 
combination with doravirine containing-regimen. 
4. Confirm absence of drug/drug interactions between 
bictegravir/emtricitabine/tenofovir alafenamide in combination 
with doravirine based on 24-hour PK at week 4 (+/- 14 days) with 
time points at predose (-0.5 hr), 0.5, 1, 2, 4, 6, 8, 12, and 24 hours 
for a subset of 10 subjects. 
5. Assess AE’s of any grade and relationship to the drug combination 
occurring in at least 5% of participants or more. 
6. Improvement in well-being and sleep inventory as measured by 
The Pittsburgh Sleep Quality Index (PSQI) & The Work 
Productivity and Activity Impairment Questionnaire (WPAI). 
Study Duration 
1. Duration of enrolment period: 12 months 
2. Subjects entering treatment per month: 10 patients 
3. First subject in to 50% enrolment: 3 months 
4. 50% enrolment to last subject in: 6 months (100% at 6 months) 
Number of Subjects 
30 (10 PK subjects as a subset) 
Subject Population 
Male HIV+ subjects over 45 years old with stable effective antiviral 
response (HIV RNA copies less than 50/mL on at least one occasion in 
the six months prior to switching therapy) with 
rilpivirine/emtricitabine/tenofovir alafenamide in combination with 
dolutegravir switching to bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine 
Inclusion Criteria 
1. HIV positive Males, age 45 or older 
2. Any genotypic or phenotypic resistance except k65R, 69 insertion, 
integrase resistance, or resistance to rilpivarine or doravirine. 
3. Receiving combination antiretroviral regimen of 
rilpivirine/emtricitabine/tenofovir alafenamide in combination 
with dolutegravir > 12 months and with viral load <50 copies/ mL 
on at least one occasion within the six months prior to switch. 
4. Suppressed viral load as defined by one plasma HIV RNA level < 
50 copies/mL within previous 6 months. 
5. Capable of providing informed consent 
Exclusion Criteria 
1. Any current or prior integrase inhibitor resistance 

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2. Nucleoside reverse transcriptase (NRTI) mutation 69 insertion or 
k65R mutation 
3. Documented second generation non-nucleoside reverse 
transcriptase inhibitor (NNRTI) resistance (rilpivirine or 
doravirine) 
Statistical Methods 
In this study, subjects will have stable prior antiretroviral therapy (HIV 
RNA copies <50/mL on at least one occasion in the 6 months prior to 
the study), and the aim is to determine if the protocol therapy will 
continue to suppress HIV activity. The goal is to determine the 
number of subjects who have 1) less than 50 copies/mL and 2) less 
than 200 copies/mL HIV at week 48. 
The secondary objective of the study is to determine the quality of life 
and weight stabilization provided by the switch therapy as measured 
by the Pittsburgh Sleep Quality Index (PSQI), The Work Productivity 
and Activity Impairment Questionnaire (WPAI) and BMI assessment. 
Values will be compared at baseline and at 48 weeks. 

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3.0 
BACKGROUND INFORMATION 
 
3.1 
Study Rationale 
 
In recent years with the advent of high barrier integrase strand transfer inhibitors 
(INSTI) and the aging HIV/AIDS population, providers have initiated proactive anti- 
retroviral (ARV) switches away from protease inhibitors, for minimization of 
coronary artery disease (CAD) risk associated with protease inhibition (1). Many 
legacy HIV patients have 2 and 3 class resistant viruses. Common regimens that 
were used for switch to overcome resistant virus and maintain un-detectability off 
protease regimens included a switch to rilpivirine, emtricitabine, tenofovir 
alafenamide 
plus 
dolutegravir. 
With 
the 
approval 
of 
bictegravir/emtricitabine/tenofovir alafenamide and doravirine, both very high 
genetic barrier antivirals, and with this regimen being two single small daily 
tablets, both with the advantage of elimination of need for food requirement in 
an antiviral regimen and fewer drug/drug/interactions (DDI), switching from 
rilpivirine/emtricitabine/tenofovir alafenamide plus dolutegravir to bictegravir/ 
emtricitabine/ tenofovir alafenamide plus doravirine is a very attractive current 
option. There are no theoretical pharmacokinetic (PK) interactions between these 
medications, but there exists a data gap as they have not been studied in 
combination for safety and efficacy. The current study proposal is an open label 
observational trial for maintenance of virologic suppression, and is designed as a 
non-inferiority switch trial. The study will involve approximately 30 patients, 
which includes a PK arm of approximately 10 patients. Given known incidence of 
adverse events with dolutegravir, including CNS toxicities(9), it might be expected 
that the switch regimen will have an improved adverse event profile. There is 
increasing evidence of weight gain challenges with integrase inhibitor class 
(including dolutegravir) containing regimens, but bictegravir containing regimens 
appear to offer equivalent weight gain compared with dolutegravir(10). The 
study will also include secondary outcomes of quality of life (QOL) as measured by 
the Pittsburgh Sleep Quality Index (PSQI) and The Work Productivity and Activity 
Impairment Questionnaire (WPAI), and subject weight as measured by Body Mass 
Index at baseline and 48 weeks. 
 
3.2 
Anticipated Risks and Safety concerns for the switch 
 
There are known risks associated with bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine (see data information for the 
combination in the product prescribing information in Appendices 4 and 5). 
It is not anticipated that the switch will place subjects at greater risk than their 
current therapy. 

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If subjects participate in the PK evaluation, there are minor risks associated with 
blood sampling. 
4.0 
STUDY OBJECTIVES 
Primary objectives: 
1. Percentage of patients with viral HIV load (VL) <50 and <200 copies/mL at 48 weeks 
 
Secondary objectives: 
1. Tolerability 
2. Changes in body mass index (BMI) from baseline to 48 weeks 
3. Provide 
safety 
and 
pharmacokinetic 
data 
on 
subjects 
switching 
to 
a 
bictegravir/emtricitabine/tenofovir alafenamide in combination with doravirine 
regimen. 
4. Confirm 
absence 
of 
drug/drug 
interaction 
between 
bictegravir/emtricitabine/tenofovir alafenamide in combination with doravirine 
based on 24 hour PK at week 4 (+/- 14 days) with time points at predose (-0.5 hr), 0.5, 
1, 2, 4, 6, 8, 12, and 24 hours for n=10. 
5. Improvement in well-being and sleep inventory as measured by the Pittsburgh Sleep 
Quality Index (PSQI) and The Work Productivity and Activity Impairment 
Questionnaire (WPAI). 
 
 
5.0 
INVESTIGATIONAL PLAN 
 
5.1 
Overall Study Design and Plan 
 
The current study proposal is an open label observational trial for maintenance of 
virologic suppression, and is designed as a non-inferiority switch trial. The study 
will involve approximately 30 patients, which includes a PK arm of approximately 
10 patients. The study will also include secondary outcomes of quality of life (QOL) 
as measured by the Pittsburgh Sleep Quality Index (PSQI) and The Work 
Productivity and Activity Impairment Questionnaire (WPAI), and weight changes 
measured by body mass index (BMI) over the 48 week study period. 
 
Hypothesis: 
HIV+ male patients 45 years and older with prior NUC or NNRTI resistance (but not 
to rilpivirine or doravirine) will maintain their virologic suppression after a drug 
regimen 
switch 
from 
rilpivirine/emtricitabine/tenofovir 
alafenamide 
in 
combination with dolutegravir to bictegravir/emtricitabine/tenofovir alafenamide 

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in combination with doravirine. Subjects will maintain weight, and will tolerate the 
switch therapy. Subject's quality of life will be maintained or improved. 
 
5.2 
Duration of Study Participation 
 
For each Subject, the study duration will span from the date of signed, written 
informed consent through the end of treatment (EOT) visit, expected to be about 
48 weeks with the option of returning for additional unscheduled visits if retests 
are required. 
 
Subjects who have signed the informed consent form and subsequently fail to 
meet the inclusion and/or exclusion criteria are defined as screen failures. For all 
screen failures, the Investigator is to maintain a screening log that documents the 
Subject initials and reason(s) for screen failure. A copy of the log should be 
retained in the Investigator's study files. Instructions on how to handle Subject 
screening, screen failure, and recruitment will be provided in a dedicated 
document. 
 
5.2.1 Study Procedures 
 
The procedures to be performed at each study visit are outlined below. 
 
5.2.2 Screening/Baseline 
 
The following activities will be performed at baseline: 
 Informed consent (prior to any study-specific procedures). 
 Study inclusion/exclusion criteria. 
 Collect year of HIV diagnosis 
 Demographic information (age, gender, race, ethnicity, as allowed 
by local regulation). 
 Height and weight, body mass index (BMI). 
 Pittsburgh Sleep Quality Index (PSQI) 
 The Work Productivity and Activity Impairment Questionnaire 
(WPAI) 
 HIV viral load 
 CD4 count within 3 months of study entry 
 Physical examination 
 Vital signs, including HR, systolic and diastolic blood pressure, 
respiratory rate, and body temperature. 
 Hematology: complete blood cell count (CBC) 
 Serum chemistry 
 Urinalysis 
 Adverse events reported after the Subject provides informed 

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consent. 

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 Treatment switch initiated 
5.2.3 28 Days (+/- 14 days) 
 
 Pharmacokinetic sampling (subset of 10 subjects) 
 Physical examination 
 Weight & Body Mass Index (BMI) 
 Vital signs, including HR, systolic and diastolic blood pressure, 
respiratory rate, and body temperature. 
 Hematology for CBC assessment 
 HIV viral load 
 Serum chemistry 
 Urinalysis 
 Adverse event updates. 
 
5.2.4 Week 12 (+/- 14 days) 
 
 Physical examination 
 Weight & Body Mass Index (BMI) 
 Vital signs, including HR, systolic and diastolic blood pressure, 
respiratory rate, and body temperature. 
 Hematology: for CBC assessment 
 HIV viral load 
 Serum chemistry 
 Urinalysis 
 Adverse event updates. 
5.2.5 Week 24 (+/- 14 days) 
 
 Physical examination 
 Weight & Body Mass Index (BMI) 
 Vital signs, including HR, systolic and diastolic blood pressure, 
respiratory rate, and body temperature. 
 Hematology: for CBC assessment 
 HIV viral load 
 Serum chemistry 
 Urinalysis 
 Adverse event updates. 
5.2.6 Week 36 (+/- 14 days) 

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 Physical examination 
 Weight & Body Mass Index (BMI)Vital signs, including HR, systolic 
and diastolic blood pressure, respiratory rate, and body 
temperature. 
 Hematology: for CBC assessment 16aematocrit16aematocrit 
 HIV viral load 
 Serum chemistry: 
 Adverse event updates. 
5.2.7 Week 48/End-of-treatment (EOT)/Early Termination Visit (+/- 14 days) 
 
The following procedures will be performed at the EOT visit: 
 Weight & Body Mass Index (BMI) 
 Pittsburgh Sleep Quality Index (PSQI) 
 The Work Productivity and Activity Impairment Questionnaire 
(WPAI). 
 Physical examination 
 Vital signs, including HR, systolic and diastolic blood pressure, 
respiratory rate, and body temperature. 
 Hematology: for CBC assessment 
 HIV viral load 
 CD4 count 
 Serum chemistry: 
 Urinalysis 
 Adverse event updates. 
5.3 
Randomisation and Blinding 
 
Not applicable. 
 
 
5.4 
Source Data 
 
Source documents (including all demographic and medical information, CRFs, and 
a copy of the signed informed consent form [ICF] indicating the study number and 
title) for each Subject in the study will be maintained by the Investigator (generally 
in the Subject’s files), and all information in the CRFs must be traceable to the 
source documents. 
 
All data should be recorded directly into the Subject’s medical record as source 
data. It will be confirmed at an initiation visit which documents will be considered 

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as source data for the site. These will be documented and reviewed by the monitor 
at each monitoring visit. 
 
Source documents must be available to document the participation of the Subject 
and substantiate the integrity of study data collected. 
 
6.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
6.1 
Subject Inclusion Criteria 
 
Each Subject (male) must meet all of the following criteria to be enrolled in this 
study: 
1. HIV positive Males, age 45 or older 
2. Any genotypic or phenotypic resistance except k65R, 69 insertion, 
integrase resistance, or resistance to rilpivarine or doravirine. 
3. Receiving 
combination 
antiretroviral 
regimen 
of 
rilpivirine/emtricitabine/tenofovir alafenamide in combination with 
dolutegravir > 12 months and with viral load <50 copies/ mL on at least 
one occasion within the previous 6 months. 
4. Suppressed viral load as defined by one or more plasma HIV RNA levels < 
50 copies/mL within previous 6 months. 
5. Capable of providing informed consent. 
 
 
6.2 
Subject Exclusion Criteria 
 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Any current or prior integrase inhibitor resistance 
2. Nucleoside reverse transcriptase (NRTI) mutation 69 insertion or k65 
mutation 
3. Documented second generation non-nucleoside reverse transcriptase 
inhibitor (NNRTI) resistance (rilpivirine or doravirine) 
 
7.0 
SUBJECT WITHDRAWAL CRITERIA 
 
7.1 
Removal of Subjects from Assessment 
 
A Subject may withdraw (or be withdrawn) from the study prematurely for the 
following reasons: 

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 Subject voluntarily discontinues participation in the study (consent 
withdrawal) 
 Toxicity-related criteria 
 Any clinically relevant signs or symptoms that, in the opinion of the 
Investigator, warrant Subject withdrawal. 
 Protocol deviation (including non-compliance). 
 Disease progression or relapse 
 Lost to follow-up 
 The Investigator determines it is in the best interest of the Subject to 
discontinue the Subject’s participation in the study 
 
The Investigator will also withdraw a Subject if the Investigator terminates the 
study. If a Subject is discontinued because of an AE, the event will be followed 
until it is resolved, resolved with sequelae, not recovered (death due to another 
cause), or death (due to an SAE). 
 
Reasonable effort should be made to contact any Subject lost to follow-up during 
the course of the study in order to complete assessments. 
 
7.2 
Handling of Withdrawals 
 
Subjects who discontinue study drug or active participation in the study will no 
longer receive study drugs. When a Subject withdraws from the study, the 
reason(s) for withdrawal shall be recorded by the Investigator on the relevant 
page of the case report form (CRF). Whenever possible, all Subjects who 
discontinue study drug will undergo all the assessments at the EOT visit. Subjects 
who fail to return for final assessments will be contacted by the site in an attempt 
to have them comply with the protocol. Following a minimum of two documented 
unsuccessful telephone calls, a registered letter will be sent to the Subject in a 
final attempt to ensure protocol compliance. 
 
It is vital to obtain follow-up data on any Subject withdrawn because of an AE or 
SAE. In every case, efforts must be made to undertake protocol-specified, safety 
follow-up procedures. 
 
7.3 
Termination of Study 
 
The Investigator can terminate the study at any time for significant deviations 
from the protocol or due to difficulties experienced in running the study. 
 
The Investigator may terminate this study for any of the following reasons: 

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 Non-compliance with protocol, GCP, and/or regulatory requirements 
 Observation of unexpected, significant, or unacceptable risk to Subjects. 
 An adequate number of Subjects cannot be recruited 
 False documentation in the CRF 
 Other administrative reasons. 
 
Should the study be discontinued prematurely, all study materials must be 
returned to the Investigator or Investigator’s designee. 
 
7.3.1 Regular Termination of Study 
 
The end of this study is defined as the date of the last visit of the last 
Subject participating in the study. Within 90 days of the end of the study, 
the Investigator will notify the institutional review board/independent 
ethics committee (IRB/IEC) and the relevant regulatory authorities about 
the regular termination of the study as required according to national laws 
and regulations. If the study has to be terminated early, this period shall 
be reduced to 15 days and the reasons clearly explained. 
 
7.3.2 Premature Termination of Study 
 
The study may be terminated prematurely for any reason and at any time 
by the Investigator, IRB/IEC or regulatory authorities. The IRB/IEC and the 
relevant regulatory authorities will be informed about reason and time of 
termination according to the applicable laws and regulations. 
 
8.0 
TREATMENT OF SUBJECTS 
 
8.1 
Treatments Administered 
 
Orally administered (single doses daily) bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine at physician prescribed doses. 
 
50 mg of bictegravir (equivalent to 52.5 mg of bictegravir sodium), 200 mg of 
emtricitabine, and 25 mg of tenofovir alafenamide (equivalent to 28 mg of 
tenofovir alafenamide fumarate) as a single tablet daily. 
 
Doravirine 100mg tablet daily. 

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8.2 
Assessment of Compliance and procedures 
 
Investigator or designee will record time of administration of study drugs in the 
CRF on the day prior to PK sampling, the day of PK sampling, and the day after PK 
sampling for subjects participating in the PK portion of the study.  Study drug 
should be taken in the morning on the day prior to PK sampling, the day of PK 
sampling, and after the 24 hour PK draw on the day after PK sampling.  
 
9.0 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS 
 
9.1 
Pharmacokinetic Analyses 
 
Full PK assessments will be taken pre-dose (-0.5 hr), and at 0.5, 1, 2, 4, 6, 8, 12, 
and 24 hours after dosing on day 28 (+/- 14 days).  Subjects may be asked to 
return for an unscheduled visit to test/retest PK samples if the initial data is 
found to be invalid 
 
The PK parameters to be calculated will include, but are not limited to, AUC0-inf, 
AUC0-t, Cmax, kel, tmax, tlag, CL, Vd and t½. The PK parameters and concentrations will 
be summarised by dose levels among the PK evaluable Subjects. Plots of mean 
plasma concentration of bictegravir and doravirine over time will be provided. 
 
10.0 
ASSESSMENT OF SAFETY 
 
The Investigator is responsible for the detection and documentation of events meeting 
the criteria and definition of an AE or SAE, as provided in this protocol. 
 
Follow-Up for Toxicities 
Subjects whose treatment is interrupted or permanently discontinued due to an AE or 
clinically significant laboratory value must be followed at least once a week for 4 weeks, 
and subsequently at 4 week intervals, until resolution or stabilisation of the event, 
whichever comes first. All Subjects must be followed up for AEs and SAEs for 30 days 
following the last dose of study therapy. 
 
10.1 
Safety Parameters 
 
10.1.1 Adverse Events 
 
Adverse events are continuously monitored beginning at enrolment (date 
of signed informed consent) and up to 30 days after the last dose of the 
study drug. Adverse events will be graded using CTCAE version 5.0 
 
10.1.2 Adverse Event Definition 
 

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An AE is any untoward medical occurrence in a Subject or clinical 
investigation. Subject will have been administered a pharmaceutical 

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product, which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational product, whether 
or not related to the investigational product. 
 
10.1.3 Laboratory investigations criteria for AE 
 
Any abnormal laboratory results (hematology, clinical chemistry, or 
urinalysis) or other safety parameters (e.g., radiological scans, ECGs, and 
vital sign measurements, etc), felt to be clinically significant in the medical 
and scientific judgement of the Investigator are considered AEs. Examples 
of criteria for determining whether an abnormal finding is clinically 
significant and should be reported as an AE are: 
 CTCAE Grade 4
 Laboratory result is associated with accompanying symptoms or 
signs
 Laboratory result requires additional diagnostic testing or 
medical/surgical intervention
 Laboratory result leads to a change in study dosing or 
discontinuation from the study significant additional concomitant 
drug treatment, or other therapy
 Laboratory results worsen from baseline
 Laboratory result is considered to be an AE by the Investigator or 
Sponsor.
 
However, merely repeating an abnormal test, in the absence of any of the 
above conditions, does not constitute an AE. Any abnormal test result that 
is determined to be an error does not require reporting as an AE. Any 
clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the Investigator to be more severe 
than expected for the Subject population and Subject’s individual 
condition, are not to be reported as AEs. 
 
Laboratory and other safety assessments can be considered SAEs when 
criteria apply 
 
Relationship of Adverse Events 
 
Not related: 
An AE for which there is no reasonable temporal 
association between its onset and administration of 

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the investigational drug, or that can reasonably be 
explained by other factors, including underlying 
disease, complications, concomitant drugs or 
concurrent treatment. 
Note: Even if the Investigator feels there was no 
relationship to study medication, the AE experience 
is to be reported. 
Unlikely to be related: 
A clinical event, including laboratory test 
abnormality, with a temporal relationship to drug 
administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations. 
Possibly related:         An AE for which there is  a reasonable temporal 
association between its onset and administration of 
the investigational drug (including the course of 
treatment after withdrawal of the drug), for which 
other causal factors may not be excluded. 
Probably related:       An AE for which there is  a reasonable temporal 
association 
between 
its 
onset 
and 
the 
administration of the investigational drug, including 
the course after treatment withdrawal, and which is 
more likely to be explained by the test drug than by 
any 
other 
cause 
(e.g., 
underlying 
disease, 
complications, concomitant drugs or concurrent 
treatment). 
Definitely related: An AE that is judged as undeniably related to the 
administration of study medication. Factors taken 
into consideration when a definite relationship is 
assigned include whether the AE: 
 Followed a clear temporal sequence from 
administration of study medication. 
 Could not be possibly explained by the known 
characteristics of the Subject’s clinical state, 
environmental or toxic factors, other modes of 
therapy administered to the Subject. 
 Disappeared or decreased on cessation or 
reduction in dose of study medication. 
 Reappeared 
or 
worsened 
when 
study 
medication was re-administered. 

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 Followed a response pattern known to be 
associated 
with 
administration 
of 
study 
medication. 
 
10.1.4 Intensity of Adverse Events 
 
For grading the intensity of an AE, the following CTCAE categories will be 
applied: 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 Moderate; minimal, local or non-invasive intervention 
indicated. 
Grade 3 Severe or medically significant but not immediately life- 
threatening; hospitalisation or prolongation of hospitalisation 
indicated; disabling; limiting self-care. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE. 
 
10.1.5 Treatment-Emergent Adverse Events 
 
An AE is defined as treatment-emergent adverse event (TEAE) if first onset 
or worsening is after first intake of study drugs. 
 
10.1.6 Serious Adverse Events 
 
An SAE is an AE that suggests a significant hazard, contraindication, side-
effect, or precaution. With respect to human clinical experience, this 
includes any event that: 
 
Results in death.
 
Is life-threatening.*
 
Requires in-Subject hospitalisation or prolongation of existing 
hospitalisation.
 
Results in persistent or significant disability/incapacity.
 
Is a congenital anomaly/birth defect.
 
Other medically important condition.
* Life-threatening in the definition of a SAE or adverse reaction 
refers to an event in which the Subject was at risk of death at the 
time of event; it does not refer to an event that hypothetically 
might have caused death if it were more severe. 

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All of the above criteria apply to the case as a whole and should not be 
confused with the outcomes of individual reactions/events. More than one 
of the above criteria can be applicable to the one event. 
 
10.1.7 AE or SAE Exceptions 
 
The following events must not be reported as AEs or SAEs: 
 Admissions to the hospital, not associated with deterioration in 
condition, for the following:
o supportive therapy, e.g., respite care, 
o standard procedures, e.g., pre-planned treatments, 
o elective procedures, e.g., a previously scheduled surgical 
procedure, 
o disease-related investigations, e.g., pre-planned laboratory or 
instrumental assessments. 
 
10.1.8 Laboratory Evaluation 
 
10.1.8.1 Safety Laboratory Parameters 
 
The following safety laboratory tests will be performed: 
Hematology (peripheral blood) 
 
Serum chemistry (peripheral blood): 
 
 
Urine Testing 
 
10.1.9 Other Safety Parameters 
 
10.1.9.1 Vital Signs 
 
Vital signs, including HR, systolic and diastolic blood pressure, respiratory 
rate, and body temperature will be recorded throughout the study as 
noted in Section 5.2.1 and Appendix 1. 
 
10.1.9.2 Physical Examination 
 
Physical examinations will be performed as noted in Section 5.2.1 and 
Appendix 1. The physical examination will consist of the following: 
evaluation of the general appearance, head, eyes, ears, nose, throat, 

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lymph nodes, heart/cardiovascular, respiratory, abdomen, genitourinary, 
musculoskeletal/extremities, neurological status, and dermatology. 
 
Body weight (with BMI) and height will be measured at as noted in Section 
5.2.1 and Appendix 1. 
 
10.2 
Recording and Reporting Adverse Event/Intercurrent Illnesses 
 
It is the responsibility of the Investigator to document all AEs that occur during the 
study. All AEs observed during the study from the time the Subject signs the ICF 
through 30 days after the last dose of the study drug on the AE page of the CRF. 
Information to be collected includes: event term, date of onset , pattern of AE 
(intermittent or continuous), outcome of the event, Investigator-specified 
assessments of severity, seriousness, relationship to study drug, date of resolution 
of the event, any required treatment or evaluations, and whether the event 
caused study discontinuation. 
 
Adverse events resulting from concurrent illnesses, reactions to concurrent 
illnesses, or reactions to concurrent medications must also be reported. 
 
Adverse events will be elicited by asking the Subject a non-leading question, for 
example “Have you experienced or are you experiencing any new or changed 
symptoms since we last asked/since your last visit?” Adverse events should be 
reported on the appropriate page of the CRF. 
 
10.3 
Adverse Event Follow-up Procedures 
 
All AEs must be followed-up until the event has resolved or stabilised or the 
relationship to study medication is clarified. 
 
11.0 
STATISTICAL METHODS 
 
11.1 
General Methods 
 
A SAP will be prepared as a separate document that will include a detailed 
description of statistical analyses and summarisation procedures (including 
templates for tables, listings, and figures). The SAP will be finalised before 
initiating any statistical analysis. 
 
All statistical tests will be two-sided with a significance level of α=0.05, unless 
specified otherwise, and will be performed using SAS® Version 9.2 or higher. All 

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summaries, listings, figures, and analyses will be performed by dose 
level/schedule (as applicable). 
 
Data will be summarised using descriptive statistics (number of Subjects, mean, 
standard deviation [SD], median, minimum, and maximum) for continuous 
variables and using frequency and percentage for discrete variables. 
 
Plasma concentration data at each time point will be summarised with number of 
Subjects, mean, median, minimum, maximum, SD, and coefficient of variation (CV; 
%) for each dose level/schedule (as applicable). All PK parameters will be 
summarised with number of Subjects, mean, standard deviation, median, 
minimum, maximum, geometric mean, CV (%), and log-transformed SD. 
 
All data will be provided in by-Subject listings. 
 
11.2 
Demographics and baseline characteristics 
 
Demographic and baseline disease characteristic data will be summarised by dose. 
 
 
11.3 
Analysis of Primary endpoints 
 
11.3.1 Safety and Tolerability 
 
The safety of the therapies will be assessed by monitoring incidence of AEs, 
clinical laboratory tests, vital signs, and physical examination. Safety will 
be monitored throughout the study for all Subjects. Safety data will be 
summarised by dose level/schedule (as applicable). Safety summaries will 
contain only data collected during on-treatment period, unless specified 
otherwise. 
 
11.3.1.1 Adverse Events 
 
The verbatim terms used in the CRF by the Investigator to identify AEs will 
be coded by system organ class and preferred terms using MedDRA 
(current version). All reported TEAEs will be included in the analysis. 
AEs will be summarised by system organ class and preferred term. 
The following summaries will be produced: 
 All TEAEs 
 Treatment related TEAEs 

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 Grade 3 or higher TEAEs 
 Most commonly reported TEAEs (i.e., those events reported by ≥ 5% 
of all Subjects) 
 SAEs 
 Discontinuations due to AEs. 
By-Subject listings will be provided for all AEs, SAEs, AEs leading to 
discontinuation of treatment, and deaths. 
 
11.3.1.2 Clinical Laboratory Tests 
 
Safety laboratory data (hematology, serum chemistry and urinalysis) will 
be summarised for each laboratory parameter. 
 
In addition to the above-mentioned tables and listings, graphical displays 
of key safety parameters, such as scatter plots of actual or change in 
laboratory tests over time or box plots may be specified in the SAP. 
 
11.3.1.3 Vital Signs 
 
The vital signs parameters that will be summarised are pulse, blood 
pressure (systolic and diastolic), respiratory rate, and body temperature. 
 
Descriptive statistics for the actual values and changes from baseline in 
vital signs data for each dose level over time will be summarised. 
 
11.3.1.4 Physical Examination 
 
A data listing of Subjects with abnormal physical examination results will 
be provided. 
 
11.3.1.5 Tolerability 
 
Tolerability of study drugs will be assessed by summarising the number of 
AE/SAE occurring during the study. 
 
11.3.1.6 Pharmacokinetic Analyses 
 
Individual Subject plasma concentration-time data of bictegravir and 
doravirine will be determined as listed in the protocol. 
The PK parameters to be calculated will include, but are not limited to, 
AUC0-inf, AUC0-t, Cmax, kel, tmax, tlag, CL, Vd and t½. The PK parameters and 
concentrations will be summarised by dose levels among the PK evaluable 

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Subjects. Plots of individual and mean plasma concentration of over time, 
data summaries, and data listings will be provided for the PK analysis set. 
 
The SAP will provide details of the analysis and presentation of the results. 
 
11.3.2 Safety and Tolerability 
 
Safety and tolerability of the new dosing regimen will be assessed by 
evaluation of the AE/SAE events occurring after the switch. 
 
11.3.3 Pharmacokinetics Analyses 
 
Individual Subject plasma concentration-time data of bictegravir and 
doravirine will be analysed using non-compartmental model (WinNonlin®). 
 
In the 10 subject sub-cohort, the plasma samples of bictegravir and doravirine 
for PK assessments will be taken prior to dosing (-0.5 hr), and at 0.5, 1, 2, 4, 6, 8, 
12, and 24 hours on day 28 (+/- 14 days). Subjects may be asked to return for an 
unscheduled visit to test/retest PK samples if the initial data is found to be 
invalid.  All calculations will be based on actual sampling times. 
 
The PK parameters to be calculated will include, but are not limited to, 
AUC0-inf, AUC0-t, Cmax, kel, tmax, tlag, CL, Vd and t½. The PK parameters and 
concentrations will be summarised by dose levels among the PK evaluable 
Subjects. Plots of individual and mean plasma concentration of over time, 
data summaries, and data listings will be provided for the PAS. 
 
The PK parameters will be Log (e) transformed prior to analysis. 
 
The SAP will provide details of the analysis and presentation of the results. 
 
11.3.4 Preliminary Assessment of Clinical Activity 
 
In this study, subjects will have stable prior antiretroviral therapy (HIV RNA 
copies <50/mL on at least one occasion in the 6 months prior to the 
switch), and the aim is to determine if the protocol therapy will continue 
to suppress HIV activity. The goal is to determine the number of subjects 
who have 1) < 50 copies/mL and 2) less than 200 copies/mL HIV at week 
48. 
 
The secondary objective of the study is to determine the quality of life and 
weight stabilization provided by the switch therapy. 

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11.4 
interim analysis 
 
No formal interim analyses are planned. 
 
11.5 
Statistical Considerations 
 
The target sample size for the study is 30 subjects. 
 
Number of subjects maintaining HIV suppression (either <50 copies/mL or <200 
copies/mL) will be tabulated. 
 
Descriptive analyses will be tabulated for subject weight and body mass index 
(BMI) prior to commencing therapy and at 48 weeks after dosing commences. 
 
Quality of life analysis will be determined by comparison of baseline QOL scores 
(Improvement in well-being and sleep inventory as measured by The Pittsburgh 
Sleep Quality Index (PSQI) & The Work Productivity and Activity Impairment 
Questionnaire (WPAI)) with scores at 48 weeks. 
 
11.6 
Procedure For Accounting for Missing, Unused, and Spurious Data 
 
In general, the values for missing data will not be imputed. For laboratory data the 
missing baseline values will be replaced by Screening value if available, otherwise 
it will be treated as normal for summary of graded laboratory of abnormalities. 
Subjects may be asked to return to the clinic to test or retest PK values if the 
initial results are found to be invalid.   
 
The values will not be imputed for missing vital signs and other safety data, 
however, missing baseline values will be replaced by Screening values if available. 
Also, missing relationship between AE and study medication will be considered as 
related to treatment and missing severity of an AE will be summarised as severe 
AE, following conservative principle. 
 
All available data for a Subject who do not complete the study will be included in 
the data listing. 
 
11.7 
Derived And Transformed Data 
 
Pharmacokinetic concentration values below the limit of quantification (BLQ) will 
be treated as zero for the determination of summary and order statistics. 
Individual values that are BLQ will be presented as “BLQ” in the concentration data 
listing. For the presentation of summary and order statistics, if at least 1 Subject 
has a concentration value BLQ for the time point, then the minimum value will be 

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displayed as BLQ. If more than 50% of the Subjects have a concentration data 
value BLQ for the time point, then the minimum and median values will be 
displayed as BLQ. If all Subjects have concentration data values BLQ for the time 
point, then all order statistics (minimum, first quartile, median, third quartile, 
maximum) will be displayed as BLQ. 
 
PK parameters selected for statistical analysis will be log transformed. 
Concentration values that are BLQ will be considered missing for any ratio or 
natural-log transformed statistical analyses. 
 
Laboratory data that are continuous in nature, but are less than the lower limit of 
quantification or above the upper limit of quantification, will be imputed to the 
value of the lower or upper limit minus or plus 1 significant digit, respectively (e.g., 
if the result of a continuous laboratory test is < 20, a value of 19 will be assigned). 
 
11.8 
Deviations From The Original Statistical Plan 
 
Any deviations from the original SAP as described in this protocol will be agreed 
to by the Investigator, documented, and justified in an amendment, the final SAP, 
or the final study report, as appropriate. 
 
11.9 
Subject Selection For Analyses 
 
The following analysis sets will be evaluated and used for presentation of data: 
 Dose Determining Set (DDS): All Subjects who complete at least 28 days 
dosing. Subjects in this set will be denoted as evaluable for safety 
assessment. 
 Safety Analysis Set (SAS): All Subjects who are enrolled and receive at least 
one dose of study treatment. Subjects will be classified according to the 
treatment received. The SAS will be the primary set for the analysis of 
safety data. 
 Full Analysis Set (FAS): All Subjects who are enrolled and receive at least 
one dose of study treatment. Subjects will be classified according to the 
assigned dose level and schedule. The FAS will be the primary analysis set 
for efficacy analysis and the default analysis set for all other analyses, 
unless otherwise specified. 
 PK Analysis Set (PAS): All Subjects who have at least one blood sample 
providing evaluable PK data. The PAS will be used for PK analyses. 
 
12.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 

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The clinical monitor(s) should be given direct access to primary subject data (i.e., source 
data) which supports the data on the CRFs for the study, i.e., general practice charts, 
hospital notes, appointment books, original laboratory records etc. Because this enters 
into the realm of subject confidentiality, this fact must be included in the ICF that the 
subject signs. Other authorised persons such as auditors may need to have direct access 
to this source data. 
 
12.1 
Source Data 
 
Source data is defined as all information in original records and certified copies of 
original records of clinical findings, observations or other activities in a clinical 
study necessary for the reconstruction and evaluation of the study. Source data 
are contained in source documents (original records or certified copies). 
 
12.2 
Source Documents 
 
Source documents are defined as original documents, data and records (e.g., 
hospital records, clinical and office charts, laboratory notes, memoranda, or 
evaluation check lists, pharmacy dispensing records, recorded data from 
automated instruments, copies or manuscripts certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic 
media, X-rays, Subject files, records kept at the pharmacy, at the laboratories and 
at medico-technical departments involved in the clinical study). 
 
12.3 
Direct Access 
 
Direct access is defined as the permission to examine, analyse, verify and 
reproduce any records and reports that are important to evaluation of a clinical 
study. Any party (e.g., domestic and foreign regulatory authorities) with direct 
access should take all reasonable precautions within the constraints of the 
applicable regulatory requirements to maintain the confidentiality of Subject 
identities. 
 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
An independent audit at the study site may take place at any time during or after the 
study. The independent audit can be carried by the Quality Assurance (QA) department 
of a regulatory authority. 
 
13.1 
Quality Control 

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Quality control is defined as the operational techniques and activities undertaken 
within the quality assurance system to verify that the requirements for quality of 
the study related activities have been fulfilled. 
 
Quality control should be applied to each stage of data handling to ensure that all 
data are reliable and have been processed correctly. 
 
13.2 
Quality Assurance 
 
Quality Assurance is defined as the planned and systematic actions that are 
established to ensure that the study is performed and the data are generated, 
documented (recorded) and reported in compliance with GCP and the applicable 
regulatory requirements. 
 
13.2.1 Inspection 
 
An inspection is defined as the act by a regulatory authority of conducting 
an official review of documents, facilities, records and any other resources 
that are deemed by the authorities to be related to the clinical study and 
that may be located at the site of the study, or at any other establishments 
deemed appropriate by the regulatory authorities. 
 
13.2.2 Audit 
 
An audit is a systematic and independent review of study related activities 
and documents to determine whether the validated study related 
activities were conducted and the data were recorded, analysed and 
accurately reported according to the protocol, designated standard 
operating procedures (SOPs), GCP and the applicable regulatory 
requirements. 
 
14.0 
ETHICS 
 
14.1 
Ethical Conduct of the Study 
 
This clinical study will be conducted in compliance to this protocol, and in 
accordance with ICH GCP, the provisions of the guidelines of the World Medical 
Association Declaration of Helsinki in its revised edition (Fortaleza, Brazil, 2013), 
designated SOPs, and with local laws and regulations relevant to the use of new 
therapeutic agents in the country of conduct. The IRB/IEC must be constituted 
according to the local laws/guidelines. 

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14.2 
Institutional Review Board/Independent Ethics Committee Approval 
 
Before initiating a study, the Investigator will have the written and dated 
approval/favorable opinion from the relevant IRB/IEC for the study protocol (and 
any   amendments),   ICF,   ICF   updates,   Subject   recruitment    procedures 
(e.g., advertisements), and any other written information to be provided to 
Subjects. Approval will be indicated in writing with reference to the final protocol 
number and date. Details of the IRB/IEC’s constitution, including names of its 
members and what function they perform on the committee (e.g., chairman, 
specialist, lay-member) should be documented by the Investigator. 
 
During the study the Investigator should provide to the IRB/IEC all documents that 
are subject to review. 
The Investigator will submit the protocol to the IRB/IEC and their written 
unconditional approval will be obtained before the start of the study. 
 
The Investigator will provide all supportive literature (product data sheets) to the 
IRB/IEC for the protocol’s review and approval. Verification of the IRB/IEC’s 
unconditional approval of the protocol will be transmitted to the Investigator prior 
to the start of the study. This approval must refer to the study by exact protocol 
title and number, identify the documents reviewed, and state the date of review. 
 
The IRB/IEC must be informed by the Investigator of all subsequent protocol 
amendments and of unexpected SAEs occurring during the study that are likely to 
affect the safety of the Subjects or the conduct of the study. Approval for protocol 
amendments must be transmitted in writing by the Investigator. 
 
The Investigator should provide the IRB/IEC with all relevant amendments or 
updates of the protocol and product information guidance. Also, the Investigator 
should provide written reports to the IRB/IEC annually or more frequently if 
requested on any change significantly affecting the conduct of the study and/or 
increasing risk to the Subjects. A final report of study outcome, if required, should 
also be submitted by the Investigator to the IRB/IEC. 
 
14.3 
Informed Consent 
 
The principles of informed consent in the Declaration of Helsinki should be 
implemented in this clinical study before protocol-specified procedures are 
carried out. Information should be given in both oral and written form whenever 
possible and deemed appropriate by the IRB/IEC. Subjects, their relatives, or, if 
necessary, their legal representatives must be given ample opportunity to inquire 
about details of the study. 

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The Investigator or designee will explain the nature, purpose and risks of the study 
and provide the Subject with a copy of the study information sheet. The Subject 
will be given sufficient time to consider the study’s implications before deciding 
whether to participate. Should the Investigators choose to produce their own 
information sheet, then the detail provided by the Sponsor information sheet 
should be regarded as the minimum written explanation required. 
 
Consent forms must be in a language fully comprehensible to the prospective 
Subject. Informed consent will be documented by the use of an ICF approved by 
the IRB/IEC and signed by the Subject and the Investigator obtaining the consent. 
The ICF will also be annotated with the study Subject number. 
 
The written consent document will embody the elements of informed consent as 
described in the Declaration of Helsinki and will also comply with local regulations. 
Consent must be documented by the Subject’s dated signature. The signature 
confirms the consent is based on information that has been understood. Each 
Subject’s signed ICF must be kept on file by the Investigator for possible inspection 
by regulatory authorities. 
 
Should there be any amendments to the protocol that would directly affect the 
Subject’s participation in the study, e.g., a change in any procedure, the ICF must 
be amended to incorporate this modification and the Subject must agree to sign 
this amended form indicating re-consent to participate in the study. 
 
Subjects will be instructed that they are free to obtain further information from 
the Investigator at any time and that they are free to withdraw their consent/ 
assent and discontinue participation in the project at any time without prejudice. 
 
The Subject will also be advised that access to medical records will be required 
and his/her general practitioner will be informed of the Subject’s intention to 
participate in this study 
 
14.4 
Modification of Protocol 
 
The Investigator should not implement any deviation from, or changes of, the 
protocol without documented approval/favourable opinion from the IRB/IEC of an 
amendment. The only exceptions are where necessary to eliminate an immediate 
hazard(s) to study Subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor[s], change of 
telephone number[s]). Non-substantial protocol amendments may or may not be 

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required to be submitted for approval/notification to the IRBs and regulatory 
agencies. 
 
As soon as possible, the implemented deviation or change, the reasons for it, and, 
if appropriate, the proposed protocol amendment(s) should be submitted 
(according to national legislation): 
 to the IRB for review and approval/favourable opinion, 
 to the regulatory authority(ies). 
 
The party initiating an amendment must confirm it clearly in writing and it must 
be signed and dated by the Investigator. The Investigator will submit protocol 
amendments, as necessary, to the appropriate IRB/IEC. 
 
All protocol amendments must be clearly documented using standard procedures 
and must be signed and dated by the Investigator. 
 
15.0 
INVESTIGATOR OBLIGATIONS 
 
The following administrative items are meant to guide the Investigator in the conduct of 
the study, but may be subject to change based on industry and government standard 
operating procedures, working practice documents, or guidelines. Changes will be 
reported to the IRB/IEC, but will not result in protocol amendments. 
 
15.1 
Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records will be 
identified in a manner designed to maintain Subject confidentiality. All records will 
be kept in a secure storage area with limited access. Clinical information will not 
be released without the written permission of the Subject (or the Subject’s legal 
guardian), except as necessary for monitoring and auditing by the FDA or the 
IRB/IEC. 
 
The Investigator and all employees and co-workers involved with this study may 
not disclose or use for any purpose other than performance of the study any data, 
record, or other unpublished, confidential information disclosed to those 
individuals for the purpose of the study. Prior written agreement from the Sponsor 
or its designee must be obtained for the disclosure of any said confidential 
information to other parties. 
 
15.2 
Investigator Documentation 

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Prior to beginning the study, the Investigator will be asked to comply with ICH 
E6(R2) 8.2 and 21 CFR by providing the following essential documents, including 
but not limited to: 
 IRB/IEC approval 
 Original Investigator-signed Investigator agreement page of the protocol 
 IRB/IEC-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding 
this study that is to be provided to the Subject or legal guardian 
 
15.3 
Study Conduct 
 
The Investigator agrees that the study will be conducted according to the 
principles of ICH E6(R2). The Investigator will conduct all aspects of this study in 
accordance with all national, state, and local laws or regulations. Study 
information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of Subjects begins. 
 
15.4 
Adherence to Protocol 
 
The Investigator agrees to conduct the study as outlined in this protocol in 
accordance with ICH E6(R2) and all applicable guidelines and regulations. 
 
15.5 
Adverse Events and Study Report Requirements 
 
By participating in this study, the Investigator agrees to submit reports of AEs and 
SAEs according to the time line and method outlined in the protocol. In addition, 
the Investigator agrees to submit annual reports to the study site IRB/IEC as 
appropriate. 
 
15.6 
Investigator’s Final Report 
 
Upon completion of the study, the Investigator should provide the IRB/IEC with a 
summary of the study’s outcome and the regulatory authority(ies) with any 
reports required. 
 
16.0 
DATA HANDLING AND RECORD KEEPING 
 
16.1 
Completion of Case Report Forms 
 
The Investigator will be provided with detailed CRF completion guidelines that will 
identify the required data points to be collected, how to document them, and 
when the data should be documented. 

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It is the responsibility of the Investigator to maintain adequate and accurate CRFs 
to record (according to the CRF completion guidelines) all observations and other 
data pertinent to the clinical trial obtained during scheduled or unscheduled visits. 
All CRFs should be fully completed to ensure accurate data interpretation. 
 
16.2 
Archiving 
 
According to ICH-GCP, the documents which should be archived are ‘essential 
documents’ which individually and collectively permit the evaluation of the 
conduct of a study and the quality of the data produced. 
 
Source documentation must also be archived. This may include observations and 
source data contained in medical records (certified copies or originals are 
acceptable for archiving purposes), data collection forms or CRFs and research 
related records held in support departments. All hard copies of source documents 
must be retained. If electronic records of documents exist these must be backed 
up and retained with the hard copies. 
 
17.0 
FINANCING AND INSURANCE 
 
The costs necessary to perform the study will be the responsibility of the Investigator and 
Sponsor 
 
18.0 
PUBLICATION POLICY 
 
Study data may be considered for reporting at a scientific meeting or for publication in a 
scientific journal. In these cases, the Investigator will be responsible for these activities 
and will determine how the manuscript is written and edited, the number and order of 
authors, the publication to which it will be submitted, and other related issues. 
 
19.0 
REFERENCES 
 
1. Alvi et al. Protease Inhibitors and Cardiovascular Outcomes in Patients with HIV and 
Heart 
Failure. 
J 
Am 
Coll 
Cardiol. 
2018 
Jul 
31;72(5):518-530. 
doi: 
10.1016/j.jacc.2018.04.083. 
 
2. Lake JE et al. Risk factors for excess weight gain following switch to integrase 
inhibitor–basedART. Poster abstract 669. 
https://www.croiconference.org/sessions/risk-factors-excess-weight-gain-following- 
switch-integrase-inhibitor–based-art (abstract) 
https://www.croiconference.org/sites/default/files/posters- 

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2019/1430_Lake_0669.pdf (poster) 
http://www.croiwebcasts.org/p/2019croi/669 (webcast) 
 
3. Bourgi K et al. Greater weight gain among treatment-naive persons starting 
integrase inhibitors. Poster abstract 670. 
https://www.croiconference.org/sessions/greater-weight-gain-among-treatment- 
naive-persons-starting-integrase-inhibitors (abstract) 
https://www.croiconference.org/sites/default/files/posters- 
2019/1430_Bourgi_0670.pdf (poster) 
http://www.croiwebcasts.org/p/2019croi/670 (webcast) 
 
4. McComsey GA et al. Weight gain during treatment among 3,468 treatment- 
experienced adults with HIV. Poster abstract 671. 
https://www.croiconference.org/sessions/weight-gain-during-treatment-among- 
3468-treatment-experienced-adults-hiv (abstract) 
https://www.croiconference.org/sites/default/files/posters- 
2019/1430_McComsey_0671.pdf (poster) 
http://www.croiwebcasts.org/p/2019croi/671 (webcast) 
 
5. Palella FJ et al. Weight gain among virally suppressed persons who switch to InSTI- 
based ART. Poster abstract 674. 
https://www.croiconference.org/sessions/weight-gain-among-virally-suppressed- 
persons-who-switch-insti-based-art (abstract) 
https://www.croiconference.org/sites/default/files/posters- 
2019/1430_Palella_0674.pdf (poster) 
 
6. Bedimo R et al. Differential BMI changes following PI- and InSTI-based ART initiation 
by sex and race. Poster abstract 675. 
https://www.croiconference.org/sessions/differential-bmi-changes-following-pi- 
and-insti-based-art-initiation-sex-and-race (abstract) 
https://www.croiconference.org/sites/default/files/posters- 
2019/1430_Bedimo_0675.pdf (poster) 
 
7. Landovitz RJ et al. Cabotegravir is not associated with weight gain in HIV-negative 
individuals: HPTN 077. Oral abstract 34. 
https://www.croiconference.org/sessions/cabotegravir-not-associated-weight-gain- 
hiv-negative-individuals-hptn-077 (abstract) 
 
8. Hill A et al. Are new antiretroviral treatments increasing the risks of clinical obesity? 
Journal of Virus Eradication 2019;5: e45–e47. 

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http://viruseradication.com/journal- 
details/Are_new_antiretroviral_treatments_increasing_the_risks_of_clinical_obesity 
 
9. Hill AM, Mitchell N, Hughes S, Pozniak AL. Risks of cardiovascular or central nervous 
system adverse events and immune reconstitution inflammatory syndrome, for 
dolutegravir versus other antiretrovirals: meta-analysis of randomized trials. 
Curr Opin HIV AIDS. 2018 Mar;13(2):102-111. 
 
10. Sax PE et al. Weight Gain Following Initiation of Antiretroviral Therapy: Risk Factors 
in Randomized Comparative Clinical Trials 
Clinical Infectious Diseases, ciz999, https://doi.org/10.1093/cid/ciz999 

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APPENDICES 
 
Appendix 1 
Study Schedules of Events 
Appendix 2 
Investigator Signature Page 
Appendix 3 
Common Terminology Criteria for Adverse Events (CTCAE) 
Appendix 4 
Product Information for bictegravir/emtricitabine/tenofovir alafenamide 
(Biktarvy®) 
Appendix 5 
Product Information for doravirine (Pifeltro®) 
Appendix 6 
Pittsburgh Sleep Quality Index 
Appendix 7 
Work Productivity and Activity Impairment Questionnaire 

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APPENDIX 1: STUDY SCHEDULE OF EVENTS 
 
Schedule of Events: 
 
Evaluations 
Screening/ 
Baseline 
Day 28 (+/-14 days) Week 12 
(+/- 14 
days) 
Week 24
(+/- 14 
days) 
Week 36
(+/- 14 
days) 
Week 
48/EOS/Early 
Termination 
(+/- 14 days) 
Inclusion/exclusion criteria 
X
 
 
 
 
 
Demographya 
X 
 
 
 
 
 
HIV viral load 
X
X
X
X
X
X
CD4 count 
X (within 3 
months) 
 
 
 
 
X 
Height, Weight, BMIb 
X
X
X
X
X
X
Physical examination, including other signs
and symptoms 
X 
X 
X 
X 
X 
X 
Vital signsc 
X
X
X
X
X
X
Hematology (CBC 
with differential) 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
Blood sampling for PKd 
 
X
 
 
 
 
Adverse eventse 
X
X
X
X
X
X
Pittsburgh Sleep Quality Index 
X
 
 
 
 
X
WPAI Questionnaire 
X
 
 
 
 
X
Drug Treatment Switch 
X
 
 
 
 
 
a Demographic information consists of age, gender, race, year of HIV diagnosis and ethnicity 

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b Subject’s height must be recorded at Screening; weight should be recorded at every examination and body mass index (BMI) 
calculated. 
c Vital signs include pulse, systolic and diastolic blood pressure, respiratory rate, and body temperature. 
dPlasma samples for PK assessments will be collected before dosing at -0.5 hr (time 0) and at 0.5, 1, 2, 4, 6, 8, 12, and 24 
hours after dosing on day 28 (+/- 14 days) in the PK cohort.  Subjects may be asked to return for an unscheduled visit to 
test/retest PK samples if the initial data is found to be invalid 
 
e Adverse events will be assessed beginning at enrolment (date of signed informed consent) and up to last dose of study drug. 
Treatment-emergent AEs will be assessed during the dosing period. 

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APPENDIX 2: INVESTIGATOR SIGNATURE PAGE 
 
 
INVESTIGATOR STUDY ACKNOWLEDGEMENT / PROTOCOL SIGNATURE PAGE 
 
Investigator’s Statement: 
 
I have read and understand the foregoing clinical study protocol entitled, “An open label study 
evaluating the safety and efficacy of switching from rilpivirine/emtricitabine/tenofovir 
alafenamide in combination with dolutegravir, to bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine, in male HIV+ subjects > 45 years with multi-drug 
resistant virus and virologic suppression (documented with at least one viral load result < 50 
copies per mL) during the last 6 months on current therapy. Protocol No.: BETD-001. 
 
I understand and recognize its confidentiality and agree to conduct this study as described in the 
protocol, in compliance with Good Clinical Practices (GCP), designated standard operating 
procedures, all applicable regulations of the country in which the study is being conducted, and 
within the principles of the current version of the Declaration of Helsinki. 
 
 
 
 
 
Investigator’s Name (please print) 
 
Investigator’s Title 
Date (dd-mm-yyyy) 
 
Investigator’s Signature

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APPENDIX 3: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) 
 
 
The United States of America (USA) Common Terminology Criteria for Adverse Events, version 
5.0 can be found online at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_ 
Reference_5x7.pdf 

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APPENDIX 4: DATA SHEET FOR BICTEGRAVIR/EMTRICITABINE/TENOFOVIR ALAFENAMIDE 
(BIKTARVY®) 
 
https://www.gilead.com/~/media/files/pdfs/medicines/hiv/biktarvy/biktarvy_pi.pdf 

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APPENDIX 5: DATA SHEET FOR DORAVIRINE (PIFELTRO ®) 
 
https://www.merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_pi.pdf 

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APPENDIX 6: PITTSBURGH SLEEP QUALITY INDEX 
 
https://www.opapc.com/uploads/documents/PSQI.pdf 

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APPENDIX 7: WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT QUESTIONNAIRE 
 
http://oml.eular.org/sysModules/obxOML/docs/id_98/WPAI-GH_English_US_V2.pdf