Clinical trial NCT04442737
Conditions: HIV-1
Sponsor: Janssen Scientific Affairs, LLC
Start date: 2020-07-01; Completion date: 2023-08-30
Enrollment: 103 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the percent change in body weight when switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) (Immediate Switch Arm) compared to continuing the current integrase (INI) + tenofovir alafenamide/emtricitabine (TAF/FTC) antiretroviral (ARV) regimen (Delayed Switch Arm) in virologically-suppressed human immunodeficiency virus (HIV)-1 infected participants who have experienced rapid and significant body weight gain.

Detailed description:

Arms: arm 1: Participants will be immediately switched to a regimen of darunavir 800 milligram (mg)/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg (D/C/F/TAF) fixed-dose combination (FDC) once daily for 48 weeks. arm 2: Participants will continue to receive current baseline integrase (INI)-based regimen plus Tenofovir Alafenamide/Emtricitabine (TAF/FTC) antiretroviral (ARV) regimen for 24 weeks. After 24 weeks participants will switch to a regimen of D/C/F/TAF FDC once daily for an additional 24 weeks.
Interventions: intervention 1: D/C/F/TAF FDC intervention 2: TAF/FTC FDC intervention 3: INI Based Regimen
Intervention descriptions: intervention 1: A FDC tablet containing darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir alafenamide 10 mg will be administered once daily. intervention 2: TAF/FTC ARV regimen will be administered once daily. intervention 3: The integrase (INI) inhibitors (for example, bictegravir, dolutegravir, elvitegravir/cobicistat, and raltegravir) will be administered in combination with TAF/FTC, as appropriate. Regimen may consist of a single tablet regimen or a combination of two separate pills.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
1
Janssen Scientific Affairs, LLC
Clinical Protocol
Protocol Title
A Phase 4, Randomized, Active-Controlled, Open-label Study to Evaluate the Safety and
Tolerability of Switching to Once-Daily Darunavir/Cobicistat/Emtricitabine/Tenofovir
Alafenamide (D/C/F/TAF) Fixed-dose Combination (FDC) Regimen in
Virologically-suppressed Human Immunodeficiency Virus Type 1 (HIV-1) Infected
Participants Experiencing Rapid Weight Gain with an INI + TAF/FTC ARV Regimen
DEFINE
Short Title
D/C/F/TAF FDC Evaluated as a Fixed Dose Combination Regimen in Participants
Switching from an Integrase Inhibitor who have Experienced Rapid Weight Gain
Protocol TMC114FD2HTX4004; Phase 4
AMENDMENT 3
TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA (darunavir 800
mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
This study will be conducted under US Food & Drug Administration IND regulations (21
CFR Part 312).
Status: 
Approved
Date: 
29 April 2022
Prepared by: Janssen Scientific Affairs, LLC
EDMS number: 
EDMS-ERI-178641402, 5.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
2
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 3 
29-April-2022
Amendment 2 
21-May-2021
Amendment 1 
24-April-2020
Original Protocol 
16-December-2019
Amendment 3 (29April 2022)
Overall Rationale for the Amendment:- The overall reason for this amendment is to account for new data
and investigator feedback indicating 10% weight gain may not occur within 12 months but could occur
more gradually over a longer period of time.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1. Synopsis
(Overall Design);
1.2 Schema;
4.1. Overall Design;
5.1. Inclusion
Criteria #4
Eligible patients need to have a rapid and
significant body weight gain which is defined as a
≥10% increase within a 36-month time period prior
to screening and after starting an INI-based
regimen.
The weight gain criterion has
caused confusion as written and is
re-worded for clarity to capture the
intended population for enrollment
5.1 Inclusion criteria
5.4 Screen failures
10.5 Appendix 5:
Contraceptive and
Barrier Guidance
and Collection of
Pregnancy
Information
The text was updated to reflect the updated
template text as per the latest template dated 21
March 2022, version 15.
To align with the latest protocol
template
1.1 Synopsis
4.1 Overall Design
The text was modified (deletion in strikethrough)
to:
After Week 24, all participants in the Delayed
Switch Arm will be given the option to receive the
D/C/F/TAF FDC tablet and will be followed for an
additional 24 weeks.
The sentence regarding participants
randomized to the Delayed Switch
Arm switching to D/C/F/TAF FDC
at Week 24 was re-worded for
clarity
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
3
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
1. 
PROTOCOL SUMMARY..................................................................................................................... 7
1.1. 
Synopsis........................................................................................................................................... 7
1.2. 
Schema.......................................................................................................................................... 18
1.3. 
Schedule of Activities (SoA)........................................................................................................... 19
2. 
INTRODUCTION................................................................................................................................ 24
2.1. 
Study Rationale.............................................................................................................................. 25
2.2. 
Background.................................................................................................................................... 27
2.3. 
Benefit-Risk Assessment............................................................................................................... 30
2.3.1. 
Benefits for Study Participation .................................................................................................. 30
2.3.2. 
Benefit-Risk Assessment Considerations for Study Participation .............................................. 30
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 32
3.1. 
Week 24 Objectives and Endpoints............................................................................................... 32
3.2. 
Week 48 Objectives and Endpoints............................................................................................... 35
3.3. 
Consistency of Effect of Baseline to Week 24 (Immediate Switch) versus Week 24 to
Week 48 (Delayed Switch)............................................................................................................. 37
4. 
STUDY DESIGN ................................................................................................................................ 37
4.1. 
Overall Design................................................................................................................................ 37
4.2. 
Scientific Rationale for Study Design............................................................................................. 40
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 42
4.3. 
Justification for Dose...................................................................................................................... 42
4.4. 
End of Study Definition................................................................................................................... 42
5. 
STUDY POPULATION ...................................................................................................................... 42
5.1. 
Inclusion Criteria............................................................................................................................ 43
5.2. 
Exclusion Criteria........................................................................................................................... 45
5.3. 
Lifestyle Considerations................................................................................................................. 47
5.4. 
Screen Failures.............................................................................................................................. 48
5.5. 
Criteria for Temporarily Delaying Enrollment, Randomization, Administration of Study
Intervention .................................................................................................................................... 48
6. 
STUDY INTERVENTION................................................................................................................... 48
6.1. 
Study Interventions Administered .................................................................................................. 48
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 49
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 50
6.4. 
Study Intervention Compliance...................................................................................................... 51
6.5. 
Dose Modification........................................................................................................................... 51
6.6. 
Continued Access to Study Intervention After the End of the Study ............................................. 52
6.7. 
Treatment of Overdose .................................................................................................................. 52
6.8. 
Concomitant Therapy..................................................................................................................... 52
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 54
7.1. 
Discontinuation of Study Intervention ............................................................................................ 54
7.1.1. 
Temporary Discontinuation......................................................................................................... 55
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 55
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 56
7.3. 
Lost to Follow-up............................................................................................................................ 56
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
4
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 57
8.1. 
Assessments.................................................................................................................................. 58
8.1.1. 
Primary Endpoint (Percent Change in Body Weight) ................................................................. 58
8.1.2. 
Metabolic Assessments.............................................................................................................. 58
8.1.3. 
Efficacy Assessments................................................................................................................. 59
8.1.3.1. 
Antiviral Efficacy and Immunologic Change............................................................................ 59
8.1.3.2. 
Resistance Determinations...................................................................................................... 60
8.1.3.3. 
Management of Virologic Rebound ......................................................................................... 60
8.1.4. 
Adherence .................................................................................................................................. 61
8.2. 
Safety Assessments....................................................................................................................... 61
8.2.1. 
Physical Examination.................................................................................................................. 62
8.2.2. 
Vital Signs................................................................................................................................... 62
8.2.3. 
Electrocardiogram (ECG) ........................................................................................................... 62
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 62
8.2.5. 
Patient-reported Outcomes ........................................................................................................ 63
8.2.5.1. 
HIV-Symptom Index (HIV-SI) .................................................................................................. 63
8.2.5.2. 
Body Shape Questionnaire (BSQ-8D)..................................................................................... 64
8.2.5.3. 
DAILY EATS............................................................................................................................ 64
8.2.5.4. 
Patient Global Impression of Change...................................................................................... 64
8.2.6. 
Toxicity Management.................................................................................................................. 64
8.2.6.1. 
General Guidance for the Management of Clinical Events and Laboratory
Abnormalities........................................................................................................................... 65
8.2.6.2. 
Cutaneous Events/Rash.......................................................................................................... 65
8.2.6.3. 
Acute Systemic Allergic Reaction............................................................................................ 67
8.2.6.4. 
Potential Renal Toxicity........................................................................................................... 69
8.2.6.5. 
Potential Posterior Uveitis Cases ............................................................................................ 69
8.2.6.6. 
Hyperglycemia......................................................................................................................... 70
8.2.6.7. 
Hypertriglyceridemia and Hypercholesterolemia..................................................................... 71
8.2.6.8. 
Lipodystrophy/Fat Redistribution/Body Changes .................................................................... 71
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 71
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 72
8.3.2. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 72
8.3.3. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 72
8.3.4. 
Pregnancy................................................................................................................................... 72
8.3.5. 
Adverse Events of Special Interest............................................................................................. 73
8.4. 
Pharmacokinetics........................................................................................................................... 73
8.4.1. 
Evaluations ................................................................................................................................. 73
8.4.2. 
Pharmacokinetic Parameters and Evaluations........................................................................... 73
8.5. 
Genetics ......................................................................................................................................... 73
8.6. 
Biomarkers..................................................................................................................................... 73
8.6.1. 
Pharmacodynamics .................................................................................................................... 74
8.7. 
Immunogenicity Assessments ....................................................................................................... 74
8.8. 
Health Economics OR Medical Resource Utilization and Health Economics................................ 74
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 74
9.1. 
Statistical Hypotheses.................................................................................................................... 74
9.2. 
Sample Size Determination ........................................................................................................... 75
9.3. 
Populations for Analysis Sets ........................................................................................................ 76
9.4. 
Statistical Analyses ........................................................................................................................ 77
9.4.1. 
General Considerations.............................................................................................................. 77
9.4.2. 
Primary Analysis......................................................................................................................... 77
9.4.3. 
Secondary Analyses................................................................................................................... 77
9.4.3.1. 
Metabolic Analyses.................................................................................................................. 77
9.4.3.2. 
Resistance/Efficacy Analyses.................................................................................................. 77
9.4.3.3. 
Adherence Analyses................................................................................................................ 78
9.4.4. 
Safety Analyses.......................................................................................................................... 78
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
5
9.4.5. 
Patient-reported Outcomes Analyses......................................................................................... 79
9.5. 
Interim Analysis.............................................................................................................................. 79
9.6. 
Data Monitoring Committee or Other Review Board ..................................................................... 79
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 81
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 81
10.2. 
Appendix 2: Clinical Laboratory Tests and Calculations................................................................ 82
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 85
REGULATORY AND ETHICAL CONSIDERATIONS................................................................................. 85
FINANCIAL DISCLOSURE......................................................................................................................... 87
INFORMED CONSENT PROCESS............................................................................................................ 87
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH ............................ 88
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA................................................. 89
CASE REPORT FORM COMPLETION...................................................................................................... 90
SOURCE DOCUMENTS............................................................................................................................. 91
MONITORING............................................................................................................................................. 92
ON-SITE AUDITS ....................................................................................................................................... 92
RECORD RETENTION............................................................................................................................... 93
STUDY AND SITE START AND CLOSURE .............................................................................................. 93
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................... 95
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS .................................................................... 95
ATTRIBUTION DEFINITIONS .................................................................................................................... 96
SEVERITY CRITERIA................................................................................................................................. 96
SPECIAL REPORTING SITUATIONS........................................................................................................ 97
PROCEDURES........................................................................................................................................... 97
CONTACTING SPONSOR REGARDING SAFETY ................................................................................... 98
PRODUCT QUALITY COMPLAINT HANDLING ........................................................................................ 99
10.5. 
Appendix 5: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 100
10.6. 
Appendix 6: Management of Clinically Significant Laboratory Toxicities..................................... 103
10.7. 
Appendix 7: DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events....... 104
10.8. 
Appendix 8: Patient Reported Outcomes Questionnaires ........................................................... 132
10.8.1. 
HIV-Symptom Index (HIV-SI) ................................................................................................... 132
10.8.2. 
Body Shape Questionnaire (BSQ-8D)...................................................................................... 134
10.8.3. 
DAILY EATS ............................................................................................................................. 136
10.8.4. 
Patient Global Impression of Change (PGIC)........................................................................... 144
10.8.5. 
Patient Global Impression of Change-Satiety (PGIC-S)........................................................... 145
10.9. 
Appendix 9: Characteristics, Prevention, and Management of Cardiovascular Diseases in
People Living with HIV by American Heart Association............................................................... 146
10.10. Appendix 10: 2017 American College of Cardiology (ACC) Guideline for the Prevention,
Detection, Evaluation, and Management of High Blood Pressure in Adults................................ 147
10.11. Appendix 11: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus
Report by the American Diabetes Association (ADA) and the European Association for
the Study of Diabetes (EASD) ..................................................................................................... 148
10.12. Appendix 12: WHO Clinical Staging of HIV/AIDS........................................................................ 149
10.13. Appendix 13: Management of Virologic Rebound ....................................................................... 151
10.14. Appendix 14: Protocol Amendment History................................................................................. 152
REFERENCES.......................................................................................................................................... 155
INVESTIGATOR AGREEMENT............................................................................................................... 157
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
6
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Summary of Cutaneous Reaction/Rash Follow-up ................................................................... 67
Table 2: 
Summary of Allergic Reaction Follow-up.................................................................................. 69
Table 3: 
Phase 3 Studies on D/C/F/TAF FDC Arm ................................................................................ 75
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 18
Figure 2: Waist Circumference Measurement ......................................................................................... 59
Figure 3: Sample Size Estimation by Treatment Effect Size ................................................................... 76
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
7
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 4, Randomized, Active-Controlled, Open-label Study to Evaluate the Safety and Tolerability of
Switching to Once Daily Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Fixed-
dose Combination (FDC) Regimen in Virologically-suppressed Human Immunodeficiency Virus Type 1
(HIV-1) Infected Participants Experiencing Rapid Weight Gain with an INI + TAF/FTC ARV Regimen
Short Title: D/C/F/TAF FDC Evaluated as a Fixed Dose Combination Regimen in Participants Switching
from an Integrase Inhibitor who have Experienced Rapid Weight Gain.
Primary Study Intervention
The primary study intervention is the darunavir/cobicistat/emtricitabine/tenofovir alafenamide
(D/C/F/TAF) fixed-dose combination (FDC). D/C/F/TAF FDC is a 4-agent tablet for oral once-daily use
for the treatment of human immunodeficiency virus (HIV)-1 infection in adults. This tablet contains the
protease inhibitor (PI) darunavir (D or DRV) (800 mg), the pharmacokinetic (PK) enhancer cobicistat
(COBI or C) (150 mg), the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC or F) (200
mg), and the tenofovir (TFV) prodrug tenofovir alafenamide (TAF) (10 mg). The D/C/F/TAF FDC tablet
(SYMTUZA®) was approved by the United States (US) Food and Drug Administration as a complete
regimen for the treatment of HIV-1 infection in adults who have no prior antiretroviral (ARV) treatment
history or who are virologically-suppressed (human immunodeficiency virus type 1 ribonucleic acid [HIV-1
RNA] less than 50 copies per mL) on a stable ARV regimen for at least 6 months and have no known
substitutions associated with resistance to DRV or TFV.
Participants will be randomized 1:1 to either remain on their baseline integrase (INI)-based regimen
(Delayed Switch) or to switch to a regimen of D/C/F/TAF  FDC (Immediate Switch). After 24 weeks
participants who were randomized to remain on their INI-based regimen will also be switched to
D/C/F/TAF FDC for an additional 24 weeks. All enrolled participants will be assigned randomized
treatments in an open-label manner.
 
D/C/F/TAF FDC Arm (Immediate Switch): Switch to a regimen of DRV 800 mg + COBI 150 mg
+ FTC 200 mg + TAF 10 mg FDC once daily, (n=55) for 48 weeks;
 
Active-Control Arm (Delayed Switch): Continue current INI + TAF/FTC ARV regimen, (n=55) for
24 weeks. After 24 weeks participants will switch to a regimen of DRV 800 mg + COBI 150 mg +
FTC 200 mg + TAF 10 mg FDC once daily for an additional 24 weeks.
Currently, four INIs are FDA approved (bictegravir, dolutegravir, elvitegravir/cobicistat, and raltegravir)
to treat both treatment naïve and certain  treatment experienced patients in combination with other
antiretroviral agents and have demonstrated favorable efficacy and tolerability profiles in registrational
clinical studies. The individual agents bictegravir, dolutegravir, and elvitegravir/cobicistat are available in
several co-formulated single tablet regimens including NRTIs. Tenofovir alafenamide is an NRTI approved
for treatment of patients living with HIV-1 in combination with other antiretrovirals and is available in
several fixed dose combinations or single tablet regimens with FTC.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
8
OBJECTIVES AND ENDPOINTS
Week 24 Objectives and Endpoints
Objectives 
Endpoints
Primary
 
To assess the percent change in body weight when 
switching to D/C/F/TAF FDC (Immediate Switch 
Arm) compared to continuing the current INI +
TAF/FTC ARV regimen (Delayed Switch Arm) in
virologically-suppressed 
(HIV-1 
RNA 
<50
copies/mL) HIV-1 infected participants who have
experienced rapid and significant body weight gain
 
Percent change from Baseline in body
weight at Week 24
Secondary
Metabolic
 
To assess changes in body weight when switching 
to D/C/F/TAF FDC (Immediate Switch Arm) 
compared to continuing the current INI + TAF/FTC 
ARV regimen (Delayed Switch Arm) 
 
Change from Baseline in absolute body
weight at Week 24
 
Proportion of participants with % change
in body weight >3% at Week 24
 
Proportion of participants with % change
in body weight >5% at Week 24
 
Change from Baseline in BMI at Week
24
 
To assess changes in body composition when 
switching to D/C/F/TAF FDC (Immediate Switch 
Arm) compared to continuing the current INI + 
TAF/FTC ARV regimen (Delayed Switch Arm) 
 
Change 
from 
Baseline 
in 
body
composition as measured by DEXA scan
at Week 24
 
Change 
from 
Baseline 
in 
waist
circumference at Week 24
 
To assess change in blood pressure when switching 
to D/C/F/TAF FDC (Immediate Switch Arm) 
compared to continuing the current INI + TAF/FTC
ARV regimen (Delayed Switch Arm)
 
Change in SBP and DBP from Baseline
at Week 24
 
To assess changes in clinical laboratory tests when 
switching to D/C/F/TAF FDC (Immediate Switch 
Arm) compared to continuing the current INI + 
TAF/FTC ARV regimen (Delayed Switch Arm) 
 
Change from Baseline in fasting lipids at
Week 24
 
Change from Baseline in fasting glucose
at Week 24
 
Change from Baseline in HOMA-IR at
Week 24
 
Change from Baseline in HbA1c at
Week 24
 
Change from Baseline in leptin and
adiponectin at Week 24
 
To assess changes in liver biomarkers when 
switching to D/C/F/TAF FDC (Immediate Switch 
Arm) compared to continuing the current INI + 
TAF/FTC ARV regimen (Delayed Switch Arm) 
 
Change from Baseline in the proportion
of participants with advanced fibrosis
according to the NAFLD fibrosis score
at Week 24
 
Change from Baseline in the proportion
of participants at high risk of NASH
according to the HAIR score at Week 24
 
To assess changes in concomitant medications of 
interest 
(including 
anti-hypertensive, 
anti- 
hyperglycemic, and lipid lowering agents) when 
switching to D/C/F/TAF FDC (Immediate Switch 
 
Proportion of participants having a dose-
reduction or complete withdrawal of
anti-hypertensive, anti-hyperglycemic,
or lipid lowering agents in the Immediate
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
9
Objectives 
Endpoints
Arm) compared to continuing the current INI + 
TAF/FTC ARV regimen (Delayed Switch Arm) 
Switch Arm or Delayed Switch Arm
from Baseline to Week 24
 
Proportion of participants initiating an
anti-hypertensive, anti-hyperglycemic,
or lipid lowering agent in the Immediate
Switch Arm or Delayed Switch Arm
from Baseline to Week 24
Safety
 
To evaluate the safety of switching to D/C/F/TAF 
FDC (Immediate Switch Arm) compared to 
continuing the current INI + TAF/FTC ARV 
regimen (Delayed Switch Arm) 
 
Incidence of any Grade AEs (related and
not related) through Week 24
 
Incidence of Grade 3 and 4 AEs (related
and not related) through Week 24
 
Incidence of discontinuations due to AEs
through Week 24
 
Incidence of SAEs (related and not
related) through Week 24
 
Change from Baseline in clinical
laboratory tests through Week 24
 
Incidence of Grade 3 and 4 laboratory
abnormalities through Week 24
Efficacy
 
To evaluate the virologic outcomes when switching 
to D/C/F/TAF FDC (Immediate Switch Arm) 
compared to continuing the current INI + TAF/FTC 
ARV regimen (Delayed Switch Arm) 
 
Proportion 
of 
participants 
with
confirmed virologic rebound through
Week 24
 
Proportion of participants with virologic
response (HIV-1 RNA<50 copies/mL) at
Week 24 according to the FDA snapshot
algorithm
 
Proportion of participants with virologic
failure (HIV-1 RNA ≥50 copies/mL) at
Week 24 according to the FDA snapshot
algorithm
 
Proportion 
of 
participants 
having
virologic response (HIV-1 RNA<200
copies/mL) at Week 24 according to the
FDA snapshot algorithm
 
Proportion 
of 
participants 
having
virologic failure (HIV-1 RNA ≥200
copies/mL) at Week 24 according to the
FDA snapshot algorithm
 
To evaluate immunological changes when 
switching to D/C/F/TAF FDC (Immediate Switch 
Arm) compared to continuing the current INI +
TAF/FTC ARV regimen (Delayed Switch Arm)
 
Change from Baseline in CD4+ cell
count at Week 24
Resistance
 
To assess viral resistance in participants with 
confirmed HIV-1 RNA rebound for participants 
switching to D/C/F/TAF FDC (Immediate Switch 
Arm) compared to continuing the current INI + 
TAF/FTC ARV regimen (Delayed Switch Arm) 
 
Proportion of participants with pre-
baseline PR, RT, and INI resistance-
associated mutations (RAMs) based on
historical genotypes
 
Incidence of observed genotypic and
phenotypic 
ARV 
resistance 
for
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
10
Objectives 
Endpoints
participants 
meeting 
HIV-1 
RNA
rebound criteria through Week 24
 
Proportion of participants with newly
identified post-baseline RAMs and
phenotypic resistance, compared to pre-
baseline resistance tests when available,
upon meeting confirmed virologic
rebound through Week 24
PROs
 
To assess changes in the burden of common 
symptoms associated with HIV treatment or 
disease for participants switching to D/C/F/TAF 
FDC (Immediate Switch Arm) compared to 
continuing the current INI + TAF/FTC ARV 
regimen (Delayed Switch Arm) 
 
Change from Baseline in the proportion
of participants who have bothersome
symptoms (scores of 2, 3 or 4) across all
items of the HIV-SI at Week 24
 
Change from Baseline in the proportion
of participants who have any symptoms
(scores of 1, 2, 3 or 4) across all items of
the HIV-SI at Week 24
 
Association between treatment arm and
each bothersome symptom of the HIV-
SI adjusting for Baseline variables at
Week 24
 
To describe responses on the PGIC in participants 
switching to D/C/F/TAF FDC (Immediate Switch
Arm) and in participants continuing the current INI
+ TAF/FTC ARV regimen (Delayed Switch Arm)
 
PGIC at Week 24
Adherence
 
To evaluate adherence in participants switching to 
D/C/F/TAF FDC (Immediate Switch Arm) 
compared to continuing the current INI + TAF/FTC 
ARV regimen (Delayed Switch Arm)
 
Adherence rates by participant self-
report using 4-day recall at Week 4, 12,
and 24
Exploratory
Exploratory clinical biomarker
 
To assess changes in alpha melanocyte-stimulating 
hormone when switching to D/C/F/TAF FDC 
(Immediate Switch Arm) compared to continuing 
the current INI + TAF/FTC ARV regimen
(Delayed Switch Arm)
 
Change from 
Baseline 
in 
alpha
melanocyte-stimulating 
hormone 
at
Week 24
Exploratory PROs
 
To assess changes in eating-related concepts 
(hunger, appetite, cravings, and satiety) for 
participants switching to D/C/F/TAF FDC
(Immediate Switch Arm) compared to continuing
the current INI + TAF/FTC ARV regimen
(Delayed Switch Arm)
 
Change from Baseline in the scores on
the DAILY EATS at Week 24
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
11
Objectives 
Endpoints
 
To assess changes in concerns about body shape for 
participants switching to D/C/F/TAF FDC (Immediate 
Switch Arm) compared to continuing the current INI + 
TAF/FTC ARV regimen (Delayed Switch Arm) 
 
Change from Baseline in the scores on the
BSQ-8D at Week 24
 
Change from Baseline in the proportion of
participants who have no concern (<19), mild
concern (19-25), moderate concern (26-33)
or marked concern (>33) with their body
shape at Week 24
Abbreviations: AE: adverse event, ARV: antiretroviral, BMI: body  mass index, BSQ 8D: body shape questionnaire, D/C/F/TAF FDC:
Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Fixed dose Combination, DBP: diastolic blood pressure, DEXA: dual energy X ray
absorptiometry, FDA: Food Drug Administration, FTC: emtricitabine, HAIR: hypertension, age, insulin, resistance, HIV 1 RNA: human
immunodeficiency virus type 1 ribonucleic acid, HIV SI: HIV Symptom Index, HOMA IR: homeostatic model assessment of insulin resistance,
INI: integrase, NAFLD: non alcoholic fatty liver disease, NASH: Nonalcoholic fatty liver disease, PGIC: patient global impression of change, PR:
protease, PROs: patient reported outcomes, RT: reverse transcriptase, SAE: serious adverse event, SBP: systolic blood pressure.
Secondary objectives/endpoints at Week 48 are similar to the Week 24 Objectives and Endpoints and thus
will be used to assess 1) outcomes for the Immediate Switch Arm at Week 48 and 2) the consistency of
effect on outcomes from Baseline to Week 24 in the Immediate Switch Arm versus the Week 24 to Week
48 in the Delayed Switch Arm.
Hypothesis
Based on the primary endpoint, the percent change in body weight at Week 24 from baseline in the
Immediate Switch Arm is less than that of the Delayed Switch Arm (INI + TAF/FTC ARV).
OVERALL DESIGN
This is a randomized, 48 week, active-controlled, open-label, prospective, multicenter, Phase 4 study to
evaluate the safety and tolerability of switching to D/C/F/TAF FDC compared to continuing the current INI
+ TAF/FTC ARV regimen  in virologically-suppressed HIV-1 infected adult participants who have
experienced rapid and significant body weight gain while receiving an INI + TAF/FTC ARV regimen.
Approximately, 110 participants will be included in this study. A maximum enrollment of approximately
70% male participants will be utilized to ensure adequate recruitment of female participants. A maximum
enrollment of approximately 70% non-black participants will be utilized to ensure adequate recruitment of
diverse races.
Eligible participants are to:
 
have documented HIV-1 infection currently treated with a stable ARV regimen consisting of an INI
combined with TAF/FTC for ≥6 consecutive months preceding the screening visit.
 
BMI of ≥18 kg/m2 at the time of starting an INI + TAF/FTC ARV regimen.
 
have a rapid and significant weight gain, defined as a ≥10% increase in body weight within a 36-month
time period prior to screening and while on the current INI + TAF/FTC ARV regimen.
 
be virologically suppressed, with at least 1 plasma HIV-1 RNA measurement <50 copies/mL occurring
between 12 and 2 months prior to screening while being on the stable INI + TAF/FTC ARV regimen
and having HIV-1 RNA<50 copies/mL at the screening visit.
 
Not have had previous failure on DRV treatment or known documented history of ≥1 DRV resistance-
associated mutations (RAMs).
The study will consist of 3 phases: Screening (approximately 30 days [up to a maximum of 6 weeks]),
Open-Label Treatment (48 weeks), and Follow-up (for any participant who has an ongoing adverse event
(AE) or serious adverse event (SAE) at the time of his/her last study visit).
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
12
After obtaining the informed consent form (ICF) from the participant, selection criteria will be reviewed to
confirm the participant’s eligibility. At baseline (Day 1), participants who meet all eligibility criteria will
be randomized in a 1:1 ratio to 1 of the following 2 treatment arms in an open-label manner. Randomization
will be stratified by sex (Male or Female) and race (Black/African American or Non-Black/African
American) at Baseline.
 
D/C/F/TAF FDC Arm (Immediate Switch): Switch to a regimen of DRV 800 mg + COBI 150 mg
+ FTC 200 mg + TAF 10 mg FDC once daily, (n=55) for 48 weeks;
 
Active-Control Arm (Delayed Switch): Continue current INI + TAF/FTC ARV regimen, (n=55) for
24 weeks. After 24 weeks participants will switch to a regimen of DRV 800 mg + COBI 150 mg +
FTC 200 mg + TAF 10 mg FDC once daily for an additional 24 weeks.
Participants randomized to the Immediate Switch Arm must start D/C/F/TAF FDC within 24 hours of the
Baseline visit and will continue to receive D/C/F/TAF treatment for a total of 48 weeks. Participants
randomized to the Delayed Switch arm, will continue their current INI + TAF/FTC ARV regimen for
24 weeks.  After Week 24, all participants in the Delayed Switch Arm will receive the D/C/F/TAF FDC
tablet and will be followed for an additional 24 weeks.
Participants will return for study visits at Weeks 4, 12, 24, 36, and 48. Additionally, participants randomized
to the Delayed Switch Arm will have a study visit at Week 28 (ie, 4 weeks after switching from the
INI + TAF/FTC ARV regimen to D/C/F/TAF FDC).  Key metabolic assessments include body weight
measurement, body composition assessed via dual-energy x-ray absorptiometry (DEXA) scan, waist
circumference measurements, vital sign measurements, select clinical laboratory tests (including fasting
lipids, fasting glucose, homeostatic model assessment of insulin resistance [HOMA-IR], HbA1c, leptin,
adiponectin), and liver biomarkers.  Key efficacy assessments include HIV-1 viral load, CD4+/CD8+ cell
count, and HIV-1 genotype/phenotype resistance testing if necessary. Key safety assessments will include
AEs, physical examinations, standard clinical laboratory tests, and pregnancy testing. Concomitant
medications will be recorded. Self-reported adherence will be assessed using 4-day recall, and reasons for
non-adherence will be monitored. Patient Reported Outcomes (PRO) (Body Shape Questionnaire
[BSQ-8D], DAILY EATS, HIV-Symptom Index [HIV-SI], and patient global impression of change [PGIC]
including PGIC-S) will be completed.
HIV-1 genotypic and phenotypic resistance testing (using PhenoSense GT® Plus Integrase) will be
performed for participants with confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥200
copies/mL at a scheduled or unscheduled visit) and a HIV-1 RNA >400 copies/mL at the time of confirmed
rebound or at later timepoints; the confirmatory testing should be conducted 2 to 4 weeks after the initial
HIV-1 RNA value ≥200 copies/mL. If genotypic/phenotypic resistance to study intervention is determined,
study intervention may be discontinued, and the participant will be referred for continued medical care
outside of the study if the decision is made to discontinue study intervention.
Plasma concentrations of DRV and COBI may be determined in participants experiencing virologic
rebound using stored blood samples collected throughout the study, if deemed necessary. Plasma
concentrations of INIs for the Delayed Switch Arm may be determined in participants experiencing
virologic rebound using stored blood samples collected throughout the study, if deemed necessary.
The end of the study is defined as completion of the last data collection visit for the last participants
participating in the study. For the purpose of the primary analysis, a participant will be considered to have
completed the study if data collection as required per protocol through the complete course of 24 weeks of
ART has been completed. The primary analysis of this study will be performed once all participants have
completed the Week 24 visit or discontinued earlier. At the end of the study, participants will resume routine
clinical care with the care provider who will determine their future care.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
13
A follow-up visit is required for any participant who has an ongoing AE or SAE after completion of the
last study-related visit (unless consent is withdrawn).
NUMBER OF PARTICIPANTS
The planned sample size is 110 participants (55 participants per treatment arm). This sample size should
provide 80% power to detect a treatment effect size of 0.54 at the significance level of 0.05, 2-sided. An
interim analysis (IA) is planned when approximately 60% of the initial planned 110 participants have
completed the Week 12 visit and approximately 30% of participants have completed the Week 24 visit to
re-estimate the sample size to ensure adequate power for the hypothesis testing. All cumulative data will be
used for the interim analysis. Details for the sample size re-estimation (SSR), threshold for the conditional
power, and protection of overall significance level will be provided in the statistical analysis plan (SAP)
for the IA and monitoring. The planned maximum total sample size after SSR is 150 participants.
INTERVENTION ARMS AND DURATION
Description of Intervention
Eligible participants will be randomized in a 1:1 ratio to the Immediate Switch Arm (switch to D/C/F/TAF
FDC) or the Delayed Switch Arm (maintain current INI + TAF/FTC ARV regimen).
 
Immediate Switch Arm: D/C/F/TAF FDC (DRV 800 mg + COBI 150 mg + FTC 200 mg + TAF 10
mg FDC) once daily for 48 weeks.
 
Delayed Switch Arm: continue current INI + TAF/FTC ARV regimen for 24 weeks. After 24 weeks
participants will switch  to a regimen of D/C/F/TAF (DRV 800 mg + COBI 150 mg + FTC 200
mg + TAF 10 mg) FDC once daily for an additional 24 weeks.
The D/C/F/TAF FDC tablet must be taken orally with food and with approximately 240 mL (8 ounces) of
water. The tablet should be swallowed whole; alternatively, for participants who are unable to swallow the
tablet whole, D/C/F/TAF FDC may be split into 2 pieces using a tablet-cutter, and the entire dose should
be consumed immediately after splitting. Participants should not attempt to dissolve the tablet in water.
If participants notice that they have missed a D/C/F/TAF FDC intake and it is still within 12 hours of their
regular dosing time, they should take the D/C/F/TAF FDC immediately with food. Participants can then
continue their usual dosing schedule. If participants notice that they have missed a dose more than 12 hours
after the time it is usually taken, they should be instructed not to take it and simply resume the usual dosing
schedule. Participants should not take a double dose to make up for a missed dose.
Instructions regarding how to take D/C/F/TAF FDC tablet, what to do if a dose is missed and how to store
the D/C/F/TAF FDC tablet will be provided on the wallet (study) card.
For the Delayed Switch Arm, all components of the INI + TAF/FTC ARV regimen should be dosed and
administered using the dosing schedule specified in the ARV agent’s Prescribing Information.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
14
ASSESSMENTS
Metabolic Assessments
The primary evaluation will be body weight measurements.  Participants should be weighed on a calibrated
scale wearing underwear and a gown; they will be instructed to take off their shoes and to empty their
bladders before being weighed. The scale should be calibrated according to the manufacturer's
specifications and at the frequency  recommended by the manufacturer before the first participant is
weighed. Calibration must be documented in the calibration log.
Systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate (supine after at least 5 minutes
rest) will be recorded in a quiet setting without distractions, with a completely automated technique. Manual
techniques will be used only if an automated device is not available. Body Mass Index (BMI) will be
calculated using body weight method described for primary end point and height. Height will be measured
at screening using a wall-mounted stadiometer or one mounted on a balance beam scale, whichever is most
appropriate for the individual participant.  Participants should be wearing socks or barefoot and should not
be wearing shoes. Body composition will be assessed via DEXA scans. Waist circumference will be
measured with the participant standing, wearing underwear, with or without a gown. The measurement will
be performed at a level midway between the superior aspect of the iliac crests and the lower lateral margin
of the ribs. The measurement need not be at the level of the umbilicus. The measuring tape will be kept
horizontal. Fasting clinical laboratory tests will assess changes in the lipids, calculated HOMA-IR, HbA1c,
leptin, adiponectin, and alpha melanocyte-stimulating hormone. Non-alcoholic fatty liver disease (NAFLD)
Fibrosis and hypertension, age, insulin, resistance (HAIR) scores will be calculated based on receipt of
central laboratory assessments and clinical status of the participant. If a participant has not fasted prior to
the visit, the visit may proceed, but participant must return within 72 hours in a fasted state to have a blood
draw for the metabolic assessments.
Efficacy Assessments
Blood samples for determination of plasma HIV-1 RNA viral load and immunologic parameters and for
HIV-1 genotypic/phenotypic resistance testing (PhenoSense GT® Plus Integrase) will be taken at the time
points specified in the Schedule of Assessments (SoA).
Plasma viral load will be measured using a validated assay at a central laboratory (ie, Roche COBAS
AmpliPrep/COBAS TaqMan HIV-1 Test, Version 2.0.) The assay linear range is 20 to 10,000,000
copies/mL with a lower limit of quantification (LLOQ) of 20 copies/mL and a limit of detection (LOD) of
20 copies/mL). Immunologic change will be determined by changes in CD4+ cell count (absolute and %).
Changes in viral load, changes in CD4+ cell counts (either decreases or increases) or detected resistance
will be part of the efficacy analysis and should not be reported as AEs or SAEs.
Participants will be considered to have virologic rebound if they have 2 consecutive HIV-1 RNA values
≥200 copies/mL at a scheduled or unscheduled visit after maintaining HIV-1 RNA <50 copies/mL;
confirmatory testing should be conducted 2 to 4 weeks after the initial HIV-1 RNA value ≥200 copies/mL.
For participants with confirmed virologic rebound, HIV-1 genotypic and phenotypic resistance testing
(PhenoSense GT® Plus Integrase) will be performed on the confirmed rebound sample, if HIV 1 RNA ≥400
copies/mL or on a following visit with HIV-1 RNA ≥400 copies/mL. Genotype/phenotype testing at other
time points may be requested if deemed necessary by the sponsor.
Adherence
Treatment adherence for the study will be assessed at all study visits by participant self-report using a 4-day
recall.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
15
Safety Assessments
Safety will be evaluated throughout the study from the time a signed and date ICF is obtained until
completion of the participant’s last study-related activity.  The study will include following evaluations of
safety:
 
AEs;
 
Clinical laboratory tests (biochemistry, hematology, urinalysis, urine chemistry);
 
Vital signs measurements;
 
Physical examination (complete or symptom directed).
Patient Reported Outcomes:
Patient reported outcomes, including the BSQ-8D, DAILY EATS, HIV-SI, and PGIC (including PGIC-S)
will be completed.
Pharmacokinetic Assessments
Plasma samples may be used to evaluate the concentration of DRV and COBI in participants experiencing
confirmed virologic rebound using stored blood samples collected throughout the study at the discretion of
the sponsor. Plasma concentrations of INIs for the Delayed Switch arm may be determined in participants
experiencing confirmed virologic rebound using stored blood samples collected throughout the study, if
deemed necessary by the sponsor.
STATISTICAL METHODS
Statistical Hypothesis
The statistical hypothesis is the following:
H0: Dt -Dc=0 vs. H1: Dt -Dc ≠ 0.
Where H0 is the null hypothesis, H1 is the alternative hypothesis; Dt=%body weight change from baseline
at Week 24 for treatment D/C/F/TAF, Dc for the Delayed Switch arm.
The statistical hypothesis will be tested using repeated measures longitudinal method (linear mixed-effects
model) at 0.05 significance level, 2-sided.
For all participants who receive at least 1 dose of study intervention descriptive statistics will be provided.
Participant information will be analyzed based on the Intent-to-treat (ITT) population, unless otherwise
specified.
Primary Endpoint Analysis:  The primary endpoint analysis will be based on the ITT population. It will be
evaluated using linear mixed-effects model with participant as random effect adjusted by baseline BMI and
stratification factors in a longitudinal data with repeated measures (percent body weight change measured
at multiple visits).
Secondary Endpoint Analyses:
Metabolic Analyses: For the metabolic endpoints of change from baseline, the same statistical model as
described for the primary endpoint will be used for analysis. Other secondary metabolic endpoints will be
analyzed using descriptive statistics.
Resistance/Efficacy  Analyses: HIV-1 genotypes, and phenotypes if applicable, will be analyzed from
samples of participants with virologic rebound and with HIV-1 RNA ≥400 copies/mL.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
16
Virologic suppression (HIV-1 RNA<50 copies/mL) and failure (HIV-1 RNA ≥50 copies/mL) using the
Food and Drug Administration (FDA) Snapshot algorithm in the ITT will also be analyzed as a secondary
endpoint at Weeks 24 and 48.
The proportion of participants experiencing virologic rebound through Weeks 24 and 48 will be tabulated
using descriptive statistics along with the 95% confidence intervals (CIs). The Wilson (Score) method for
the CI will be used. The changes from screening/baseline in CD4+ cell count at Weeks 24 and 48 will be
summarized using descriptive statistics.
The number of identified protease (PR) mutations (including International Acquired Immunodeficiency
Virus (AIDS) Society [IAS]-USA primary and secondary  PI resistance-associated mutations [RAMs],
reverse transcriptase (RT) mutations (including International AIDS  Society-United States of America
[IAS-USA] nucleoside/nucleotide RT inhibitor [N[t]RTI] RAMs, IAS-USA non-nucleoside RT inhibitor
[non-N[t]RTI] RAMs), and integrase (INI) mutations (including International AIDS Society [IAS]-USA
INI-RAMs and IAS-USA primary INI mutations), as well as specific mutations associated with resistance
to DRV, FTC, and TAF, will be tabulated based on the observed virologic rebound through the study period.
Retrospectively, fold change (FC) in 50% effective concentration (EC50) of ARVs may be analyzed and
tabulated dependent on the number of virologic rebound and phenotypes available through the study period.
Adherence Analyses: Treatment adherence based on participant self-report, using a 4-day recall will be
summarized by means of descriptive statistics and frequency tabulations for both D/C/F/TAF FDC and the
INI + TAF/FTC ARV regimen.
Adherence rates will be reported according to the proportion of participants missing 0, 1, 2, 3 or 4 doses
using participant self-report 4-day recall at Weeks 4, 12, 24, 36, and 48.
Safety Analyses: For all safety endpoints, descriptive statistics will be used to summarize the endpoints.
The verbatim terms used in the case report form (CRF) by investigators to identify AEs will be categorized
according to system organ class and graded according to Division of Acquired Immunodeficiency
Syndrome (DAIDS).
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue study intervention due to an AE, or who experience a severe or a
SAE.
Laboratory data will be summarized by treatment arm and type of laboratory test. Reference ranges and
markedly abnormal results (specified in the SAP) will be used in the summary of laboratory data.
Descriptive statistics will be calculated foreach laboratory analyte and for changes from Screening/Baseline
at each scheduled time point. Laboratory abnormalities will be categorized according to analyte and graded
according to DAIDS.
Descriptive statistics of vital signs including temperature, pulse/heart rate, body weight, and blood pressure
(systolic and diastolic) [(supine)] values and changes from baseline will be summarized at each scheduled
time point. The percentage of participants with values beyond clinically important limits will be
summarized. Vital signs abnormalities will be categorized according to parameter and graded according to
DAIDS.
Physical examination findings will be summarized at each scheduled time point. Descriptive statistics will
be calculated at baseline and for observed values and changes from baseline at each scheduled time point.
Frequency tabulations of the abnormalities will be made.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
17
Patient-reported Outcomes Analyses: Descriptive statistics for absolute values will be calculated for each
PRO measure including BSQ-8D, HIV-SI, DAILY EATS, and PGIC and at each timepoint. In addition,
changes from baseline in the proportion of participants who have bothersome symptoms (scores of 2, 3 or
4) across all items of the HIV-SI at Weeks 24 and 48, changes from baseline in the proportion of participants
who have any symptoms (scores of 1, 2, 3 or 4) across all items of the HIV-SI at Weeks 24 and 48, and
changes from baseline in the scores on the BSQ-8D and proportion of participants who have no concern
(<19), mild concern (19-25), moderate concern (26-33) or marked concern (>33) with their body shape at
Weeks 24 and 48 and changes from baseline in the scores on the DAILY EATS at Weeks 24 and 48 will
be summarized. Association between treatment arm and each bothersome symptoms of the HIV-SI
adjusting for baseline variables at Weeks 24 will be calculated.  To understand meaningful change in scores
on PRO measures, PGIC-S will be used as an anchor to assess meaningful change scores for the DAILY
EATS in participants living with HIV.
Interim Analysis: An IA will be performed when approximately 60% of the initial 110 planned participants
have completed the Week 12 Visit and approximately 30% of participants have completed the Week 24
Visit. At that time, an unblinded SSR will be performed to ensure adequate power for the hypothesis testing
for the primary endpoint. More detail will be included in the IA statistical analysis plan (SAP).
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
18
1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
Abbreviations: ARV = antiretroviral; C = cobicistat; D = darunavir; F or FTC = Emtricitabine; INI = integrase inhibitor; QD = once a day;
TAF = Tenofovir Alafenamide
NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
24
2. 
INTRODUCTION
The primary study intervention is the darunavir/cobicistat/emtricitabine/tenofovir alafenamide
(D/C/F/TAF) fixed-dose combination (FDC). The first approval for D/C/F/TAF FDC was granted by
the European Commission on 25 September 2017. D/C/F/TAF is launched in Canada, United States
of America (USA), Hong Kong, Argentina, Macau, European Union (EU), Norway, Iceland, and
Liechtenstein. D/C/F/TAF FDC is a 4-agent tablet for oral once-daily use for the treatment of human
immunodeficiency virus (HIV)-1 infection in adults. This tablet contains the protease inhibitor (PI)
darunavir (D or DRV) (800 mg), the pharmacokinetic (PK) enhancer cobicistat (COBI or C) (150
mg), the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC or F) (200 mg), and
the tenofovir (TFV) prodrug tenofovir alafenamide (TAF) (10 mg). The D/C/F/TAF FDC
(SYMTUZA®) tablet was approved by the US Food and Drug Administration (FDA) as a complete
regimen for the treatment of HIV-1 infection in adults who have no prior antiretroviral (ARV)
treatment history or who are virologically-suppressed (human immunodeficiency virus type 1
ribonucleic acid [HIV-1 RNA] less than 50 copies per mL) on a stable ARV regimen for at least 6
months and have no known substitutions associated with resistance to DRV or TFV. 35,36
The integrase inhibitor (INI) class represents one of the newer mainstream classes of ARVs.
Currently, 4 INIs are FDA approved (bictegravir, dolutegravir, elvitegravir/cobicistat, and raltegravir)
to treat both treatment naïve and certain treatment experienced patients.4,17,20,34,36 Co-formulated
single tablet regimens containing dolutegravir, elvitegravir/cobicistat and bictegravir have
demonstrated favorable efficacy and tolerability profiles in registrational clinical studies.
Tenofovir alafenamide is an approved NRTI for use in combination with other antiretroviral agents
for the treatment of HIV-1 infection and is contained in a number of fixed dose combinations or single
tablet regimens.10,14,17,28
Participants not initially randomized to receive treatment with the D/C/F/TAF FDC will be assigned
to maintain treatment on their baseline ARV regimen. The baseline/control ARV regimen in this
study will be comprised of an INI + TAF/FTC for 24 weeks. After 24 weeks participants will switch
to D/C/F/TAF FDC for an additional 24 weeks.
For the most comprehensive non-clinical and clinical information regarding D/C/F/TAF FDC, refer
to the Investigators Brochure.19 For further information on the INI + TAF/FTC ARV regimens, please
refer to ARV-specific Prescribing Information.
The term “study intervention” throughout the protocol, refers to D/C/F/TAF FDC and
INI + TAF/FTC ARV regimen; otherwise, the individual study intervention names are used.
The term “sponsor” used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "subject".
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
25
2.1. 
Study Rationale
The primary goal of this study is to assess the safety and tolerability of D/C/F/TAF FDC in HIV-1
infected participants who are virologically-suppressed (HIV-1 RNA <50 copies/mL) and have
experienced rapid and significant body weight gain on an INI + TAF/FTC ARV regimen.
D/C/F/TAF FDC has been studied in treatment naïve HIV-1 infected patients as well as in
virologically-suppressed switch patients. 6,15,29
The efficacy and safety profile of D/C/F/TAF FDC was examined in 2 Phase 3 clinical studies
(AMBER; ClinicalTrials.gov: NCT02431247, a study assessing the efficacy and safety of D/C/F/TAF
FDC versus D/C+TDF/FTC in treatment naïve participants15 and EMERALD; ClinicalTrials.gov:
NCT02269917, a study assessing the efficacy and safety of switching to D/C/F/TAF FDC versus
staying on a multi-tablet boosted protease inhibitor (PI)-based regimen with TDF/FTC in
virologically-suppressed participants.30 In both studies, D/C/F/TAF FDC demonstrated non-inferior
efficacy and a safety profile consistent with that of the individual components of D/C/F/TAF.
D/C/F/TAF FDC at Week 48 in these studies demonstrated high virologic response rates, low
virologic failure/rebound rates, and there were no observed resistance-associated mutations (RAMs)
to DRV or TFV that developed in any participant. Importantly, the safety and tolerability of
D/C/F/TAF FDC was demonstrated from these studies, showing overall similar safety versus the
control groups through 48 weeks, and low rates (<2%) of discontinuations due to adverse events (AE).
In both studies, the change in body weight for participants starting or switching to D/C/F/TAF FDC
was minimal. The median change in body weight in AMBER and EMERALD was 1.5 kg and 1.3 kg,
respectively, at 48 weeks.
The INI class represents one of the newer mainstream classes of ARVs. Currently, 4 INIs are FDA
approved (bictegravir, dolutegravir, elvitegravir/cobicistat, and raltegravir) to treat both treatment
naïve and certain treatment experienced patients. Co-formulated single tablet regimens containing
dolutegravir, elvitegravir/cobicistat, or bictegravir, in combination with other antiretroviral agents
have demonstrated favorable efficacy and tolerability profiles in registrational clinical studies.
While this evidence has supported the placement of these regimens as part of Department of Health
and Human Services (DHHS) recommended treatment options for most patients, recent data has
suggested the INI class may be associated with significant body weight gain (≥3 kgover 6-12 months)
or increases in body mass index  (BMI).2 5,18,22 27  Initially, these data were limited to either case
reports,3 or retrospective observational analyses4,22,23 in both treatment naïve patients starting an
INI-based regimen and suppressed patients switching treatment to an INI-based regimen. Recently, a
larger randomized controlled study (NAMSAL ANRS 12313) compared a dolutegravir-based
regimen with a low-dose efavirenz based regimen for the treatment of HIV-1 infection in a
resource-limited setting. The results of this randomized, Phase 3 study showed the noninferiority of
a dolutegravir-based regimen to a low-dose efavirenz based regimen with regard to viral suppression
at week 48, however participants receiving treatment with DTG gained 5.0 kg compared to
participants receiving treatment with Efavirenz (EFV) who gained 3.0 kg.25
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
26
Some studies have suggested that these body weight changes may occur rapidly and be sizable.
Increases in body weight and/or BMI are of clinical concern, as obesity can lead to other metabolic
complications such as hypertension, changes in lipid parameters, and/or insulin resistance, all of
which ultimately may increase cardiovascular risk. Furthermore, it is not well understood how to
manage patients who experience rapid body weight gain on an INI-based regimen. There is therefore,
a need to conduct a well-controlled study of patients who experience rapid body weight gain on an
INI-based regimen to examine if switching off the INI-based regimen results in improvement in body
weight change and/or metabolic parameters. In a recent analysis of large electronic medical record
system, virologically-suppressed patients switching to boosted darunavir demonstrated smaller
increases in BMI relative to those patients who switched treatment to dolutegravir.26
As the association between INIs and changes in body weight is still being investigated, some have
also questioned the role of TAF and changes in body weight. In the ADVANCE study, treatment
naive participants were randomized to one of three regimens; dolutegravir with
emtricitabine/tenofovir alafenamide, dolutegravir with emtricitabine/tenofovir disoproxil fumarate,
or efavirenz/emtricitabine/tenofovir disoproxil fumarate. Over 96 weeks, participants randomized to
either of the dolutegravir based regimens gained significantly more body weight compared to those
randomized to the efavirenz based regimen. DTG + FTC/TAF 8 kg, DTG + FTC/TDF 5 kg,
EFV/FTC/TDF 2 kg, (p<0.001 versus EFV/FTC/TDF).39 In the AMBER study, participants initially
randomized to receive D/C+TDF/FTC, and subsequently switched to D/C/F/TAF FDC gained an
average of 1.24 kg after 48 weeks of treatment. Similar changes were observed in the EMERALD
study when participants switched from a TDF/FTC based regimen to D/C/F/TAF FDC (Data on file).
Given this possible relationship, the current study is designed to assess if body weight gain is slowed
or reversed in participants already taking an INI-based regimen with TAF, when switching off of the
INI to another TAF-based regimen.  Therefore, there is plausibility to changes in weight following a
switch from an INI to a boosted darunavir regimen in a randomized controlled trial.
TMC114FD2HTX4004 is a Phase 4, 48 week, randomized, active-controlled, open-label,
prospective, multicenter, study to evaluate the safety and tolerability ofswitching to D/C/F/TAF FDC
in HIV-1 infected individuals who are virologically-suppressed and have experienced rapid and
significant body weight gain on their current stable INI + TAF/FTC ARV regimen.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
27
2.2. 
Background
Nonclinical Studies
Based on the nonclinical program and clinical experience to date with all 4 compounds, no additive
or synergistic toxicology/safety effects are expected for the D/C/F/TAF FDC beyond the expected
PK boosting of DRV by COBI. In view of the established nonclinical profile for each of these
compounds, new nonclinical studies to support the D/C/F/TAF FDC have not been conducted. The
absence of nonclinical safety studies with the combination is in accordance with the FDA Guidance
for Industry on the Nonclinical Safety Evaluation of Drug or Combinations.38,37
Toxicology
In DRV repeat dose toxicity studies, the key target organs/systems identified in rodents were the
hematopoietic system, the blood coagulation system, liver, and thyroid. The effects observed in the
liver and thyroid were consistent with the liver enzyme inducing property of DRV. In a 6-month study
in rats, the combination of DRV with ritonavir showed a small increase in effect on red blood cell
(RBC) count parameters, liver and thyroid in rats. These hematological, liver, and thyroid changes
appeared to be not clinically relevant, as in clinical practice, DRV in combination with ritonavir or
COBI is generally safe and well tolerated in HIV-infected patients. In COBI repeat-dose toxicity rat
studies, the slight hepatocellular hypertrophy and follicular cell hyperplasia/hypertrophy in the
thyroid, and the 1 follicular cell carcinoma in the thyroid (1 high-dose male animal in the 26-week
study) are considered rodent-specific changes that are commonly seen with microsomal enzyme
inducers. Given the species specificity of the effects, these findings are not of concern for humans.
Minimal-to-mild increases in liver enzyme activities (alanine aminotransferase [ALT], bilirubin, and
alkaline phosphatase [ALP]) were observed in dogs after 4 weeks of dosing, and hepatocyte
vacuolation and/or hypertrophy were observed in the liver of dogs treated with COBI in 4-week and
39-week studies. These findings do not indicate a safety concern for D/C/F/TAF FDC.
Given the favorable toxicity profile of FTC and no evidence of overlapping toxicity, combinations
with other agents are unlikely to induce new toxicities caused by FTC or to exacerbate the known
toxicity of other agents (ie, DRV, COBI, and TAF).
For TAF, kidney (renal tubular karyomegaly and tubular degeneration) and bone (atrophy of
metaphyseal cancellous bone) were the primary target organs in rats and dogs. The potential of the 2
renally excreted compounds (FTC and TAF) to interact has not been tested but the combination of
FTC and TDF did not exacerbate the renal toxicity of TDF when tested in a 4-week dog study. While
the combination of D/C/F/TAF is not anticipated to have an effect on kidney function, monitoring of
creatinine along with other standard clinical pathology tests is performed in clinical studies of the
D/C/F/TAF FDC.
DRV, COBI, and FTC have not shown any potential for bone toxicity in chronic rat and dog toxicity
studies; thus, exacerbation of any TAF effects on bone is not expected with the D/C/F/TAF FDC.
There were no drug-related effects on ophthalmic exams or microscopic exams of ocular tissue
observed in repeat dose toxicity studies in mice (up to 13 weeks), rats (up to 26 weeks), and nonhuman
primates (4 weeks) or in the 4-week dog toxicology study. None of the 4 components had positive
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
28
findings in genotoxicity studies. The combination of the 4 components is not expected to have an
altered genotoxicity profile as compared with that of the individual agents. Carcinogenicity studies
with DRV showed an increase in the incidence of hepatocellular adenomas and carcinomas in mice
and rats and thyroid follicular cell adenomas in male rats, at exposure levels below those observed in
humans at the recommended therapeutic doses. These findings are considered to be of limited to no
relevance to humans based on mechanistic and epidemiological data. Although data is not available
for all 4 compounds, it is considered unlikely that combination dosing would change these profiles
based on the TAF chronic data and TDF carcinogenicity data.
No significant adverse effects have been observed in developmental toxicity studies with DRV,
COBI, FTC, or TAF. No significant adverse effects have been observed in fertility toxicity studies
with DRV, COBI, or FTC. The combination of the 4 components is not expected to have an altered
reproductive toxicity profile based on the TAF chronic data and TDF reproductive toxicity data.
Overall, DRV safety pharmacology studies did not detect any significant nonclinical safety signals.
The thorough QT studies (TMC114-C153, GS-US-216-0107 and GS-US-120-0107) were interpreted
as negative according to the E14 International Council for Harmonisation of Technical Requirements
for Pharmaceuticals for Human Use (ICH) Guidelines since the results demonstrated that
administration of respectively DRV/ ritonavir 1600/100 mg or 800/100 mg for 7 days, COBI doses
of 250 mg or 400 mg, and TAF doses of 25 or 125 mg are not associated with a clinically relevant
increase in QT interval.
Pharmacokinetic and Metabolism Profile
After oral administration, DRV was rapidly absorbed and eliminated. DRV is primarily eliminated
by metabolism via the cytochrome 3A (CYP3A) iso-enzyme. DRV was an inhibitor of CYP3A4 at
clinically relevant concentrations and showed a concentration-dependent effect on CYP3A4
induction in vitro. The exposure to DRV in humans was equivalent when co-administered with COBI
as a booster compared to ritonavir as a booster.
After moderate doses of COBI, oral bioavailability in nonclinical species was low due to metabolic
instability and resulting high first-pass elimination. COBI is a mechanism-based inactivators (MBIs)
of human CYP3A enzymes. Overall, the difference in boosting effect of COBI across species
including human is similar to that for ritonavir.
Emtricitabine shows high passive permeability. Emtricitabine does not undergo extensive first-pass
or systemic metabolism and is eliminated primarily by renal excretion of unchanged drug. The total
body clearance of FTC exceeds the glomerular filtration rate (GFR), suggesting the drug is actively
secreted by renal tubules into the urine. TAF is a prodrug of TFV which is intracellularly converted
to its pharmacologically active Tenofovir-diphosphate (TFV-DP) by cellular enzymes including
Hepatic extraction of TAF was estimated to be approximately 65% in dogs. Renal excretion is the
primary systemic route of elimination of TFV in all preclinical species tested.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
29
Clinical Studies
The development program of the D/C/F/TAF FDC product is based on 7 clinical studies conducted
with the D/C/F/TAF FDC, including 2 completed pivotal Phase 3 studies in anti-retroviral therapy
(ART)-naïve and ART-experienced, virologically-suppressed HIV-1 infected participants (Studies
TMC114FD2HTX3001 and TMC114IFD3013), 1 completed Phase 2 study in HIV-1 infected, ART-
naïve participants (Study GS-US-299-0102), and 4 completed Phase 1 studies in healthy participants
(Studies 
GS-US-299-0101, 
TMC114FD2HTX1001, 
TMC114FD2HTX1002, 
and
TMC114FD2HTX1004).
Human Pharmacokinetics
The PK properties of the D/C/F/TAF FDC have been evaluated in healthy adult volunteers and in
HIV-1 infected participants. DRV is primarily metabolized by CYP3A. COBI is an MBI of CYP3A,
thereby enhancing the plasma concentrations of DRV considerably, to a similar extent as another PK
booster, ritonavir. FTC is a nucleoside analogue of 2’-deoxycytidine, which is phosphorylated by
cellular enzymes to form FTC triphosphate. TAF is a phosphonoamidate prodrug of TFV
(2’-deoxyadenosine monophosphate analogue) and intracellular TFV is subsequently phosphorylated
to the pharmacologically active metabolite TFV-DP. Once daily dosing of the D/C/F/TAF
800/150/200/10 mg FDC tablet in healthy volunteers resulted in similar drug exposures as the
individual components. For information on absorption, distribution, metabolism, and elimination of
the components of the D/C/F/TAF FDC tablets.19
Efficacy/Safety Studies
Below, an overview is provided of the clinical data that are relevant to the stage of clinical
development of the D/C/F/TAF FDC: ie, Week-48 results from the pivotal Phase 3 studies in
antiretroviral treatment (ART)-naïve (Study TMC114FD2HTX3001) and ART-experienced,
virologically-suppressed participants (Study TMC114IFD3013), data on use of DRV/COBI in
pregnant HIV-1 infected women, updated drug-drug interactions, information on marketing
experience and updated reference safety information.
Efficacy
The Week-48 results from the 2 pivotal Phase 3 TMC114FD2HTX3001 and TMC114IFD3013
studies with the D/C/F/TAF FDC tablet demonstrate the following:
High response rate (defined as HIV-1 RNA <50 copies/mL; Food and Drug Administration
[FDA]-defined snapshot approach) comparable to a control treatment in the randomized,
active-controlled, double-blind, Phase 3 Study TMC114FD2HTX3001 in HIV-1 infected, ART-naïve
participants: in the intent-to-treat (ITT) population, the proportion of virologic responders at Week
48 was 91.4% with the D/C/F/TAF FDC versus 88.4% with the control treatment
(DRV/COBI+F/TDF).  Very low virologic rebound rate (2.5% with the D/C/F/TAF FDC versus 2.1%
with the control treatment consisting of a boosted PI combined with F/TDF) and high response rate
(94.9% with the D/C/F/TAF FDC versus 93.7% with the control treatment) at Week 48 in the
randomized, active-controlled, open-label, Phase 3 Study TMC114IFD3013 in HIV-1 infected,
ART-experienced, 
virologically-suppressed 
(HIV-1 
RNA 
<50 copies/mL) 
participants.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
30
 Immunologic benefits of treatment with the D/C/F/TAF FDC were demonstrated by increases in
CD4+ cell counts and were similar to control treatment. In the Phase 3 studies with the D/C/F/TAF
FDC, no genotypic or phenotypic resistance was observed against DRV and TAF. Development of
resistance to FTC was rare (1 participant treated with D/C/F/TAF developed an M184I/V mutation,
conferring resistance to FTC).
Safety and Tolerability
Treatment with the D/C/F/TAF FDC was generally safe and well tolerated.  No new adverse drug
reactions (ADRs) were identified in the Week-48 analysis of the Phase 3 studies compared to the
previously identified ADRs.19
2.3. 
Benefit-Risk Assessment
2.3.1. 
Benefits for Study Participation
The evidence for a positive benefit-risk balance for the D/C/F/TAF FDC is based on the favorable
benefit-risk balance of the single agents (ie, DRV, COBI, FTC, and TAF), the FDCs DRV/COBI and
FTC/TAF, and the completed and ongoing clinical studies with the D/C/F/TAF FDC.
Based on a review of nonclinical and clinical data, epidemiologic information, and scientific
literature, no new data have been identified that modify the benefit-risk profile
ofthe D/C/F/TAF FDC during the drug safety update report (DSUR) reporting period.11 The
D/C/F/TAF FDC continues to demonstrate a favorable benefit-risk profile. The sponsor will continue
to monitor suspect adverse reactions in association with the use of the D/C/F/TAF FDC. Continuous
safety monitoring will ensure that updated safety information is available. More detailed information
about the known and expected benefits and risks of D/C/F/TAF FDC tablet may be found in the
Investigator’s Brochure.19
2.3.2. 
Benefit-Risk Assessment Considerations for Study Participation
Increases in body weight and/or BMI are of clinical concern, as obesity can lead to other metabolic
complications such as hypertension, changes in lipid parameters, and/or insulin resistance, all of
which 
ultimately 
may 
increase 
cardiovascular 
risk. 
This 
study 
aims 
to 
switch
virologically-suppressed participants who have gained significant weight on an INI + TAF/FTC
regimen to D/C/F/TAF FDC to understand if this weight gain can be attenuated or reversed.
The DHHS guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV
acknowledge that switching virologically-suppressed patients to a new regimen may be prompted by
AEs, such as weight gain for example. The Panel recommends carefully reviewing patient’s antiviral
treatment history and or available resistance test results to ensure the new regimen will maintain
virologic suppression.
As part of this study, participants must not have had prior virologic failure on a darunavir based
regimen and have no known darunavir resistance associated mutations. As D/C/F/TAF FDC has
demonstrated high virologic response rates and low virologic rebound rates in virologically-
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
31
suppressed patients, and the proposed use of D/C/F/TAF FDC in this study is similar to that of study
TMC114IFD3013, the risk of deleterious virologic outcomes is very likely minimal.
When switching treatments there is always the possibility of new onset adverse drug reactions.  Based
on data from 2 pivotal clinical studies TMC114FD2HTX3001 and TMC114IFD3013, the overall
safety profile of D/C/F/TAF FDC has been well described. The most common adverse drug reactions
(occurring at rates ≥1/10) are diarrhea, headache, and rash. Participants will be monitored clinically
for AEs, and undergo relevant laboratory testing as outlined in the Schedule of Activities (SoA).
It is unknown if switching to D/C/F/TAF FDC will yield clinically relevant changes in body weight
in patients who have gained weight on an INI + TAF/FTC ARV regimen.  In study TMC114IDF3013,
participants switching from a boosted-protease based regimen in combination with tenofovir
disoproxil fumarate/emtricitabine to D/C/F/TAF FDC experienced a median increase in body weight
of 1.3 kg through 48 weeks, while those remaining on boosted-protease based regimen in combination
with tenofovir disoproxil fumarate/emtricitabine experienced a median increase in body weight of 0.5
kg. It is possible that TAF may contribute to changes in body weight. In study
TMC114FD2HTX3001, treatment naive participants receiving D/C/F/TAF FDC experienced a
median increase in body weight of 1.5 kg versus 0.0 kg for those participants assigned to
darunavir/cobicistat in combination with tenofovir disoproxil fumarate/emtricitabine. As this study
population will already be on a regimen containing TAF, the risk of additional weight gain associated
with TAF is considered minimal.
Considering the measures taken to minimize risk to participants of this study, the potential risks
identified in association with D/C/F/TAF FDC are justified by the potential benefits that may be
afforded to virologically-suppressed HIV-1 infected participant experiencing rapid body weight gain
with an INI + TAF/FTC ARV regimen.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
32
3. 
OBJECTIVES AND ENDPOINTS
3.1. 
Week 24 Objectives and Endpoints
Objectives 
Endpoints
Primary
 To assess the percent change in body 
weight when switching to D/C/F/TAF
FDC 
(Immediate 
Switch 
Arm)
compared to continuing the current INI
+ TAF/FTC ARV regimen (Delayed
Switch 
Arm) 
in 
virologically-
suppressed 
(HIV-1 
RNA 
<50
copies/mL) HIV-1 infected participants
who have experienced rapid and
significant body weight gain
 Percent change from Baseline in body weight at Week 24
Secondary
Metabolic
 To assess changes in body weight when 
switching 
to 
D/C/F/TAF 
FDC 
(Immediate Switch Arm) compared to 
continuing the current INI + TAF/FTC 
ARV regimen (Delayed Switch Arm) 
 Change from Baseline in absolute body weight at Week 24
 Proportion of participants with % change in body weight >3%
at Week 24
 Proportion of participants with % change in body weight >5%
at Week 24
 Change from Baseline in BMI at Week 24
 To assess changes in body composition 
when  switching to D/C/F/TAF FDC 
(Immediate Switch Arm) compared to 
continuing the current INI + TAF/FTC
ARV regimen (Delayed Switch Arm)
 Change from Baseline in body composition as measured by
DEXA scan at Week 24
 Change from Baseline in waist circumference at Week 24
 To assess change in blood pressure 
when switching to D/C/F/TAF FDC
(Immediate Switch Arm) compared to
continuing the current INI + TAF/FTC
ARV regimen (Delayed Switch Arm)
 Change in SBP and DBP from Baseline at Week 24
 To assess changes in clinical laboratory 
tests when switching to D/C/F/TAF 
FDC 
(Immediate 
Switch 
Arm) 
compared to continuing the current INI
+ TAF/FTC ARV regimen (Delayed
Switch Arm)
 Change from Baseline in fasting lipids at Week 24
 Change from Baseline in fasting glucose at Week 24
 Change from Baseline in HOMA-IR at Week 24

Change from Baseline in HbA1c at Week 24

Change from Baseline in leptin and adiponectin at Week 24
 To assess changes in liver biomarkers 
when switching to D/C/F/TAF FDC 
(Immediate Switch Arm) compared to 
continuing the current INI + TAF/FTC 
ARV regimen (Delayed Switch Arm) 
 Change from Baseline in the proportion of participants with
advanced fibrosis according to the NAFLD fibrosis score at
Week 24
 Change from Baseline in the proportion of participants at high
risk of NASH according to the HAIR score at Week 24
 To assess changes in concomitant 
medications of interest (including anti- 
hypertensive, anti-hyperglycemic, and 
lipid lowering agents) when switching 
to D/C/F/TAF FDC (Immediate Switch
Arm) compared to continuing the 
current INI + TAF/FTC ARV regimen 
(Delayed Switch Arm) 
 Proportion of participants having a dose-reduction or complete
withdrawal of anti-hypertensive, anti-hyperglycemic, or lipid
lowering agents in the Immediate Switch Arm or Delayed
Switch Arm from Baseline to Week 24
 Proportion of participants initiating an anti-hypertensive, anti-
hyperglycemic, or lipid lowering agent in the Immediate Switch
Arm or Delayed Switch Arm from Baseline to Week 24
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
33
Objectives 
Endpoints
Safety
 To evaluate the safety of switching to 
D/C/F/TAF FDC (Immediate Switch 
Arm) compared to continuing the 
current INI + TAF/FTC ARV regimen 
(Delayed Switch Arm) 
 Incidence of any Grade AEs (related and not related) through
Week 24
 Incidence of Grade 3 and 4 AEs (related and not related)
through Week 24
 Incidence of discontinuations due to AEs through Week 24
 Incidence of SAEs (related and not related) through Week 24
 Change from Baseline in clinical laboratory tests through Week
24
 Incidence of Grade 3 and 4 laboratory abnormalities through
Week 24
Efficacy
 To evaluate the virologic outcomes 
when switching to D/C/F/TAF FDC 
(Immediate Switch Arm) compared to 
continuing the current INI + TAF/FTC 
ARV regimen (Delayed Switch Arm) 
 Proportion of participants with confirmed virologic rebound
through Week 24
 Proportion of participants with virologic response (HIV-1
RNA<50 copies/mL) at Week 24 according to the FDA
snapshot algorithm
 Proportion of participants with virologic failure (HIV-1 RNA
≥50 copies/mL) at Week 24 according to the FDA snapshot
algorithm
 Proportion of participants having virologic response (HIV-1
RNA<200 copies/mL) at Week 24 according to the FDA
snapshot algorithm
 Proportion of participants having virologic failure (HIV-1 RNA
≥200 copies/mL) at Week 24 according to the FDA snapshot
algorithm
 To evaluate immunological changes 
when switching to D/C/F/TAF FDC
(Immediate Switch Arm) compared to
continuing the current INI + TAF/FTC
ARV regimen (Delayed Switch Arm)
 Change from Baseline in CD4+ cell count at Week 24
Resistance
 To assess viral resistance in participants 
with confirmed HIV-1 RNA rebound 
for participants switching to D/C/F/TAF 
FDC 
(Immediate 
Switch 
Arm) 
compared to continuing the current INI 
+ TAF/FTC ARV regimen (Delayed 
Switch Arm) 
 Proportion of participants with pre-baseline PR, RT, and INI
RAMs based on historical genotypes
 Incidence of observed genotypic and phenotypic ARV
resistance for participants meeting HIV-1 RNA rebound criteria
through Week 24
 Proportion of participants with newly identified post-baseline
RAMs and phenotypic resistance compared to pre-baseline
resistance tests when available, upon meeting confirmed
virologic rebound through Week 24
PROs
 To assess changes in the burden of 
common symptoms associated with 
HIV 
treatment 
or 
disease 
for 
participants switching to D/C/F/TAF 
FDC 
(Immediate 
Switch 
Arm) 
compared to continuing the current INI 
+ TAF/FTC ARV regimen (Delayed 
Switch Arm) 
 Change from Baseline in the proportion of participants who
have bothersome symptoms (scores of 2, 3 or 4) across all items
of the HIV-SI at Week 24
 Change from Baseline in the proportion of participants who
have any symptoms (scores of 1, 2, 3 or 4) across all items of
the HIV-SI at Week 24
 Association between treatment arm and each bothersome
symptom of the HIV-SI adjusting for Baseline variables at
Week 24
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
34
Objectives 
Endpoints
 To describe responses on the PGIC in 
participants switching to D/C/F/TAF
FDC (Immediate Switch Arm) and in
participants continuing the current INI
+ TAF/FTC ARV regimen (Delayed
Switch Arm)
 PGIC at Week 24
Adherence
 To evaluate adherence in participants 
switching 
to 
D/C/F/TAF 
FDC 
(Immediate Switch Arm) compared to
continuing the current INI + TAF/FTC
ARV regimen (Delayed Switch Arm)
 Adherence rates by participant self-report using 4-day recall at
Weeks 4, 12 and 24
Exploratory
Exploratory clinical biomarker
 To assess changes in alpha-melanocyte 
stimulating hormone when switching to 
D/C/F/TAF FDC (Immediate Switch
Arm) compared to continuing the
current INI + TAF/FTC ARV regimen
(Delayed Switch Arm)
 Change from Baseline in alpha melanocyte-stimulating
hormone at Week 24
Exploratory PROs
 To assess changes in eating-related 
concepts (hunger, appetite, cravings, 
and satiety) for participants switching to
D/C/F/TAF FDC (Immediate Switch
Arm) compared to continuing the
current INI + TAF/FTC ARV regimen
(Delayed Switch Arm)
 Change from Baseline in the scores on the DAILY EATS at
Week 24
 To assess changes in concerns about 
body shape for participants switching to 
D/C/F/TAF FDC (Immediate Switch 
Arm) compared to continuing the 
current INI + TAF/FTC ARV regimen 
(Delayed Switch Arm)
 Change from Baseline in the scores on the BSQ-8D at Week 24
 Change from Baseline in the proportion of participants who
have no concern (<19), mild concern (19-25), moderate concern
(26-33) or marked concern (>33) with their body shape at Week
24
Abbreviations: AE: adverse event, ARV: antiretroviral, BMI: body mass index, BSQ 8D: body shape questionnaire, D/C/F/TAF FDC:
Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Fixed dose Combination, DBP: diastolic blood pressure, DEXA: dual energy X ray
absorptiometry, FDA: Food Drug Administration, FTC: emtricitabine, HAIR: hypertension, age, insulin, resistance, HIV 1 RNA: human
immunodeficiency virus type 1 ribonucleic acid, HIV SI: HIV Symptom Index, HOMA IR: homeostatic model assessment of insulin resistance,
INI: integrase, NAFLD: non alcoholic fatty liver disease, NASH: Nonalcoholic fatty liver disease, PGIC: patient global impression of change, PR:
protease, PROs: patient reported outcomes, RT: reverse transcriptase, SAE: serious adverse event, SBP: systolic blood pressure.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
35
3.2. 
Week 48 Objectives and Endpoints
Objectives 
Endpoints
Secondary
Metabolic
 To assess the percent change in body
weight when switching to D/C/F/TAF
FDC (Immediate Switch Arm)

Percent change from Baseline in body weight at Week 48
 To assess change in body weight when
switching 
to 
D/C/F/TAF 
FDC
(Immediate Switch Arm)

Change from Baseline in absolute body weight at Week 48

Proportion of participants with % change in body weight
>3% at Week 48

Proportion of participants with % change in body weight
>5% at Week 48

Change from Baseline in BMI at Week 48

To assess changes in body composition
when  switching to D/C/F/TAF FDC
(Immediate Switch Arm)

Change from Baseline in body composition as measured by
DEXA scan at Week 48

Change from Baseline in waist circumference at Week 48

To assess change in blood pressure when
switching 
to 
D/C/F/TAF 
FDC
(Immediate Switch Arm)

Change in SBP and DBP from Baseline at Week 48

To assess changes in clinical laboratory
tests when switching to D/C/F/TAF FDC
(Immediate Switch Arm)

Change from Baseline in fasting lipids at Week 48

Change from Baseline in fasting glucose at Week 48

Change from Baseline in HOMA-IR at Week 48

Change from Baseline in HbA1c at Week 48

Change from Baseline in leptin and adiponectin at Week 48
 To assess changes in liver biomarkers
when switching to D/C/F/TAF FDC
(Immediate Switch Arm)

Change from Baseline in the proportion of participants with
advanced fibrosis according to the NAFLD fibrosis score at
Week 48

Change from Baseline in the proportion of participants at
high risk of NASH according to the HAIR score at Week 48
 To assess changes in concomitant
medications of interest (including anti-
hypertensive, anti-hyperglycemic, and
lipid lowering agents) when switching to
D/C/F/TAF FDC (Immediate Switch
Arm)

Proportion of participants having a dose-reduction or
complete 
withdrawal 
of 
anti-hypertensive, 
anti-
hyperglycemic, or lipid lowering agents in the Immediate
Switch Arm from Baseline to Week 48

Proportion of participants starting an anti-hypertensive, anti-
hyperglycemic, or lipid lowering agent in the Immediate
Switch Arm from Baseline to Week 48
Safety
 To evaluate the safety of switching to
D/C/F/TAF FDC (Immediate Switch
Arm)

Incidence of any Grade AEs (related and not related) through
Week 48

Incidence of Grade 3 and 4 AEs (related and not related)
through Week 48

Incidence of discontinuations due to AEs through Week 48

Incidence of SAEs (related and not related) through Week 48

Change from Baseline in clinical laboratory tests through
Week 48

Incidence of Grade 3 and 4 laboratory abnormalities through
Week 48
Efficacy
 To evaluate the virologic outcomes when
switching 
to 
D/C/F/TAF 
FDC
(Immediate Switch Arm)

Proportion of participants with confirmed virologic rebound
through Week 48
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
36
Objectives 
Endpoints
 Proportion of participants with virologic response (HIV-1
RNA<50 copies/mL) at Week 48 according to the FDA
snapshot algorithm
 Proportion of participants with virologic failure (HIV-1 RNA
≥50 copies/mL) at Week 48 according to the FDA snapshot
algorithm
 Proportion of participants having virologic response (HIV-1
RNA<200 copies/mL) at Week 48 according to the FDA
snapshot algorithm
 Proportion of participants having virologic failure (HIV-1
RNA ≥200 copies/mL) at Week 48 according to the FDA
snapshot algorithm
 To evaluate immunological changes 
when switching to D/C/F/TAF FDC
(Immediate Switch Arm)
 Change from Baseline in CD4+ cell count at Week 48
Resistance
 To assess viral resistance in participants 
with confirmed HIV-1 RNA rebound 
when switching to D/C/F/TAF FDC  
 Incidence of observed genotypic and phenotypic ARV
resistance for participants meeting HIV-1 RNA rebound
criteria through Week 48

Proportion of participant with newly identified post-baseline
RAMs and phenotypic resistance compared to pre-baseline
resistance tests when available, upon meeting confirmed
virologic rebound through Week 48
PROs
 To assess changes in the burden of
common symptoms associated with HIV
treatment or disease for participants
switching 
to 
D/C/F/TAF 
FDC
(Immediate Switch Arm)

Change from Baseline in the proportion of participants who
have bothersome symptoms (scores of 2, 3 or 4) across all
items of the HIV-SI at Week 48

Change from Baseline in the proportion of participants who
have any symptoms (scores of 1, 2, 3 or 4) across all items of
the HIV-SI at Week 48
 To describe responses on the PGIC in
participants switching to D/C/F/TAF
FDC (Immediate Switch Arm)

PGIC at Week 48
Adherence
 To evaluate adherence in participants
switching 
to 
D/C/F/TAF 
FDC
(Immediate Switch Arm)
 Adherence rates by participant self-report using 4-day recall
at Weeks 36 and 48
Exploratory
Exploratory clinical biomarker
 To 
assess 
changes 
in 
alpha
melanocyte-stimulating hormone when
switching 
to 
D/C/F/TAF 
FDC
(Immediate Switch Arm)
 Change from Baseline in alpha melanocyte-stimulating
hormone at Week 48
Exploratory PROs
 To assess changes in eating-related
concepts (hunger, appetite, cravings, and
satiety) for participants switching to
D/C/F/TAF FDC (Immediate Switch
Arm)
 Change from Baseline in the scores on the DAILY EATS at
Week 48
 To assess changes in concerns about body
shape for participants switching to
 Change from Baseline in the scores on the BSQ-8D at Week
48
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
37
Objectives 
Endpoints
D/C/F/TAF FDC (Immediate Switch 
Arm) 
 Change from Baseline in the proportion of participants who
have no concern (<19), mild concern (19-25), moderate
concern (26-33) or marked concern (>33) with their body
shape on the BSQ-8D at Week 48
Abbreviations: AE: adverse event, ARV: antiretroviral, BMI: body mass index, BSQ 8D: body shape questionnaire, D/C/F/TAF FDC:
Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Fixed dose Combination, DBP: diastolic blood pressure, DEXA: dual energy X ray
absorptiometry, FDA: Food Drug Administration, FTC: emtricitabine, HAIR: hypertension, age, insulin, resistance, HIV 1 RNA: human
immunodeficiency virus type 1 ribonucleic acid, HIV SI: HIV Symptom Index, HOMA IR: homeostatic model assessment of insulin resistance,
INI: integrase, NAFLD: non alcoholic fatty liver disease, NASH: Nonalcoholic fatty liver disease, PGIC: patient global impression of change, PR:
protease, PROs: patient reported outcomes, RT: reverse transcriptase, SAE: serious adverse event, SBP: systolic blood pressure.
3.3. 
Consistency of Effect of Baseline to Week 24 (Immediate Switch) versus
Week 24 to Week 48 (Delayed Switch)
Additional secondary objectives/endpoints will evaluate the consistency of effect on outcomes from
Baseline to Week 24 in the Immediate Switch Arm versus the Week 24 to Week 48 in the Delayed
Switch Arm. The endpoints for the Delayed Switch Arm from Week 24 to Week 48 are the same as
for the Immediate Switch to Week 24. Comparison will be made descriptively to evaluate the
consistence of outcomes between these two arms for each endpoint.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
Based on the primary endpoint, the percent change in body weight at Week 24 from baseline in the
Immediate Switch Arm is less than that of the Delayed Switch Arm (INI + TAF/FTC ARV).
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a randomized, 48 week, active-controlled, open-label, prospective, multicenter, Phase 4 study
to evaluate the safety and tolerability of switching to D/C/F/TAF FDC compared to continuing the
current INI + TAF/FTC ARV regimen in virologically-suppressed HIV-1 infected adult participants
who have experienced rapid and significant body weight gain while receiving an INI + TAF/FTC
ARV regimen.
Approximately 110 participants will be included in this study. A maximum enrollment of
approximately 70% male participants will be utilized to ensure adequate recruitment of female
participants. A maximum enrollment of approximately 70% non-black participants will be utilized to
ensure adequate recruitment of diverse races. Eligible participants are to:
 have documented HIV-1 infection currently treated with a stable ARV regimen consisting of an
INI combined with TAF/FTC for ≥6 consecutive months preceding the screening visit,
 body mass index (BMI) of ≥18 kg/m2 at the time of starting an INI + TAF/FTC ARV regimen,
 have a rapid and significant weight gain, defined as a ≥10% increase in body weight within a 36-
month time period prior to screening and while on the current INI + TAF/FTC ARV regimen,
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
38
 be virologically-suppressed, with at least 1 plasma HIV-1 RNA measurement <50 copies/mL
occurring between 12 and 2 months prior to screening while being on the stable INI + TAF/FTC
ARV regimen and having HIV-1 RNA<50 copies/mL at the screening visit,
Not have had previous failure on DRV treatment or known documented history of ≥1 DRV resistance
associated mutations (RAMs).
The study will consist of 3 phases:
 Screening (approximately 30 days [up to a maximum of 6 weeks])
 Open-Label Treatment (48 weeks)
 Follow-up (for any participant who has an ongoing AE or serious adverse event (SAE) at the time
of his/her last study visit).
Screening Phase
The informed consent form (ICF) must be signed before any study-specific procedures at the start of
the Screening Phase. After obtaining the ICF from the participant, selection criteria will be reviewed
to confirm the participant’s eligibility. At baseline (Day 1), participants who meet all eligibility
criteria will be randomized in a 1:1 ratio to 1 of the following 2 treatment arms. Randomization will
be stratified by sex (Male or Female) and race (Black/African American or Non-Black/African
American) at Baseline. All enrolled participants will be assigned randomized treatments in an
open-label manner.
 D/C/F/TAF FDC Arm (Immediate Switch): Switch to a regimen of DRV 800 mg + COBI
150 mg + FTC 200 mg + TAF 10 mg FDC once daily, (n 55) for 48 weeks;
 Active-Control Arm (Delayed Switch):Continue current INI + TAF/FTC ARV regimen, (n 55)
for 24 weeks. After 24 weeks participants will switch to a regimen of DRV 800 mg + COBI 150
mg + FTC 200 mg + TAF 10 mg FDC once daily for an additional 24 weeks.
Treatment Phase
Participants randomized to the Immediate Switch Arm must start D/C/F/TAF FDC within 24 hours
of the Baseline visit and will continue to receive D/C/F/TAF treatment for a total of 48 weeks.
Participants randomized to the Delayed Switch Arm, will continue their current INI + TAF/FTC ARV
regimen for 24 weeks. After Week 24, all participants in the Delayed Switch Arm will receive the
D/C/F/TAF FDC tablet and will be followed for an additional 24 weeks.
Participants will return for study visits at Weeks 4, 12, 24, 36, and 48. Additionally, participants
randomized to the Delayed Switch Arm will have a study visit at Week 28 (ie, 4 weeks after switching
from the INI + TAF/FTC ARV regimen to D/C/F/TAF FDC).
Key metabolic assessments include body weight measurements, body composition assessed via dual-
energy x-ray absorptiometry (DEXA) scan, waist circumference measurements, vital sign
measurements, select clinical laboratory tests (including fasting lipids, fasting glucose, homeostatic
model assessment of insulin resistance [HOMA-IR], HbA1c, leptin, adiponectin), and liver
biomarkers.  Key efficacy assessments include HIV-1 viral load, CD4+/CD8+ cell count, and HIV-1
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
39
genotype/phenotype resistance testing (using PhenoSense GT® Plus Integrase), if necessary (refer to
Section 8.1).  Key safety assessments will include AEs, physical examinations, standard clinical
laboratory tests, and pregnancy testing. Concomitant medications will be recorded. D/C/F/TAF FDC
study intervention  accountability and reasons for non-adherence will be monitored (refer to
Section 8.2). Patient Reported outcomes (body shape questionnaire [BSQ-8D], DAILY EATS, HIV-
Symptom Index [HIV-SI], and patient global impression of change [PGIC including PGIC-S]) will
be completed.
Unscheduled visits can be conducted as needed based on individual tolerability issues, or virologic
reasons (ie, suspected virologic rebound) that occur between scheduled visits.
HIV-1 genotypic and phenotypic resistance testing (PhenoSense GT® Plus Integrase) will be
performed for participants with confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥200
copies/mL at a scheduled or unscheduled visit) and a HIV-1 RNA >400 copies/mL at the time of
confirmed rebound or at later timepoints. The confirmatory testing should be conducted 2 to 4 weeks
after the initial HIV-1 RNA value ≥200 copies/mL. If genotypic/phenotypic resistance to study
intervention is determined, study intervention may be discontinued, and the participant will be
referred for continued medical care outside of the study if the decision is made to discontinue study
intervention.
Plasma concentrations of DRV and COBI may be determined in participants experiencing virologic
rebound using stored blood samples collected throughout the study, if deemed necessary. Plasma
concentrations of INIs for the Delayed Switch Arm may be determined in participants experiencing
virologic rebound using stored blood samples collected throughout the study, if deemed necessary.
The end of the study is defined as completion of the last data collection visit for the last participant
participating in the study. For the purpose of the primary analysis, a participant will be considered to
have completed the study if data collection as required per protocol through the complete course of
24 weeks of ART has been completed. The primary analysis of this study will be performed once all
participants have completed the Week 24 visit or discontinued earlier. An interim analysis (IA) will
be performed when approximately 60% of the planned 110 participants have completed the Week 12
visit and approximately 30% of participants have completed the Week 24 visit to assess sample size
re-estimation (SSR) unblinded to ensure adequate power for the hypothesis testing for the primary
endpoint.
Early Study Intervention Discontinuation (ESID): Participants who prematurely discontinue study
intervention but have not withdrawn consent will be required to complete ESID assessments as soon
as possible but within no later than 1 week of discontinuing study intervention.
At the end of the study (or at ESID), participants will resume routine clinical care with the care
provider who will determine their future care. In anticipation of transitioning the participant to routine
clinical care at the end of the study (or early discontinuation), the investigator should take steps to
ensure that the participants’ ART is not interrupted.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
40
Follow-up Phase
A follow-up visit is required for any participant who has an ongoing AE or SAE after completion of
the last study-related visit (unless consent is withdrawn). These participants are required to return to
the site 30 days (±7 days) after completion of the last study-related visit (unless consent is withdrawn)
and complete all procedures indicated in the Schedule of Activities (SoA).
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
The primary goal of this study is to assess the tolerability of D/C/F/TAF FDC in HIV-1 infected
participant who are virologically-suppressed suppressed (HIV-1 RNA <50 copies/mL) and have
experienced rapid and significant body weight gain on an INI + TAF/FTC ARV regimen.
Blinding, Control, Study Phase/Periods, Intervention Arms
An active control will be used to determine treatment effects in this study. Continuation of the current
ARV regimen consisting of an INI + TAF/FTC was chosen as the active control as this study evaluates
the impact of switching from an INI + TAF/FTC ARV regimen to D/C/F/TAF FDC on body weight
relative to continuation of the baseline INI + TAF/FTC ARV regimen. Given possible changes in
weight when switching ARV regimens, it is important to understand the implications of not switching
regimens and any difference in weight change among a control group.
This study will not be blinded as eligible participants may be receiving multiple INI + TAF/FTC
based ARV regimens. Some regimens may be multiple tablet regimens or single tablet regimens of
different sizes. Creating identical placebos for all possible regimens included in the active control
arm is not considered appropriate because this would result in an increased pill burden, loss of
convenience, and ease of adherence for participants who are accustomed to a simplified regimen.
Randomization will be used to minimize bias in the assignment of participants to treatment arms, to
increase the likelihood that known and unknown participant attributes (eg, demographic or baseline
characteristics) are evenly balanced across treatment arms, and to enhance the validity of statistical
comparisons across treatment arms.
Two stratification factors (sex [Male or Female] and race [Black/African American or
Non-Black/African American] at Baseline) will be applied in the randomization process.  These
stratification factors were chosen as previous studies have identified these populations being at an
increased risk of weight gain while taking an INI-based ARV regimen, therefore a need to ensure
equal distribution across the treatment arms.
Primary Analysis Time Point and Study Period
As the primary aim of this study is to assess the safety and tolerability of switching from an
INI + TAF/FTC regimen to D/C/F/TAF, the primary analysis will occur at Week 24. This time point
was chosen to describe comparative tolerability across treatment arms based on findings from
TMC114IDF3013. In this Phase 3 randomized controlled trial, of patients switching to D/C/F/TAF
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
41
from a Boosted-PI based regimen with TDF/FTC, 10 participants discontinued D/C/F/TAF
prematurely due to adverse events through Week 24. The discontinuation rate due to adverse events
did not increase significantly over the course of 48 weeks, as only one additional participant
discontinued due to adverse events between Week 24 and Week 48.  Furthermore, of 625 total adverse
events reported through Week 48, 543 adverse events were reported during the first 24 weeks of
treatment, indicating that most adverse events following a switch in ARV treatment occur within 24
weeks of switching.  Significant changes in parameters such as changes in lipids, renal and bone
makers were also detected as early as Week 24, providing further rationale that a 24-week time period
will be sufficient to observe any changes in overall tolerability across the treatment arms.
As body weight can fluctuate, or additional changes occur over longer periods of time, a treatment
duration up to 48 weeks was chosen to evaluate the sustained efficacy, tolerability and safety of the
D/C/F/TAF FDC single-tablet regimen in the selected population. The study design also permits
participants initially randomized to remain on their INI + TAF/FTC ARV regimen to switch to
D/C/F/TAF after 24 weeks. This 48-week design allows for an analysis to determine if changes in
metabolic endpoints exhibit a consistent effect after these patients switch to D/C/F/TAF over 24
weeks relative to the Immediate Switch Arm over the first 24 weeks of the study period.
To assure continued follow-up of the study participants and gain further safety information,
participants who prematurely discontinue or change study treatment during the treatment phase will
be asked to remain in the study and attend the ESID visit and 30-day follow-up (FU) visit, if
applicable.
Toxicity Management
The combination of D/C/F/TAF is not anticipated to exacerbate known toxicities or lead to new
toxicities (see Section 2.3, Benefit Risk Assessment). Measures and guidelines for the monitoring
and management of specific toxicities with DRV, COBI, FTC, TAF or TDF, and concomitant ARVs
are included in this protocol (see Section 8.2.6, Toxicity Management). The presented toxicity
management guidelines are applicable throughout the entire study, including the screening phase and
the 48-week treatment phase.
Safety and Efficacy Monitoring
All eligible participants for this study are virologically-suppressed and all study treatments utilized
in this study are FDA approved for use in this population of patients. Given this there is no need to
re-assess the risk/benefit profile of the product outside of the safety monitoring procedures outlined
in this protocol.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
42
4.2.1. 
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during the
study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits,
and potential AEs of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected in this study is approximately 261 mL.
This study involves radiation exposure from 3 whole body DEXA scans. As part of everyday living,
everyone is exposed to a small amount of background radiation that comes from soil, rocks, outer
space, and within the body itself. The radiation dose for all DEXA scans that the participant will
receive in this study is expected to be about 0.03 mSv or equivalent to approximately 4 days of
background radiation in the United States (US). The risks from these doses are small. This radiation
exposure may not be necessary for the participants’ medical care, but it is necessary to obtain the
research information desired.
4.3. 
Justification for Dose
D/C/F/TAF FDC is an FDA approved at a dose of D/C/F/TAF 800/150/200/10 mg FDC. This dose
has been studied in treatment naïve HIV-1 infected participants as well as in virologically-suppressed
participants and is the dose recommended in the US Prescribing Information.15,30
4.4. 
End of Study Definition
A participant will be considered to have complete the study if he or she has completed the assessments
at Week 48. The end of study is considered as the last data collection visit (week 48) for the last
participant in the study. The final data from the study site will be sent to the sponsor (or designee)
after completion of the final participant visit at that study site, in the time frame specified in the
Clinical Trial Agreement.
5. 
STUDY POPULATION
Screening for eligible participants will be performed in a Screening Phase of approximately 30 days
(up to maximum 6 weeks) starting from the signature of the ICF. During the Screening Visit
(Day -30), participants will undergo screening procedures outlined in the Schedule of Activities
(SoA). Participants should not be randomized until all screening procedures have been completed and
the investigator has determined that the participant meets the inclusion/exclusion criteria.
Refer to Section 5.4, Screen Failures for conditions under which the repeat of any screening
procedures may be allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with  the appropriate sponsor
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
43
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2, Sample
Size Determination.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
at least 18 years of age, inclusive.
2. 
BMI of ≥18 kg/m2 at time of starting an INI + TAF/FTC ARV regimen.
3. 
documented HIV-1 infection.
4. 
Criterion modified per Amendment 2
4.1 
currently being treated with a stable ARV regimen consisting of an INI combined with
TAF/FTC for ≥6 consecutive months preceding the screening visit and experienced a
≥10% increase in body weight within a -36-month time period prior to screening and
while on the current INI + TAF/FTC ARV regimen.
5. 
documented evidence of being virologically-suppressed while on the current stable
INI +TAF/FTC ARV regimen (described above) prior to screening: at least 1 plasma
HIV-1 RNA measurement <50 copies/mL occurring between 12 and 2 months prior to
the screening visit while on the stable INI + TAF/FTC ARV regimen and have HIV-1
RNA <50 copies/mL at the screening visit.
A single viral load elevation of ≥50 copies/mL and <200 HIV-1 RNA copies/mL after
previously reaching viral suppression within 12 months prior to screening is allowed,
provided a subsequent viral load measurement is <50 HIV-1 RNA copies/mL prior to
screening.
6. 
medically stable on the basis of physical examination, medical history, and vital signs,
performed at screening. Any abnormalities, must be consistent with the underlying illness
in the study population and this determination must be recorded in the participant’s source
documents and initialed by the investigator.
7. 
medically stable on the basis of clinical laboratory tests performed at screening. If the
results of the serum chemistry panel including liver enzymes, other specific tests, blood
coagulation, hematology, or urinalysis are outside the normal reference ranges, the
participant may be included only if the investigator judges the abnormalities or deviations
from normal to be not clinically significant or to be appropriate and reasonable for the
population under study. This determination must be recorded in the participant’s source
documents and initialed by the investigator.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
44
8. 
must be able to swallow whole or split tablets.
9. 
Must have adequate insurance in place that will cover the current INI + TAF/FTC ARV
regimen for at least 6 months.
10. 
Criterion modified per Amendment 1
10.1 
must sign an ICF indicating that he or she understands the purpose of, and procedures
required for, the study and is willing to participate in the study.
11. 
a female participant of childbearing potential must have a negative highly sensitive serum
(-hCG) at Screening and a negative urine pregnancy test at Baseline.
12. 
A female participant using oral contraceptives must use an additional contraceptive
method (above that required in Inclusion Criterion [13]).
13. 
a female participant must be (as defined in Appendix 5: Contraceptive and Barrier
Guidance and Collection of Pregnancy Information)
a. Not of childbearing potential
b. Of childbearing potential and
o 
Practicing a highly effective method of contraception (failure rate of <1%
per year when used consistently and correctly) and agrees to remain on a
highly effective method while receiving study intervention and until 90 days
after last dose the end of relevant systemic exposure. Examples of highly
effective methods of contraception are located in Appendix 5: Contraceptive
and Barrier Guidance and Collection of Pregnancy Information.
o 
Pregnancy testing (urine) at the end of study intervention.
Contraceptive (birth control) use by male or female participants should be consistent with
local regulations regarding the acceptable methods of contraception for those
participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly Use
should be consistent with local regulations regarding the use of contraceptive methods for
participants in clinical studies.
14. 
a female participant must agree not to donate eggs (ova, oocytes) for the purposes of
assisted reproduction during the study and for a period of 90 days after receiving the last
dose of study intervention.
15. 
male participants should also be advised of the benefit for a female partner to use a highly
effective method of contraception as condom may break or leak.
male participants who have had a vasectomy without reversal operation minimally 2
months prior to screening are not required to use birth control methods.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
45
16. 
a male participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum 90 days after receiving the last dose of study intervention
(or longer, if dictated by local regulations).
17 
Criterion added per the Amendment 3
A female participant must agree not to be pregnant, breastfeeding, or planning to become
pregnant while enrolled in this study or within 90 days after the last dose of study
intervention.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from participating
in the study:
1. 
known history of malignancy within the past 5 years or ongoing malignancy other than
cutaneous Kaposi’s sarcoma, basal cell carcinoma, or resected, noninvasive cutaneous
squamous carcinoma.
2. 
known allergies, hypersensitivity, or intolerance to D/C/F/TAF FDC tablet or its
excipients.19
3. 
known active cryptococcal infection, active toxoplasmic encephalitis, Mycobacterium
tuberculosis infection, or another AIDS-defining condition within 90 days prior to
Screening that in the judgement of the investigator would increase the risk of morbidity
or mortality.
4. 
active hepatitis B (HBV) or hepatitis C virus (HCV) infection.
5. 
uncontrolled diabetes that will require treatment with insulin during the study period.
6. 
history of failure on DRV treatment or known documented history of ≥1 DRV RAMs.
DRV RAMs include V11I, V32I, L33F, I47V, I50V, I54M/L, T74P, L76V, I84V, L89V
(Note: If documented historical genotypes are available, the data must be made available
to the sponsor for documentation of the criteria). If no historical genotype is available, the
participant can be included, provided no previous failure on DRV treatment has been
documented.
7. 
inadequate hematologic parameters at screening: platelets <50,000/uL, hemoglobin
<8.5 g/dL, and absolute neutrophil count <1000/u/L.
8. 
evidence of Child Pugh Class C based on clinical laboratory testing and clinical
evaluation.
9. 
screening hepatic transaminases (ALT and aspartate aminotransferase [AST]) >5x upper
limit of the normal range (ULN).
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
46
10. 
screening creatinine based estimated glomerular filtration rate (eGFRcr) <30mL/min
according to the Cockcroft-Gault formula for creatinine clearance.8
11. 
participants initiating or discontinuing concomitant medications associated with
significant changes in weight within the last 90 days:
 Diabetes Therapies:
o Insulin
o Thiazolidinediones; eg: pioglitazone.
o Sulfonylureas; eg: glipizide, glyburide, glimepiride, chlorpropamide, tolbutamide.
o Biguanides/Meglitinides; eg: Metformin, Nateglinide.
o Dipeptidyl peptidase-4 inhibitors; eg: linagliptin, saxagliptin, sitagliptin.
o Glucagon-like peptide-1 agonists; eg: exenatide, liraglutide, pramlintide.
o Alpha-Glucosidase inhibitors; eg: acarbose, miglitol.
 Psychiatric/Neurologic Therapies:
o Tricyclic antidepressants; eg: amitriptyline, doxepin, imipramine, nortriptyline,
trimipramine.
o Selective Serotonin Reuptake Inhibitors; eg: sertraline, paroxetine, fluvoxamine.
o Antipsychotics; eg: haloperidol, loxapine, clozapine, chlorpromazine, fluphenazine,
risperidone, olanzapine, quetiapine.
o Antiseizure/Anticonvulsants; ie, Valproic acid, carbamazepine, gabapentin, topiramate,
zonisamide, lamotrigine.
o Others: bupropion, nefazodone, lithium, mirtazapine.
 Steroid Hormones: chronic oral corticosteroids at an equivalent ≥5 mg of prednisone orally a day
o Use of a methylprednisolone dose pack or use of acute steroids for treatment of allergic
reactions for ≤7 days are not exclusionary.
 Hormone therapy/contraception; eg: estrogen, testosterone, progestogens, tesamorelin.
 Appetite 
Stimulants/Suppressants; 
eg: 
phentermine, 
topiramate, 
methylphenidate,
amphetamine/dextroamphetamine, megestrol, oxandrolone, dronabinol.
12. 
receiving ongoing therapy with contraindicated drugs within 30 days of screening, not
recommended drugs that cannot be adequately dose-adjusted, or participants with any
known allergies to the excipients of the D/C/F/TAF FDC tablet.
13. 
current alcohol or substance use judged by the investigator to potentially interfere with
participant study adherence or changes in body weight.
14. 
known, active, severe infections (other than HIV-1 infection) requiring parenteral
antibiotic or antifungal therapy within 30 days prior to baseline.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
47
15. 
received an investigational intervention (including investigational vaccines) or used an
invasive investigational medical device within 90 days of baseline or is currently
enrolled in an investigational study without prior approval from the sponsor.
16. 
pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study
or within 90 days after the last dose of study intervention.
17. 
plans to father a child while enrolled in this study or within 90 days after the last dose
of study intervention.
18. 
any other condition or prior therapy  for which, in the opinion of the investigator,
participation would not be in the best interest of the participant (eg, compromise the
well-being) or that could prevent, limit, or confound the protocol-specified assessments.
19. 
employee of the investigator or study site, with direct involvement in the proposed study
or other studies under the direction of that investigator or study site, as well as family
members of the employees or the investigator, or employees of Johnson & Johnson or
Gilead.
20. 
unlikely to comply with the protocol requirements, based on clinical judgment.
NOTE:Investigators should ensure that all study enrollment criteria have been met at screening. If a
participant’s clinical status changes (including any available laboratory results or receipt of additional
medical records) after screening but before the first dose of D/C/F/TAF FDC is given such that he or
she no longer meets all eligibility criteria, then the participant should be excluded from participation
in the study. The required source documentation to support meeting the enrollment criteria are noted
in Appendix 3: Regulatory, Ethical, and Study Oversight Considerations.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions during
the course of the study to be eligible for participation:
1. 
Refer to Section 6.8, Concomitant Therapy for details regarding prohibited and
restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3. 
All HIV-infected participants should be advised to take the necessary precautions to
reduce the risk of transmitting HIV.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
48
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by the
sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed by
the investigator in the study file. To ensure participant confidentiality, no copy will be made. All
reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not enrolled into
the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may  be
rescreened after consultation with sponsor. Rescreened participants must be assigned new participant
numbers.
5.5. 
Criteria for Temporarily Delaying Enrollment, Randomization, Administration
of Study Intervention
Not Applicable
6. 
STUDY INTERVENTION
6.1. 
Study Interventions Administered
At the baseline visit (Day 1), eligible participants will be randomized in a 1:1 ratio to the Immediate
Switch Arm (switch to D/C/F/TAF FDC) or the Delayed Switch Arm (maintain current
INI + TAF/FTC ARV regimen). Randomization will be stratified by sex (Male or Female) and race
(Black/African American or Non-Black/African American) at Baseline.
 Immediate Switch Arm:D/C/F/TAF FDC (DRV 800 mg + COBI 150 mg + FTC 200 mg + TAF
10 mg) once daily for 48 weeks.
 Delayed Switch Arm: continue current INI + TAF/FTC ARV regimen for 24 weeks. After 24
weeks participants will switch to a regimen of D/C/F/TAF FDC (DRV 800 mg + COBI 150 mg
+ FTC 200 mg + TAF 10 mg) once daily for an additional 24 weeks.
Participants randomized to the Immediate Switch Arm must start D/C/F/TAF FDC within 24 hours
of the Baseline visit. D/C/F/TAF FDC tablet must be taken orally with food. Participants will be
counseled to swallow D/C/F/TAF FDC tablet whole once daily at approximately the same time each
day, according to their preference. D/C/F/TAF is to be taken with approximately 240 mL (8 ounces)
of water. The D/C/F/TAF FDC tablet should be swallowed whole; alternatively, for participants who
are unable to swallow the tablet whole, D/C/F/TAF FDC may be split into 2 pieces using a
tablet-cutter, and the entire dose should be consumed immediately after splitting. Participants should
not attempt to dissolve the tablet in water.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
49
D/C/F/TAF FDC administration must be captured in the source documents and the CRF. Study-site
personnel will instruct participants on how to store D/C/F/TAF FDC for at-home use as indicated for
this protocol.
If participants notice that they have missed a D/C/F/TAF FDC intake and it is still within 12 hours of
their regular dosing time, they should take the D/C/F/TAF FDC immediately with food. Participants
can then continue their usual dosing schedule. If participants notice that they have missed a dose more
than 12 hours after the time it is usually taken, they should be instructed not to take it and simply
resume the usual dosing schedule. Participants should not take a double dose to make up for a missed
dose.
Instructions regarding how to take D/C/F/TAF FDC tablet, what to do if a dose is missed and how to
store the D/C/F/TAF FDC tablet will be provided on the wallet (study) card.
D/C/F/TAF FDC tablet will be manufactured and provided under the responsibility of the sponsor.
Each D/C/F/TAF FDC tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150
mg of cobicistat, 200 mg of emtricitabine (FTC), and tenofovir alafenamide fumarate equivalent to
10 mg of tenofovir alafenamide (TAF). The yellow to yellowish-brown, capsule-shaped, filmcoated
tablet is debossed with “8121” on one side and “JG” on the other side. D/C/F/TAF FDC is packaged
in high-density polypropylene (HDPE) bottles with a silica gel desiccant and child-resistant closure.
Refer to the IB for a list of excipients.19 D/C/F/TAF FDC labels will contain information to meet the
applicable regulatory requirements. No D/C/F/TAF FDC can be repacked or relabeled without prior
approval from sponsor.
For the Delayed Switch Arm, all components of the INI + TAF/FTC ARV regimen should be dosed
and administered using the dosing schedule specified in the ARV agent’s US Prescribing Information.
Applicable procedures and treatment guidance based on the Prescribing Information should be
respected. If a participant accidentally misses a scheduled dose of any of the ARVs in the Delayed
Switch Arm, the investigator should advise according to the PI in the individual package insert.
Participants on Delayed Switch Arm will be provided with the wallet (study) card.
The times of the previous two doses of study intervention administration will be recorded at each
visit. Prolonged temporary study intervention interruptions are only deemed acceptable if motivated
by safety reasons and if they do not last longer than 4 consecutive weeks. The sponsor should be
notified when such temporary interruption occurs.
For details on rescue medications, refer to Section 6.8. For a definition of study intervention overdose,
refer to Section 6.7, Treatment of Overdose.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All D/C/F/TAF FDC tablets must be stored 20°C to 25°C (between 68°F to 77°F) with excursions
permitted to 15°C to 30°C (59°F to 86°F). Refer to the pharmacy manual/study site investigational
product and procedures manual for additional guidance on D/C/F/TAF FDC preparation, handling,
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
50
and storage. Study site personnel will be instructed to dispense D/C/F/TAF FDC tablets only in the
original container. Study site personnel will instruct participants to store D/C/F/TAF FDC tablets in
the original container and to keep container tightly closed with desiccant inside to protect from
moisture.
Accountability
The investigator is responsible for ensuring that all D/C/F/TAF FDC tablets received at the site is
inventoried and accounted for throughout the study. The dispensing of D/C/F/TAF FDC tablets to the
participant, and the return of D/C/F/TAF FDC tablets from the participant (if applicable), must be
documented on the intervention accountability form. Participants must be instructed to return all
original containers, whether empty or containing D/C/F/TAF FDC tablets. All D/C/F/TAF FDC
tablets will be stored and disposed of according to the sponsor's instructions. Study-site personnel
must not combine contents of the D/C/F/TAF FDC tablets containers.
INI + TAF/FTC ARV regimen will not be supplied by the sponsor.
D/C/F/TAF FDC tablets must be handled in strict accordance with the protocol and the container
label and must be stored at the study site in a limited-access area or in a locked cabinet under
appropriate environmental conditions. Unused D/C/F/TAF FDC tablets, and D/C/F/TAF FDC tablets
returned by the participant, must be available for verification by the sponsor's study site monitor
during on-site monitoring visits. The return to the sponsor of unused D/C/F/TAF FDC tablets, or used
returned D/C/F/TAF FDC tablets for destruction, will be documented on the intervention return form.
When the study site is an authorized destruction unit and D/C/F/TAF  FDC tablets supplies are
destroyed on-site, this must also be documented on the intervention return form.
D/C/F/TAF FDC tablets should be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. D/C/F/TAF FDC tablets will
be supplied only to participants participating in the study. Returned D/C/F/TAF FDC tablets must not
be dispensed again, even to the same participant, unless the bottles are unopened. Whenever a
participant brings his or her D/C/F/TAF FDC tablets to the study site for pill count, this is not seen
as a return of supplies. D/C/F/TAF FDC tablets may not be relabeled for use by other participants.
The investigator agrees neither to dispense the D/C/F/TAF FDC tablets from, nor store it at, any site
other than the study sites agreed upon with the sponsor. Further guidance and information for the
final disposition of unused D/C/F/TAF FDC are provided in the Site Investigational Product
Procedures Manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Procedures for Randomization
Participants will be randomly assigned to 1 of 2 intervention arms based on a computer-generated
randomization schedule prepared before the study by or under the supervision of the sponsor.
Randomization will be based on a computer-generated schedule, constructed via random permuted
blocks to ensure balance across treatment arms in each strata of the stratification factors, and prepared
before the start of the study by the sponsor.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
51
Central randomization will be implemented in this study. Participants will be randomized in a 1:1
ratio to the Immediate Switch Arm (D/C/F/TAF FDC starting on Day 1 for 48 weeks), or the Delayed
Switch Arm (continue current INI + TAF/FTC ARV regimen for 24 weeks then switch to D/C/F/TAF
FDC for an additional 24 weeks).
Randomization will be stratified by sex (Male or Female) and race (Black/African American or
Non-Black/African American) at Baseline. A maximum enrollment of approximately 70% male
participants will be utilized to ensure adequate recruitment of female participants. A maximum
enrollment of approximately 70% non-black participants will be utilized to ensure adequate
recruitment of diverse races.
The randomization and baseline visit (Day 1) cannot proceed until the investigator has received all
results of the screening visit and participant eligibility has been confirmed in interactive web response
system (IWRS), which should occur within approximately 30 days (up to maximum 6 weeks) after
the screening visit (for further details, see Section 8).  It is the responsibility of the investigator to
ensure that the participant is eligible for the study prior to enrollment.  Randomization should be
performed on the same day as the baseline visit (Day 1), provided that all screening procedures have
been completed and participant eligibility has been confirmed.
The IWRS  will assign  open-label kit numbers at each  study  visit. D/C/F/TAF FDC  will be
dispensed to the participant in  an  open-label fashion.  The requestor must use his or her own user
identification and personal identification number when contacting the IWRS, and will then give the
relevant participant details to uniquely identify the participant.
Blinding
As this is an open study, blinding procedures are not applicable.
6.4. 
Study Intervention Compliance
Study-site personnel will maintain a log of all D/C/F/TAF FDC tablets administered. D/C/F/TAF
FDC tablets supplies for each participant will be inventoried and accounted. Participants will receive
instructions on compliance with D/C/F/TAF FDC tablets administration at the Baseline visit.
Treatment adherence will be assessed by participant self-report using 4-day recall at the time points
specified in the Schedule of Activities (SoA). During the course of the study, the investigator or
designated study-site personnel will be responsible for providing additional instruction to reeducate
any participant who is not compliant with taking the D/C/F/TAF FDC tablets. Instructions regarding
how to take D/C/F/TAF FDC, what to do if a dose is missed and how to store the D/C/F/TAF FDC
will be provided on the wallet (study) card. All participants in the study will be provided with wallet
(study) card.
6.5. 
Dose Modification
No dose modifications are allowed.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
52
6.6. 
Continued Access to Study Intervention After the End of the Study
Participants will be instructed that D/C/F/TAF FDC will not be made available to them after they
have completed/discontinued D/C/F/TAF FDC and that they should return to their primary physician
to determine standard of care.
6.7. 
Treatment of Overdose
For D/C/F/TAF FDC any dose greater than 1 tablet within a 24-hour period ±12 hours is considered
an overdose as per Prescribing information of D/C/F/TAF FDC tablet. The sponsor does not
recommend specific intervention for an overdose.
Human experience of acute overdose with D/C/F/TAF is limited. If overdose occurs, the patient must
be monitored for evidence of toxicity. There is no specific antidote for overdose with D/C/F/TAF.
Treatment of overdose with D/C/F/TAF consists of general supportive measures including monitoring
of vital signs and observation of the clinical status of the patient.
For those randomized to the delayed switch arm, receiving an INI + FTC/TAF based regimen the
individual prescribing information should be referenced to determine if an overdose has occurred,
and how such overdose should be managed.
6.8. 
Concomitant Therapy
Prestudy therapies including all previous ARV treatments and non-ARV treatments received up to
twelve months before Screening must be recorded.
Concomitant therapies must be recorded throughout the study beginning with Screening up to the last
dose of study intervention. Concomitant therapies should also be recorded beyond the last study visit
only in conjunction with new or worsening AEs, SAEs that meet the criteria outlined in Serious
Adverse Events in Section 8.3.1, Time Period and Frequency for Collecting AEs and SAE
Information.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special diets,
exercise regimens) different from the study intervention must be recorded in the case report form
(CRF). Recorded information will include a description of the type of therapy, duration of use, dosing
regimen, route of administration, and its indication. Modification of an effective preexisting therapy
should not be made for the explicit purpose of entering a participant into the studyif such modification
of treatment is not clinically acceptable. Any change in dosage of the medication must be reported in
the electronic CRF (eCRF).
For those participants with treatment emergent hyperglycemia, hypertension or dyslipidemia,
initiation of medications to address these AEs should be prescribed in accordance to national
treatment guidelines (See Figure 4 in Appendix 9: Characteristics, Prevention, and Management of
Cardiovascular Diseases in People Living with HIV by American Heart Association; page 14:
Figure 4 in Appendix 10: 2017 American College of Cardiology (ACC) Guideline for the Prevention,
Detection, Evaluation, and Management of High Blood Pressure in Adults; and page 6: Figure 2 in
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
53
Appendix 11: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the
American Diabetes Association (ADA) and the European Association for the Study of Diabetes
(EASD)]).
Investigators are reminded that certain medications may influence body weight changes or may be
contraindicated and should be avoided (see disallowed concomitant therapy below and Exclusion
Criteria No. 11). Should a participant have a need to initiate treatment with any excluded concomitant
medication, it is recommended that investigators consult with the sponsor medical monitor
beforehand to determine if an alternative therapy could be utilized that has no known impact on
weight or if the participant should be discontinued from the study. If an excluded medication is
initiated before discussion with the medical monitor, the investigator must notify the sponsor as soon
as becoming aware.
Participants who experience clinically significant changes in body weight during the course of the
study may require dose reductions or withdrawal of medications to treat hypertension, type II
diabetes, or hyperlipidemia in order to avoid events such as hypoglycemia, hypotension, etc. As part
of routine care at scheduled follow-up visits, participants should be assessed to determine if a dose
reduction or withdrawal of medications for the treatment of such conditions is warranted. These
changes will be recorded in the CRF.
Contraindicated and Disallowed Concomitant Agents
DRV co-administered with COBI is an inhibitor of CYP3A, CYP2D6, and P-glycoprotein (P-gp).
Cobicistat also inhibits the transporters breast cancer resistance protein (BCRP), multi-antimicrobial
extrusion protein (MATE)-1, organic anion-transporting polypeptide (OATP)1B1 and OATP1B3.
Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat
is not expected to induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, uridine diphosphate
glucuronosyltransferase 1A1 (UGT1A1), or multidrug resistance protein 1 (MDR1).
D/C/F/TAF FDC tablet should not be co-administered with medicinal products that are highly
dependent on CYP3A for clearance and for which increased plasma concentrations are associated
with serious and/or life-threatening events (narrow therapeutic index). These medicinal products
include alfuzosin, astemizole, carbamazepine, cisapride, colchicine (in participants with renal and/or
hepatic impairment), dronedarone, elbasvir/grazoprevir, ergot alkaloids (eg, dihydroergotamine,
ergotamine, ergonovine and methylergonovine), lomitapide, lovastatin, lurasidone, oral midazolam,
phenobarbital, phenytoin, pimozide, ranolazine, rifampin, sildenafil (when used for treatment of
pulmonary arterial hypertension), simvastatin, St John's Wort, terfenadine, and triazolam.
Emtricitabine is not an inhibitor of human CYP450 enzymes. In vitro and clinical drug interaction
studies have shown that the potential for CYP-mediated interactions involving FTC with other
medicinal products is low. Emtricitabine is primarily excreted by the kidneys by a combination of
glomerular filtration and active tubular secretion. No drug interactions due to competition for renal
excretion have been observed; however, coadministration of FTC with drugs that are eliminated by
active tubular secretion may increase concentrations of FTC and/or the co-administered drug. Drugs
that decrease renal function may increase concentrations of FTC.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
54
Tenofovir alafenamide is a substrate of the efflux transporter P-gp. Drugs that induce P-gp activity
are expected to decrease the absorption of TAF, resulting in decreased plasma concentrations of TAF,
which may lead to loss of therapeutic effect of D/C/F/TAF FDC tablet and development of resistance.
These medicinal products include antimycobacterials (rifabutin, rifampin, rifapentine) and
anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin). Coadministration of
D/C/F/TAF FDC tablet with drugs that inhibit P-gp may increase the absorption and plasma
concentration of TAF.
Given the possibility for PK interactions, investigators should refer to the IB for the D/C/F/TAF FDC
tablet and individual Prescribing Information for the components of the D/C/F/TAF FDC tablet for
potential contraindications and management of drug interactions to preserve participant safety during
the study.
Refer to the current individual agents’ PI of the continued INI + TAF/FTC ARV regimen for guidance
with regard to dose adjustments for concomitant use with other medications, and for contraindicated
medications or medications that are not recommended for concomitant use.
All contraindicated or disallowed medications must be discontinued at least 30 days before the
Screening Visit (Day 1) and for the duration of the study. If such discontinuation of treatment is not
clinically acceptable, the participant should not be allowed to participate in the study.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
 A participant's study intervention must be discontinued if:
 The participant withdraws consent to receive assigned study intervention.
 The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention.
 The participant becomes pregnant while taking study intervention  (Refer to Appendix 5:
Contraceptive and Barrier Guidance and Collection of Pregnancy Information). Study
intervention should discontinue only after the participant has obtained alternative ARV
therapy through a health care provider.
 The study is discontinued at the request of the sponsor, concerned regulatory agency, or
Independent Ethics Committee/Institutional Review Board (IEC/IRB).
 The participant experiences unacceptable toxicity  (as defined in  Section 8.2.6, Toxicity
Management).
A participant’s study intervention may be discontinued if:
 An SAE occurs.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
55
 The participant fails to comply with the protocol or study staff requirements.
 Intercurrent illness that would, in the judgment of the investigator, affect assessments of
clinical status to a significant degree.
 The participant starts disallowed treatment, or requires new onset treatment with one ofthe
disallowed medications (please refer to Section 6.8, Concomitant Therapy).
 The participant experiences virologic rebound; if genotypic/phenotypic resistance to study
intervention is determined, study intervention may be discontinued, and the participant will
be referred for continued medical care outside of the study.
 The investigator considers, for any other reason, it is in the best interest of the participant that
he/she is withdrawn. The sponsor should be contacted for further discussion and final
decision.
If a participant discontinues study intervention for any reason except for withdrawal of consent before
the end of the study, ESID assessments should be obtained as soon as possible but no later than 1
week of discontinuing study intervention. For participants who discontinue study intervention for any
reason and have HIV-1 RNA ≥400 copies/mL at the last viral load measurement, the ESID
assessments will also include genotypic and phenotypic resistance testing (using PhenoSense GT®
Plus Integrase). In case of early discontinuation, an HIV-1 resistance report will be forwarded to the
participant’s primary care provider to assist in the selection of a new ARV regimen. If the reason for
withdrawal from the study is withdrawal of consent, then no additional assessments are allowed.
D/C/F/TAF FDC assigned to the participant who discontinued D/C/F/TAF FDC may not be assigned
to another participant. Additional participants will not be entered.
7.1.1. 
Temporary Discontinuation
Prolonged temporary study intervention interruptions are only deemed acceptable if, motivated by
safety reasons and if they do not last longer than 4 consecutive weeks. The sponsor should be notified
when such temporary interruption occurs.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 Lost to follow-up
 Withdrawal of consent
 Death
When a participant withdraws before completing the study, the reason for withdrawal is to be
documented in the CRF and in the source document. If the reason for withdrawal from the study is
withdrawal on consent, then no additional assessments are allowed.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
56
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent form
apply (eg, consult with family members, contacting the participant’s other physicians, medical
records, data base searches) as local regulations permit.
Withdrawal of consent should be an infrequent occurrence in clinical studies32, therefore, prior to the
start of the study the sponsor and the investigator should discuss and reach a clear understanding of
what constitutes withdrawal of consent in the context of the available reduced follow-up mechanisms
listed.
7.2.1. 
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-term Retention
of Samples for Additional Future Research in Appendix 3: Regulatory, Ethical, and Study Oversight
Considerations). In such a case, samples will be destroyed after they are no longer needed for the
clinical study. Details of the sample retention for research are presented in the main ICF.
7.3. 
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for scheduled
visits and is unable to be contacted by the study site. A participant cannot be deemed lost to follow-
up until all reasonable efforts made by the study-site personnel to contact the participant are deemed
futile. The following actions must be taken if a participant fails to return to the study site for a required
study visit:
 The study-site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
 Before a participant is deemed lost to follow up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, e-
mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods). These contact attempts should be documented in the
participant’s medical records.
 Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.
If a participant is lost to follow-up, every reasonable effort must be made by the study site personnel
to contact the participant and determine the reason for discontinuation/withdrawal. The measures
taken to follow up must be documented. Refer to Section 7.2, Participant Discontinuation/Withdrawal
From the Study.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
57
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities (SoA) summarizes the frequency and timing ofmetabolic, efficacy, safety,
PROs, and other measurements applicable to this study. Additional visits may be required if, in the
investigator’s opinion, further clinical or laboratory evaluation is needed.
When an HIV-1 RNA repeat testing is required at an unscheduled visit to confirm protocol virologic
rebound, an HIV-1 genotype/phenotype plasma sample and a plasma storage sample should also be
drawn at the same unscheduled visit. Findings during these unscheduled visits or assessments
need to be reported in the eCRF.
Some flexibility in the planning ofthe visits is allowed, however, the total treatment duration at the
end of the study  period should be 48 weeks. All study  visits through  Week 48 are to be
completed within  ±7 days of the protocol-specified visit date.
All PRO assessments (BSQ-8D, HIV-SI and PGIC [including PGIC-S]) should be completed during
the study visit before any tests, procedures, or other consultations to prevent influencing participant
perceptions.  The PGIC and PGIC-S should be completed after the participant completes the BSQ-
8D and HIV-SI.
Other measurements may be done earlier than specified timepoints if needed. Actual dates and times
of assessments (if applicable) will be recorded in the source documentation and CRF.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the
investigator or required by local regulation, to establish the absence of pregnancy at any time during
the participation in the study. If a serum or urine pregnancy test is positive, the participant will be
withdrawn from the study. For each participant, the maximum amount of blood drawn from each
participant in this study will not exceed 261 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples or for confirmation of virologic rebound.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory requisition
form.
Refer to the Schedule of Activities (SoA) for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the laboratory
manual that will be provided. Collection, handling, storage, and shipment of samples must be under
the specified, and where applicable, controlled temperature conditions as indicated in the laboratory
manual
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
58
Study-Specific Materials
The investigator will be provided with the following supplies:
 Investigator's Brochure for D/C/F/TAF19
 pharmacy manual/study site investigational product and procedures manual
 laboratory manual and laboratory supplies
 Electronic Data Capture (eDC) Manual
 sample ICF
 Interactive Web Response System manual
 Dual-energy X-ray absorptiometry (DEXA) manual
 Patient Reported Outcomes (PROs) manual
 Contact Information Page
8.1. 
Assessments
8.1.1. 
Primary Endpoint (Percent Change in Body Weight)
Body weight will be evaluated at time points specified in the Schedule of Activities (SoA). Body
weight will be measured using a calibrated scale. Attention should be given to weigh the participant
on the same scale through the duration of the study. Participants should be weighed wearing
underwear and a gown. Participants will be instructed to take off their shoes and to empty their
bladders before being weighed. If disrobing for weighing is logistically impossible, the participant
must be dressed as lightly as possible, with consistency from visit to visit. The scale should be
calibrated according to the manufacturers specifications and at the frequency recommended by the
manufacturer before the first participant is weighted. Calibration must be documented in the
calibration log.
8.1.2. 
Metabolic Assessments
Systolic and diastolic blood pressure (SBP, DBP), pulse rate (supine after at least 5 minutes rest) will
be recorded in a quiet setting without distractions, at the time points specified in the Schedule of
Activities (SoA). Blood pressure and pulse/heart rate measurements will be assessed with a
completely automated technique. Manual techniques will be used only if an automated device is not
available. Body Mass Index will be calculated using body weight collected as described in
Section 8.1.1 and height measured at screening. Height will be measured using a wall-mounted
stadiometer or one mounted on a balance beam scale, whichever is most appropriate for the individual
participant. Participants should be wearing socks or barefoot and should not be wearing shoes.
Body composition will be assessed at time points specified in the Schedule of Activities (SoA) via
whole body DEXA scans. DEXA scans may be performed between screening and baseline (+2
weeks), at Weeks 24, 48, and the ESID visit (±10 days) (only to be performed at ESID if the last scan
is more than 12 weeks from the date of the ESID visit and the ESID visit takes place before Week
48). A rescan for technical reasons at all scheduled time points is allowed within 2 weeks. A complete
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
59
description of the procedures for the DEXA scans will be provided in the DEXA manual.  Reading
of the DEXA scans will be performed centrally.
Waist circumference will be measured at time points specified in the Schedule of Activities (SoA).
Waist circumference will be measured with the participant standing, wearing underwear, with or
without a gown. The measurement will be performed at a level midway between the superior aspect
of the iliac crests and the lower lateral margin of the ribs (see Figure 2). The measurement need not
be at the level of the umbilicus. The measuring tape will be kept horizontal. Non-alcoholic fatty liver
disease (NAFLD) Fibrosis and hypertension, age, insulin, resistance (HAIR) scores will be calculated
based on receipt of central laboratory assessments and clinical status of the participant (Appendix 2:
Clinical Laboratory Tests and Calculations)
Figure 2: 
Waist Circumference Measurement
Fasting clinical laboratory tests will be assessed at time points specified in the Schedule of Activities
(SoA) to assess changes in the following metabolic parameters:
 lipids, calculated homeostatic model assessment of insulin resistance (HOMA-IR), HbA1C,
leptin, adiponectin, and alpha melanocyte-stimulating hormone. Ifa participant has not fasted
prior to the visit, the visit may proceed, but participant must return within 72 hours in a fasted
state to have a blood draw for the metabolic assessments.
8.1.3. 
Efficacy Assessments
8.1.3.1. 
Antiviral Efficacy and Immunologic Change
Blood samples for determination of plasma HIV-1 RNA viral load and immunologic parameters will
be taken at the time points specified in the Schedule of Activities (SoA).
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
60
Plasma viral load will be measured using a validated assay at a central laboratory (ie, Roche COBAS
AmpliPrep/COBAS TaqMan HIV-1 Test, Version 2.0.) The assay linear range is 20 to 10,000,000
copies/mL with a lower limit of quantification (LLOQ) of 20 copies/mL and a limit of detection
(LOD) of 20 copies/mL). Immunologic change will be determined by changes in CD4+ cell count
(absolute and %).
Changes in viral load, changes in CD4+ cell counts (either decreases or increases) or detected
resistance will be part of the efficacy analysis and should not be reported as AEs or SAEs.
8.1.3.2. 
Resistance Determinations
Samples for HIV-1 genotype/phenotype resistance testing (PhenoSense GT® Plus Integrase) will be
taken at the time points specified in the Schedule of Activities (SoA).
For participants with confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥200
copies/mL at a scheduled or unscheduled visit) and with a HIV-1 RNA value ≥400 copies/mL, HIV-
1 genotypic/phenotypic resistance testing will be performed on the confirmed rebound sample if HIV-
1 RNA ≥400 copies/mL or on a following visit with HIV-1 RNA ≥400 copies/mL. Other time points
may still be analyzed if deemed necessary by the sponsor. For further details on the management of
virologic rebound, see Appendix 13: Management of Virologic Rebound. Whole blood samples will
be taken for storage and will be analyzed if deemed necessary by the sponsor to characterize archived
viral resistance (GenoSure Archive®).
8.1.3.3. 
Management of Virologic Rebound
Participants with HIV-1 RNA ≥200 copies/mL will be managed as follows:
 If a single viral load measurement is ≥200 copies/mL after having previously been
<50 copies/mL, participants should be contacted preferably within 48 hours to assess potential
causes (eg, active substance abuse, depression, other intercurrent illnesses, lack of adherence)
and adequate intervention should be provided (eg, additional adherence counseling). HIV-1
RNA testing should be repeated at a scheduled or unscheduled visit 2 to 4 weeks after the date
of the initial viral load result of HIV-1 RNA ≥200 copies/mL.
 Upon confirmation of HIV-1 RNA ≥200 copies/mL, potential causes of virologic rebound
should be documented. Assessment should include adherence, concomitant medication, and
comorbidities (eg, active substance abuse, depression, other intercurrent illnesses, lack of
adherence).
 If virologic rebound is confirmed at the scheduled or unscheduled visit and the HIV-1 RNA
value is ≥400 copies/mL, the blood sample from that visit or a following visit with HIV-1
RNA ≥400 copies/mL will be used for HIV-1 genotypic and phenotypic testing (using
PhenoSense GT® Plus Integrase).
 If genotypic/phenotypic resistance to study intervention is determined, study intervention may
be discontinued at the discretion of the investigator. In case of early discontinuation, and HIV-
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
61
1 RNA ≥400 copies/mL, an HIV-1 genotypic/phenotypic resistance report, if available, will
be forwarded to the investigator and/or participant’s primary care provider in order to assist
in the selection of a new ARV regimen.
 If no resistance is detected from genotypic/phenotypic resistance testing, the participant may
remain on study intervention and the viral load will be further monitored.
Genotypic/phenotypic resistance testing at other time points may be requested if deemed
necessary by the sponsor. Investigators should carefully evaluate the benefits and risks of
remaining on study intervention for each individual participant and document this assessment
in the on-site medical record. Investigators who opt to discontinue study intervention for an
individual participant must discuss this with the sponsor’s medical monitor prior to study
intervention discontinuation.
Evaluations may be performed at other time points at the sponsor’s discretion. Additional exploratory
resistance assays may be performed. A  schematic overview  of the guidance for management of
participants who meet the criteria for virologic rebound is provided in Appendix 13: Management
of Virologic Rebound.
8.1.4. 
Adherence
Treatment adherence for the study will be assessed by participant self-report using a 4-day recall for
D/C/F/TAF FDC and participants receiving an INI + TAF/FTC ARV regimen  at the time points
specified in the Schedule of Activities (SoA).
8.2. 
Safety Assessments
Adverse events will be reported and followed by the investigator as specified in Section 8.3, Adverse
Events and Serious Adverse Events and Appendix 4: Adverse Events: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting.
Special attention will be paid to those participants who discontinue the study for an AE, or who
experience severe (Grade 3) or potentially life-threatening (Grade 4) AEs, or SAEs. For reported
HIV  events, further details will be recorded if these events are AIDS-defining illnesses (World
Health Organization Clinical Staging ofHIV/AIDS, located in Appendix 12: WHO Clinical Staging
of HIV/AIDS. For participants with specific adverse events, toxicity management should be done as
described in Section 8.2.6.
Any clinically relevant changes occurring during the study must be recorded on the AE section of the
CRF. Clinical events and clinically significant laboratory abnormalities will be graded according to
the Division of AIDS (DAIDS) as specified in Appendix 7: DAIDS Table for Grading the Severity
of Adult and Pediatric Adverse Events. Any clinically significant abnormalities persisting at the end
of the study/early withdrawal will be followed by the investigator until resolution or until a clinically
stable condition is reached. All Grade 3 and Grade 4 laboratory  abnormalities and all laboratory
abnormalities resulting in an increase of 2 DAIDS grades from baseline will be followed until return
to baseline or within 1 grade from baseline (ie, ≤Grade 2). The study will include evaluations of safety
and tolerability according to the time points provided in the Schedule of Activities (SoA).
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
62
Evaluations at the ESID visit showing abnormal results indicating a possible causal relationship with
the study intervention must be followed by the investigator (as often as deemed prudent) until
satisfactory clinical resolution or stabilization. Certain long-term adverse events of anti-retroviral
therapy (ART) cannot be followed to resolution within the setting of this protocol; in  these cases,
follow-up will be the responsibility of the treating physician, which will be agreed upon with the
sponsor’s medical monitor.
Safety will be evaluated throughout the study from the time a signed and dated informed consent
form (ICF) is obtained until completion of the participant’s last study-related activity.
8.2.1. 
Physical Examination
A complete physical examination will be conducted at the time points in the Schedule of Activities
(SoA). Complete physical examinations include general appearance; skin (and mucus membranes);
eyes; ears, nose, and throat; head, neck, and thyroid; heart; lung, chest (incl. breasts); abdomen;
genitalia; anorectal; lymph nodes; musculoskeletal; and neurological. Urogenital/anorectal
examination will be performed at the discretion of the investigator if clinically relevant. Participants
should be undressed during the complete physical examinations, which should be performed by a
licensed medical doctor, physician’s assistant or nurse practitioner in accordance with local
guidelines. Physical examination will also include evidence of ascites or encephalopathy at Screening
in order to fully calculate Child Pugh Class.
Symptom directed physical examinations may be conducted at all other scheduled and unscheduled
study visits based on reported safety or tolerability issues.
8.2.2. 
Vital Signs
Pulse/heart rate (supine after at least 5 minutes rest) and blood pressure will be assessed will be
conducted at all study visits.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest in
a quiet setting without distractions (eg, television, cell phones).
8.2.3. 
Electrocardiogram (ECG)
Not applicable
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be collected
as noted in Appendix 2: Clinical Laboratory Tests and Calculations. All clinical laboratory testing
will be performed by the central laboratory  and results will be sent to the investigator. The
investigator must review the laboratory results, document this review, and record any clinically
relevant changes occurring during the study in the AE section of the CRF. The laboratory reports
must be filed with the source documents.
The central laboratory will send the investigator and sponsor an alert form whenever a Grade 3 or
Grade 4 laboratory abnormality (see Appendix 7: DAIDS Table for Grading the Severity of Adult
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
63
and Pediatric Adverse Events) is observed. In case a Grade 3 or Grade 4 laboratory abnormality
occurs, a confirmatory test should be performed preferably within 72 hours after the results have
become available, before study intervention interruption or discontinuation, unless such delayis not
consistent with good medical practice.
If a Grade 3 or Grade 4 laboratory abnormality is well documented before the start of the study
and not considered a safety concern by the investigator, a confirmatory retest is not mandatory. The
following laboratory abnormalities do not warrant mandatory confirmation:
 Asymptomatic Grade 3 or Grade 4 glucose elevations in participants with pre-existing
diabetes.
 Asymptomatic Grade 3 or Grade 4 triglyceride or cholesterol elevations.
For more details on the management of Grade 3 and 4 laboratory toxicities that occur during the
open-label treatment phase, see Section 8.2.6, and Appendix 6: Management of Clinically
Significant Laboratory Toxicities.
8.2.5. 
Patient-reported Outcomes
Following PROs will be assessed at the time points indicated in the Schedule of Activities (SoA),
(Appendix 8: Patient Reported Outcomes Questionnaires). Participants will complete the PROs using
the sponsor-provided electronic devices.  Study site personnel will train the participants on how to
use the electronic device.  All PRO assessments will be done in English-speaking and Spanish-
speaking participants.
The BSQ-8D, HIV-SI and PGIC (including PGIC-S) should be completed by the participants during
the study visit before all other study-related procedures to prevent influencing participant perceptions.
The PGIC and PGIC-S should be completed after the participant completes the BSQ-8D and HIV-SI.
8.2.5.1. 
HIV-Symptom Index (HIV-SI)
The HIV-SI is a validated PRO instrument that assesses the burden of 20 common symptoms
associated with HIV treatment or disease.21 Respondents are asked about their experience with each
of 20 symptoms during the past 4 weeks using a 5-point, Likert-type scale. Response options and
scores are as follows: (0) “I don’t have this symptom;” (1) “I have this symptom and it doesn’t bother
me;” (2) “I have this symptom and it bothers me a little;” (3) “I have this symptom and it bothers
me;” (4) “I have this symptom and it bothers me a lot.” The 20 symptoms comprising the HIV-SI are
fatigue/loss of energy, difficulty sleeping, nervous/anxious, diarrhea/loose bowels, changes in body
composition, feeling sad/down/depressed, bloating/pain/gas in stomach, muscle aches/joint pain,
problems with sex, trouble remembering, headaches, pain/numbness/tingling in hands/feet, skin
problems/rash/itching, cough/trouble breathing, fever/chills/sweats, dizzy/lightheadedness, body
weight loss/wasting, nausea/vomiting, hair loss/changes, and loss of appetite/food taste. Symptoms
scores can be dichotomized into not bothersome (scores of 0 or 1) or bothersome (scores of 2, 3 and
4) and overall bothersome symptom count at baseline can be generated by counting the number of
individual symptoms scored as bothersome.13
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
64
8.2.5.2. 
Body Shape Questionnaire (BSQ-8D)
The BSQ-8D is an 8-item version of the 34-item self-report questionnaire that was developed and
validated to measure concerns about body shape; in particular, it focused on the phenomenal
experience of “feeling fat”.9,16  Respondents are asked about how they have been feeling about their
appearances over the past four weeks. Each item from this questionnaire is answered using a 6-point
Likert scale: 1 (never), 2 (rarely), 3 (sometimes), 4 (often), 5 (very often), and 6 (always) and the
overall score is the total across the 8 items.
8.2.5.3. 
DAILY EATS
The DAILY EATS will be administered to measure eating-related concepts such as hunger, appetite,
cravings, and satiety. The home-based DAILY EATS should be completed daily, preferably in the
evening, and, whenever possible, in the same setting for 7 consecutive days. The site should contact
participants approximately 7 days prior to the Baseline (Day 1), Week 24 and Week 48 visits,
preferably by telephone, to remind the completion of the DAILY EATS for 7 consecutive days prior
to the applicable visit. For participants who discontinue early from study intervention, no DAILY
EATS completion is required at the ESID visit.
8.2.5.4. 
Patient Global Impression of Change
The PGIC is a global index that is used to rate the overall status of the participant related to the
participant’s overall condition. It is rated by the participant and is based on the single question,
“Compared to before starting the study or compared to the Week 24 visit, my overall status is," where
response choices include 1 very much improved, 2 much improved, 3 minimally improved, 4 no
change, 5 minimally worse, 6 much worse, and 7 very much worse.
The single-item PGIC for satiety (PGIC-S), with question, “Compared to before starting the study or
compared to the Week 24 visit, how would you rate your satisfaction (fullness) after meals in the past
7 days?” and where response choices include 1 much more satisfied (full), 2 moderately more
satisfied (full), 3 a little more satisfied (full), 4 no change, 5 a little less satisfied (full),
6 moderately less satisfied (full), and 7 much less satisfied (full), will also be used. The content
validity of the PGIC-S has been demonstrated in overweight and obese patients with and without
T2DM, although the psychometric properties of the PGIC-S were not evaluated.
8.2.6. 
Toxicity Management
The toxicity management guidelines in this section are applicable throughout the entire study starting
from when the participant starts study intervention through the study period.
General guidance for the management of toxicities is provided in Section 8.2.6. Guidance for specific
toxicities is provided in Sections 8.2.6.1 through 8.2.6.8. In addition, see Section 8.2, Safety
Assessments, Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting, and Appendix 6: Management of Clinically Significant Laboratory
Toxicities. Questions regarding toxicity management should be directed to the sponsor’s medical
monitor.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
65
8.2.6.1. 
General Guidance for the Management of Clinical Events and
Laboratory Abnormalities
Grade 1 and 2
Continue studyintervention at the discretion of the investigator.
Grade 3
 For a Grade 3 clinical event or clinically relevant laboratory abnormality, study intervention may
be continued if the event is considered to be unrelated to study intervention.
 For a Grade 3 clinical event, or clinically relevant laboratory abnormality confirmed by repeat
testing (see Section 8.2), that is considered related to study intervention, study intervention should
be withheld until the toxicity returns to baseline or within 1 grade from baseline, ie, ≤Grade 2.
 Mandatory confirmation is not warranted for asymptomatic Grade 3 glucose elevations in
participants with preexisting diabetes, and for asymptomatic Grade 3 triglyceride or cholesterol
elevations.
 If a laboratory abnormality recurs to ≥Grade 3 following rechallenge with study intervention and
is considered to be related to study intervention, study intervention should be permanently
discontinued, and the participant managed according to local practice. Recurrence of laboratory
abnormalities considered unrelated may not require permanent discontinuation.
Grade 4
 For a Grade 4 clinical event or clinically relevant laboratory abnormality confirmed by repeat
testing (see Section 8.2), that is considered related to study  intervention, study  intervention
should be permanentlydiscontinued, and the participant managed according to local practice. The
participant should be followed as clinically indicated until the laboratory abnormality returns to
baseline or is otherwise explained, whichever occurs first. A clinically  relevant Grade 4
laboratory abnormality that is not confirmed upon repeat testing should be managed according
to the algorithm for the new toxicity grade.
 Mandatory  confirmation is not warranted for asymptomatic Grade 4 glucose elevations in
participants with preexisting diabetes, and for asymptomatic Grade 4 triglyceride or cholesterol
elevations.
 Study intervention may be continued without dose interruption for a clinically nonrelevant Grade
4 laboratory abnormalities (eg, Grade 4 creatine phosphokinase after strenuous exercise, or
triglyceride elevation that is nonfasting or that can be medically managed), or a clinical event
considered unrelated to study intervention.
A schematic overview  of these guidelines is provided in  Appendix 6: Management of Clinically
Significant Laboratory Toxicities.
8.2.6.2. 
Cutaneous Events/Rash
Darunavir is a sulfonamide. Participants who previously experienced sulfonamide allergy will be
allowed to enter the study. To date, no potential for cross-sensitivity  between  drugs in  the
sulfonamide class and DRV has been identified.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
66
Cutaneous events/rash should be captured in the AE section of the eCRF.
Management of cutaneous events/rash  will be at the discretion  of the investigator, taking into
account the following protocol procedures (see also Table 1), and should follow generally accepted
medical standards. Cetirizine, levocetirizine, topical corticosteroids, and antipruritic agents will
be allowed at the investigator’s discretion for treatment of all grades of rashes.
Grade 1 and 2 Cutaneous Reaction/Rash
A Grade 1 cutaneous reaction/rash is defined as localized rash. A Grade 2 cutaneous reaction/rash is
defined as diffuse rash or target lesions.
Participants experiencing a Grade 1 or 2 rash or cutaneous event may continue treatment or have their
study intervention interrupted at the investigator’s discretion. Safety sampling (processed by the
central laboratory) at the time ofthe rash and clinical follow-up for these AEs will be at the discretion
of the investigator; however, close clinical follow-up is recommended to monitor for any progression
of the adverse event.
Grade 3 and 4 Cutaneous Reaction/Rash
A Grade 3 cutaneous reaction/rash is defined as:
 Diffuse rash with vesicles or limited number of bullae or superficial ulceration of mucous
membrane limited to 1 site.
 For the purpose of this study, the sponsor considers qualifying as a Grade 3 rash:
 Cutaneous reaction/rash with at least 1 of the following:
elevations ofALT/AST >2× baseline but ≥5×ULN
fever 38°C or 100°F
serum sickness-like reaction
eosinophil count >1,000/mm3
 The syndromes of drug rash with eosinophilia and systemic symptoms (DRESS) and acute
generalized exanthematous pustulosis (AGEP)
A Grade 4 cutaneous reaction/rash is defined as:
 Extensive or generalized bullous lesions
 Stevens-Johnson syndrome (SJS)
 Ulceration of mucous membrane involving at least 2 distinct mucosal sites
 Toxic epidermal necrolysis (TEN)
Participants experiencing a Grade 3 or 4 rash or cutaneous event must have their study intervention
discontinued. Referral to a dermatologist and biopsy are required for these events preferably within
24 hours after the site becomes aware of the cutaneous event/rash.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
67
Safety testing (to be processed by the central laboratory) of the following parameters is required to
determine possible liver or systemic abnormalities: ALT, AST, bilirubin (total, direct and indirect),
creatinine and a hematology profile. Close clinical follow-up and appropriate medical intervention
should be instituted for these events; daily follow-up is recommended for 5 days from the onset of
the event to monitor for progression of the event and weekly afterwards as long as Grade 3 or 4 rash
is present. Once Grade 3 or 4 rash has resolved to ≤Grade 2 rash, follow-up should be done according
to the instructions for Grade 1 or 2 rash.
Table 1: 
Summary ofCutaneous Reaction/Rash Follow-up
DAIDS Toxicity Grade 
Definitions 
InvestigatorAction
Grade 1 
Localized rash  
Participant may continue study
intervention
Grade 2 
Diffuse rash Targetlesions 
Participant may continue study
intervention
Grade 3 
Diffuse rash with vesicles or limited number 
ofbullae 
Superficial ulcerations ofmucous membrane 
limited to 1 site 
For the purpose ofthis protocol, the sponsor 
considers qualifying as a Grade 3 rash the 
following: 
Cutaneous reaction/rash with at least 1 ofthe 
following:
 
Elevations in alanine
aminotransferase (ALT) and/or
aspartate aminotransferase (AST)
(>2× baseline but ≥5× upper limit
of normal range (ULN)
 
Fever 38°C or 100°F
 
Serumsickness-like reaction
 
Eosinophils>1,000/mm3
Permanentlydiscontinue study
intervention
Referral to a dermatologist and
biopsy, preferably within 24 hours
after the site becomes aware ofthe
cutaneous event/rash
Laboratoryassessments need to be
performed
Grade 4 
Extensive or generalized bullous lesions
Stevens-Johnson syndrome (SJS)
Ulceration ofmucous membrane involving
at least 2 distinct mucosal sites
Toxic epidermal necrolysis (TEN)
Permanentlydiscontinue study
intervention
Referral to a dermatologist and
biopsy, preferably within 24 hours
after the site becomes aware ofthe
cutaneous event/rash
Laboratoryassessments need to be
performed
8.2.6.3. 
Acute Systemic Allergic Reaction
Management of acute systemic allergic reactions will be at the discretion of the investigator, taking
into account the following protocol procedures (see also Table 2), and should follow generally
accepted medical standards.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
68
Grade 1
A Grade 1 acute systemic allergic reaction is defined as localized urticaria (wheals) with no medical
intervention indicated.
Participants may continue study intervention or have their study intervention interrupted at the
investigator’s discretion. The participant should be advised to contact the investigator immediately if
there is any worsening of the pruritus, or if any systemic signs or symptoms develop. Antihistamines
or topical corticosteroids or antipruritic agents may be prescribed as long as these are in line with the
(dis)allowed medications as indicated in Section 6.7, Concomitant Therapy, or in the local Prescribing
Information of the ARV agents.
Grade 2
A Grade 2 acute systemic allergic reaction is defined as localized urticaria with medical intervention
indicated, or mild angioedema with no intervention indicated.
Participants may continue study intervention or have their study intervention interrupted at the
investigator’s discretion. If there is any worsening of the allergic reaction, the participant should be
advised to contact the investigator immediately and to discontinue study intervention. Antihistamines
or topical corticosteroids or antipruritic agents may be prescribed as supportive care as long as these
are in line with the (dis)allowed medications as indicated in Section 6.7, Concomitant Therapy, or in
the local Prescribing Information of the ARV agents.
Grade 3
A Grade 3 acute systemic allergic reaction is defined as generalized urticaria, or angioedema with
intervention indicated or symptoms of mild bronchospasm. Participants will permanently discontinue
study intervention. Participants will be treated as clinically appropriate. Standard management should
be undertaken.
Grade 4
A Grade 4 acute systemic allergic reaction is defined as acute anaphylaxis, or life-threatening
bronchospasm, or laryngeal edema. Participants will permanently discontinue study intervention.
Participants will be treated as clinically appropriate. Standard management should be undertaken.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
69
Table 2: 
Summary of Allergic Reaction Follow-up
DAIDS Toxicity  
Definitions 
InvestigatorAction
Grade 1 
Localized urticaria (wheals) with no 
medical interventionindicated 
Participant may continue study
intervention
Grade 2 
Localized urticaria with intervention  
indicated, or 
mild angioedema with no intervention
indicated
Participant may continue study
intervention
Grade 3 
Generalized urticaria, or 
angioedema with intervention indicated, or 
symptoms ofmild bronchospasm
Permanentlydiscontinue study
intervention
Grade 4 
Acute anaphylaxis, or 
life-threateningbronchospasm, or 
laryngeal edema
Permanentlydiscontinue study
intervention
8.2.6.4. 
Potential Renal Toxicity
Estimated creatinine clearance (eCrCl) will be calculated according to the Cockcroft-Gault formula
will be followed post baseline during the treatment phase. The eGFRs calculations will be performed
and provided to the investigator by the central laboratory.  Any participants who have an eCrCl of
<50 and a decrease of 20% in eCrCl from baseline, or who have other clinical and/or laboratory
evidence of acute renal failure will be discussed with the sponsor’s medical monitor and may
permanently discontinue study intervention.
The eCrCl calculations will be performed and provided to the investigator by the central laboratory.
Participants with negative or trace proteinuria at baseline who develop >1+ proteinuria on urinalysis
must have urinalysis repeated, with a concurrent urine and serum chemistry, within 2 weeks of receipt
of results. Upon confirmation of proteinuria, participants will be asked to return to the site for a
scheduled or unscheduled follow-up visit. It is recommended that the investigator contacts the
sponsor’s medical monitor to discuss if further consultation with a nephrologist is clinically
warranted.
Once an individual participant has developed any of these renal changes and the above management
guidelines have been applied, it is not necessary to further unscheduled repeat evaluations if it is
determined that it is safe for the participant to continue on treatment with standard visits as described
in the protocol.
8.2.6.5. 
Potential Posterior Uveitis Cases
In a 9-month toxicology study conducted in dogs, some animals administered the highest dose of
TAF (12 to 18 mg/kg) had minimal mononuclear cell infiltration in the posterior uvea, considered
secondary to general debilitation; this finding did not occur in animals given lower doses and it has
not occurred in other animal studies. This preclinical finding has also not been observed in humans
where the dose is much lower, nor have there been reports of posterior uveitis in human clinical
studies. Nonetheless, if participants develop signs or symptoms of posterior uveitis, which include
notable eye pain or redness, reduced visual acuity, or “floaters”, investigators in this study should
inform the sponsor’s medical monitor and determine, based on their medical judgment, the need for
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
70
ophthalmologic evaluation including dilated fundoscopy, and if required, optical coherence
tomography.
8.2.6.6. 
Hyperglycemia
Grade 3: 13.89 to 27.75 mmol/L (250-500 mg/dL)
Grade 4: >27.75 mmol/L (>500 mg/dL)
Toxicity management decisions should be based on fasted results. If elevated glucose levels are from
a nonfasted blood draw, the draw must be repeated after an 8-hour fast.
Participants who experienced asymptomatic glucose elevations of Grade 3 and participants with
preexisting diabetes who experienced asymptomatic glucose elevations of Grade 4 may continue
study intervention unless clinical assessment foresees an immediate health risk to the participant.
Appropriate clinical management of hyperglycemia must be started in a timely fashion if applicable.
Participants with persistent Grade 3 or 4 glucose elevations despite appropriate anti-hyperglycemic
treatment should permanently discontinue study intervention.
For those participants with treatment emergent hyperglycemia, initiation of medications to
address these AE should be prescribed in accordance to national treatment guidelines (See page 6:
Figure 2 in Appendix 11: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus
Report by the American Diabetes Association (ADA) and the European Association for the Study of
Diabetes (EASD).
Should a participant have a need to initiate treatment with any excluded concomitant medication, it
is recommended that investigators consult with the sponsor medical monitor beforehand to determine
if an alternative therapy could be utilized that has no known impact on weight or if the participant
should be discontinued from the study. If an excluded medication is initiated before discussion with
the medical monitor, the investigator must notify the sponsor as soon as becoming aware.
Investigators are reminded that certain medications may influence body weight changes and should
be avoided. (see disallowed concomitant therapy below). Participants should not initiate therapy with
concomitant medications associated with significant weight changes during the course of the study
as listed in Exclusion Criteria No. 11.
Participants who experience clinically significant changes in body weight during the course of the
study may require dose reductions or withdrawal of medications to treat type II diabetes in order to
avoid events such as hypoglycemia. As part of routine care at scheduled follow-up visits, participants
should be assessed to determine if a dose reduction or withdrawal of medications for the treatment of
such conditions is warranted. These changes should be recorded in the CRF.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
71
8.2.6.7. 
Hypertriglyceridemiaand Hypercholesterolemia
Hypertriglyceridemia: Grade 3: 5.7 to 11.4 mmol/L (>500-1,000 mg/dL)
Grade 4: >11.4 mmol/L (>1,000 mg/dL)
Hypercholesterolemia: Grade 3: ≥7.77 mmol/L (>300 mg/L)
Grade 4: Not applicable
Toxicity management decisions should be based on fasted results. If elevated lipid levels are from a
nonfasted blood draw, the draw must be repeated after an 8-hour fast.
Participants who experienced asymptomatic triglyceride or cholesterol elevations of Grade 3 or 4 may
continue study intervention unless clinical assessment foresees an immediate health risk to the
participant.
Hypertriglyceridemia and hypercholesterolemia should be treated according to the specific guidelines
for treating HIV-positive participants (see Figure 4 in Appendix 9: Characteristics, Prevention, and
Management of Cardiovascular Diseases in People Living with HIV by American Heart Association.
The presence or absence of other significant cardiovascular risk factors, which include smoking, age,
family history of premature cardiovascular disease, diabetes, hypertension, low high-density
lipoprotein (HDL), and prior history of cardiovascular disease should be taken into account.
Appropriate clinical management of hyperlipidemia in the setting of HIV should be started in a timely
fashion if applicable and taking into account the disallowed medications (refer to Section 6.8,
Concomitant Therapy).
8.2.6.8. 
Lipodystrophy/Fat Redistribution/Body Changes
Investigators are requested to avoid using the term ‘lipodystrophy acquired’ or ‘fat redistribution’ to
describe and report body fat abnormalities, as these terms are not descriptive nor fully accurate. The
different symptoms and gradings are listed in the DAIDS grading table (Appendix 7: DAIDS Table
for Grading the Severity of Adult and Pediatric Adverse Events) under Endocrine/Metabolic. The
following terms are included: lipohypertrophy, lipoatrophy, and gynecomastia. Although metabolic
abnormalities such as hyperlipidemia or hyperglycemia are often associated with body changes, these
events should be recorded separately at AE reporting.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information from clinical studies are
crucial for the protection of participants, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
Adverse events (AEs) will be reported by the participant (or, when appropriate, by a caregiver,
surrogate, or the participant's legally acceptable representative) for the duration of the study.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
72
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions;
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality complaints,
refer to Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF is obtained until completion of the participant's last study-related
procedure, which may include contact for follow-up of safety. Serious adverse events, including those
spontaneously reported to the investigator within 30 days after the last dose of study intervention,
must be reported using the SAE Form. The sponsor will evaluate any safety information that is
spontaneously reported by an investigator beyond the time frame specified in the protocol.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person by
study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious
Adverse Event Form and Safety Report Form of the CRF, which must be completed and reviewed by
a physician from the study site, and transmitted to the sponsor within 24 hours. The initial and follow-
up reports of a serious adverse event should be transmitted electronically or by facsimile (fax).
8.3.2. 
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in Appendix 4:
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.3.3. 
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. The
sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or sponsor
where required) must report SUSARs to the appropriate IEC/IRB that approved the protocol unless
otherwise required and documented by the IEC/IRB.
8.3.4. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be reported
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous abortion,
fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and must be
reported using the SAE Form. Any participant who becomes pregnant during the study must be
promptly withdrawn from the study.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
73
Because the effect of the D/C/F/TAF FDC on sperm is unknown, pregnancies in partners of male
participants included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.3.5. 
Adverse Events of Special Interest
Not applicable.
8.4. 
Pharmacokinetics
Plasma samples may be used to evaluate the concentration of DRV and COBI in participants
experiencing confirmed virologic rebound using stored blood samples collected throughout the study
at the discretion of the sponsor. Plasma concentrations of INIs for the Delayed Switch arm may be
determined in participants experiencing confirmed virologic rebound using stored blood samples
collected throughout the study, if deemed necessary by the sponsor. Genetic analyses will not be
performed on these plasma samples. Participant confidentiality will be maintained.
8.4.1. 
Evaluations
Venous blood samples of approximately 3mL will be collected for measurement of plasma
concentrations of DRV and COBI in participants experiencing confirmed virologic rebound using
stored blood samples collected throughout the study at the discretion of the sponsor. Plasma
concentrations of INIs for the Delayed Switch arm may be determined in participants experiencing
confirmed virologic rebound using stored blood samples collected throughout the study, if deemed
necessary by the sponsor.
Urine samples will be collected for measurement of various parameters as mentioned in Schedule of
Activities (SoA).
8.4.2. 
Pharmacokinetic Parameters and Evaluations
Not applicable.
8.5. 
Genetics
Not applicable.
8.6. 
Biomarkers
Alpha Melanocyte-Stimulating Hormone
Alpha melanocyte-stimulating hormone has multiple functions. Melanocyte-stimulating hormone is
produced from the same precursor molecule as adrenocorticotropic hormone called pro-
opiomelanocortin (POMC). The presence of alpha melanocyte-stimulating hormone induces a satiety
response. This effect is enhanced by leptin, a hormone released from fat cells. A decrease in the
presence of alpha melanocyte-stimulating hormone may lead to increased food intake and obesity.
As an exploratory endpoint, levels of alpha melanocyte-stimulating hormone will be collected to
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
74
determine if there is a change in the amount of circulating hormone in patients who have rapidly
gained weight on an INI + TAF/FTC versus being switched over to D/C/F/TAF.33
Leptin
Leptin is a hormone secreted by adipose tissue that regulates a variety of immune, metabolic, and
neuroendocrine functions. It also helps to maintain energy balance. Leptin works to regulate glucose
and lipid metabolism by affecting pancreatic release of insulin and plays a role in increasing insulin
sensitivity. Leptin increases thermogenic energy expenditure which prevents fat accumulation. Leptin
also plays a role in the maintenance of weight by inducing satiety via a hypothalamic signal during
and after a meal. In collecting the leptin levels in those patients who have rapidly gained weight on
an INI + TAF/FTC regimen, we are interested to see if these levels are changed while on the baseline
regimen compared to when participants are switched over to D/C/F/TAF.37
Adiponectin
Adiponectin is an adipokine that enhances energy metabolism and fatty acid oxidation. It also
promotes insulin sensitivity. Adiponectin is released by adipose tissue. The levels of adiponectin in
the blood are inversely related to adipose tissue mass. Lower levels of adiponectin in the blood are
associated with metabolic disease. Adiponectin levels will be collected to see if there is a change in
levels in those participants who have rapidly gained weight on an INI + TAF/FTC compared to when
participants are switched to D/C/F/TAF.7
8.6.1. 
Pharmacodynamics
Not applicable.
8.7. 
Immunogenicity Assessments
Not Applicable
8.8. 
Health Economics OR Medical Resource Utilization and Health Economics
Not applicable.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the data collected in this study is outlined
below. Specific details will be provided in the Statistical Analysis Plan.
9.1. 
Statistical Hypotheses
The statistical hypothesis is the following:
H0: Dt-Dc 0 versus H1: Dt -Dc≠0.
Where H0 is the null hypothesis, H1 is the alternative hypothesis; Dt
%body weight change from
baseline at Week 24 for treatment D/C/F/TAF, Dc for the Delayed Switch arm.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
75
The statistical hypothesis will be tested using repeated measures longitudinal method (linear mixed-
effects model) at 0.05 significance level, 2-sided.
9.2. 
Sample Size Determination
Using a T-test with 80% power to detect a difference of 3% at the significance level of 0.05, 2-sided,
the sample size per treatment arm is a simple function of effect size (ES): narm 16/(ES)^2. The effect
size is the standardized difference: ES Δ/σ, where Δ is the difference between the two arms, and σ2
is the common variance. Since there was no direct data on the study population to assume the observed
difference, Δ 3% is considered a clinical meaningful difference. Internal data from 2 Phase 3
studies15,29 on D/C/F/TAF FDC arm from different HIV patient populations (naive, switch) have
shown the % body weight change in the range of 1.5% to 1.8% and standard deviation from 4.0 to
4.6 (Table 3 and Figure 3), resulting a range of ES and corresponding sample size.
Table 3: 
Phase 3 Studies on D/C/F/TAF FDC Arm
Study  
AMBER  
D/C/F/TAF arm  
EMERALD
D/C/F/TAF arm
N 
% body weight change from baseline at week 
24 (SD)
347 
1.5 (4.6) 
738
1.8 (4.0)
N 
% body weight change from baseline at week 
48 (SD)
340 
2.3 (5.0) 
728
1.9 (5.1)
(Data on file)
Abbreviations: D/C/F/TAF FDC: darunavir/cobicistat/emtricitabine/tenofovir alafenamide fixed dose combination, N: number, SD: standard
deviation
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
76
Figure 3: 
Sample Size Estimation by Treatment Effect Size
Given the uncertainty of either the Δ or the variability, an adaptive unblinded SSR is planned to
re-estimate the sample size in an IA to ensure adequate power in the hypothesis testing for the primary
endpoint using the conditional power approach. An initial sample size of 55 participants per treatment
arm (110 participants total) will be used for a treatment effect size of 0.54 (ADDPLAN version 6).
The IA is planned when approximately 60% of the initial planned 110 participants have completed
the Week 12 Visit and approximately 30% of participants have completed the Week 24 visit to re-
estimate the sample size to ensure adequate power for the hypothesis testing. All cumulative data will
be used for the IA. The planned maximum total sample size after SSR is 150 participants. Details for
the SSR, threshold for the conditional power, and protection of overall significance level will be
provided in the statistical plan for the IA and monitoring (Section 9.6).
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population 
Description
Enrolled 
All participants who sign the informed consent form (ICF)
Intent-to-treat 
(ITT) 
includes all randomized participants who received at least 1 dose of study intervention.
Participants will be assessed according to their randomized treatment arm, regardless of the
treatment they received.
Per-protocol (PP) includes a subset of participants in the ITT who are in-compliance with the protocol.
Safety 
includes all randomized participants who received at least 1 dose of study intervention.
Participants will be assessed according to the actual intervention they received.
For all participants who receive at least 1 dose of study intervention descriptive statistics will be
provided. Participant information will be analyzed based on the ITT population, unless otherwise
specified.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
77
9.4. 
Statistical Analyses
The statistical analysis plan will be finalized prior to DBL and it will include a more technical and
detailed description of the statistical analyses described in this section. This section is a summary of
the planned statistical analyses of the most important endpoints including primary and key secondary
endpoints.
9.4.1. 
General Considerations
The following analyses will be performed:
 An interim analysis at week 12 for monitoring purpose including an unblinded sample size re-
estimation and futility analysis (see also Section 9.6).
 The primary  analysis: once all participants have completed the Week 24 assessments or
discontinued earlier. The primary hypothesis will be tested at an overall significance level of 0.05,
2-sided in a longitudinal data with repeated measures model (Section 9.4.2).
 The Week 48 analysis: once all participants have completed the Week 48 assessments or
discontinued earlier. Descriptive statistics will be conducted.
9.4.2. 
Primary Analysis
The primary endpoint analyses will be based on the ITT population. The analysis will be conducted
using linear mixed-effects model with participant as random effect adjusted by baseline BMI and
stratification factors in a longitudinal data with repeated measures (percent body weight change
measured at multiple visits).40
9.4.3. 
Secondary Analyses
9.4.3.1. 
Metabolic Analyses
For the metabolic endpoints of change from baseline, the same statistical model as described for the
primary endpoint will be used for analysis. All other endpoints will be analyzed using descriptive
statistics.
9.4.3.2. 
Resistance/Efficacy Analyses
HIV-1 genotypes, and phenotypes (PhenoSense GT® Plus Integrase) if applicable, will be analyzed
from samples of participants with virologic rebound and with HIV-1 RNA ≥400 copies/mL.
The proportion of virologic suppression (HIV-1 RNA<50 copies/mL) and failure (HIV-1 RNA ≥50
copies/mL) using the FDA snapshot algorithm in the ITT will also be analyzed as a secondary
endpoint at Weeks 24 and 48 using descriptive statistics along with 95% confidence interval (CI,
Wilson score method).
The proportion of participants experiencing virologic rebound through Week 24 and 48 will be
tabulated using descriptive statistics along with the 95% confidence intervals (CI, Wilson score
method).
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
78
The changes from screening/baseline in CD4+ cell count at Weeks 24 and 48 will be summarized
using descriptive statistics.
The number of identified protease (PR) mutations (including International AIDS Society [IAS]-USA
primary and secondary PI resistance-associated mutations [RAMs], reverse transcriptase (RT)
mutations (including IAS-USA nucleoside/nucleotide RT inhibitor [N[t]RTI] RAMs, IAS-USA non-
nucleoside RT inhibitor [N[t]RTI] RAMs), and integrase (INI) mutations (including International
AIDS Society [IAS]-USA INI-RAMs and IAS-USA primary INI mutations), as well as specific
mutations associated with resistance to DRV, FTC, and TAF, will be tabulated based on the observed
virologic rebound through the study period. Retrospectively, fold change (FC) in 50% effective
concentration (EC50) of ARVs may be analyzed and tabulated dependent on the number of virologic
rebounds and phenotypes available through the study period.
9.4.3.3. 
Adherence Analyses
Treatment adherence based on participant self-report, using a 4-day recall will be summarized by
means of descriptive statistics and frequency tabulations for both D/C/F/TAF and the INI + TAF/FTC
ARV regimen.
Adherence rates will be reported according to the proportion of participants missing 0, 1, 2, 3 or 4
doses using participant self-report 4-day recall at Weeks 4, 12, 24, 36, and 48.
9.4.4. 
Safety Analyses
All safety analyses will be made on the Safety Population. For all safety endpoints descriptive
statistics will be used to summarize the endpoints.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be categorized according
to system organ class and graded according to DAIDS as specified in Appendix 7: DAIDS Table for
Grading the Severity of Adult and Pediatric Adverse Events. Any AE occurring at or after the initial
administration of study intervention through the day of last dose plus 7 days is considered to be
treatment-emergent. All reported treatment-emergent adverse events (TEAEs) will be included in the
analysis. For each AE, the percentage of participants who experience at least 1 occurrence of the
given event will be summarized by intervention arm.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe or a
serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by treatment arm and type of laboratory test. Reference ranges
and markedly abnormal results (specified in the Statistical Analysis Plan) will be used in the summary
of laboratory data. Descriptive statistics will be calculated for all laboratory analyte for observed
values and for changes from Screening/Baseline at each scheduled time point. Laboratory
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
79
abnormalities will be categorized according to analyte and graded according to DAIDS as specified
in Appendix 7: DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events.
Vital Signs
Descriptive statistics of vital signs including temperature, pulse/heart rate, body weight, and blood
pressure (systolic and diastolic) (supine) values and changes from baseline will be summarized at
each scheduled time point. The percentage of participants with values beyond clinically important
limits will be summarized. Vital signs abnormalities will be categorized according to parameter and
graded according to DAIDS as specified in Appendix 7: DAIDS Table for Grading the Severity of
Adult and Pediatric Adverse Events.
Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
Physical examination findings will be summarized at each scheduled time point. Descriptive statistics
will be calculated at baseline and for observed values and changes from baseline at each scheduled
time point. Frequency tabulations of the abnormalities will be made.
9.4.5. 
Patient-reported Outcomes Analyses
Descriptive statistics for absolute values will be calculated for each PRO measure including BSQ-
8D, HIV-SI, DAILY EATS, and PGIC and at each timepoint per Schedule of Activities (SoA). In
addition, changes from baseline in the proportion of participants who have bothersome symptoms
(scores of 2, 3 or 4) across all items of the HIV-SI at Weeks 24 and 48, changes from baseline in the
proportion of participants who have any symptoms (scores of 1, 2, 3 or 4) across all items of the HIV-
SI at Weeks 24 and 48, and changes from baseline in the scores on the BSQ-8D and proportion of
participants who have no concern (<19), mild concern (19-25), moderate concern (26-33) or marked
concern (>33) with their body shape at Weeks 24 and 48 and changes from baseline in the scores on
the DAILY EATS at Weeks 24 and 48 will be summarized.  Association between treatment arm and
each bothersome symptom of the HIV-SI adjusting for baseline variables at Weeks 24 will be
calculated. To understand meaningful change in scores on PRO measures, PGIC-S will be used as an
anchor to assess meaningful change scores for the DAILY EATS in participants living with HIV.
9.5. 
Interim Analysis
An IA will be performed when approximately 60% of the initial planned 110 participants have
completed the Week 12 Visit and approximately 30% of participants have completed the Week 24
Visit to assess SSR unblinded to ensure adequate power for the hypothesis testing for the primary
endpoint.
9.6. 
Data Monitoring Committee or Other Review Board
A Data Review Committee (DRC) will be established to evaluate SSR at an IA from this study. An
adaptive unblinded SSR is planned to re-estimate the sample size to ensure adequate power in the
hypothesis testing for the primary endpoint using the conditional power approach, in which the
thresholds of conditional power will be considered in relation to the required sample sizes. An IA is
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
80
planned when approximately 60% of the initial planned 110 participants have completed the Week
12 Visit and approximately 30% of participants have completed the Week 24 Visit to re-estimate the
sample size to ensure adequate power for the hypothesis testing. In addition, a futility will be
evaluated regarding the statistical hypothesis based on available interim data and conditional power.
All cumulative data will be used in a Bayesian posterior predictive probability approach to assess
SSR and futility. Further details regarding the derivation of the conditional power and the choice of
threshold for the conditional power for SSR, futility and protection of overall significance level will
be provided in the DRC charter and DRC SAP. The SSR and futility analysis will be guided by the
DRC, and the study team will remain blinded to the analysis. It is not the intention to stop the study
early in case of superiority of the D/C/F/TAF FDC regimen versus the Delayed Switch arm. The DRC
will consist of 2 medical experts in the relevant therapeutic area and 1 statistician, independent to the
study team. The DRC responsibilities, authorities, and procedures will be provided in the DRC
charter.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
81
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
AE  
adverse event
AIDS  
Acquired Immunodeficiency Syndrome
ALT  
alanineaminotransferase
ARV  
antiretroviral
ART  
antiretroviral therapy
AST  
aspartate aminotransferase
BMI 
body metabolic index
BSQ-8D 
body shape questionnaire
C 
cobicistat (COBI)
CI 
confidence interval
CRF  
case report form(s) (paper or electronic as appropriate for this study)
D 
darunavir (DRV)
DAIDS  
Division of Acquired Immunodeficiency Syndrome
DBP 
diastolic blood pressure
DEXA  
dual-energy X-ray absorptiometry
DHHS  
Department of Health and Human Services
eCrCl 
estimated creatinine clearance
eDC  
electronic data capture
eGFRcr 
creatinine-based estimated glomerular filtration rate
ESID  
early study intervention discontinuation
F 
emtricitabine
FDA 
food drug administration
FDC  
fixed-dose combination
HAIR  
hypertension, age, insulin, resistance
HCV  
hepatitis C virus
HIV  
human immunodeficiency virus
HIV-1 RNA  
human immunodeficiency virus type-1 ribonucleic acid
HIV-SI 
HIV-Symptom Index
HOMA-IR  
homeostatic model assessment ofinsulin resistance
IA  
interim analysis
IAS-USA  
International AIDS Society-United States ofAmerica
ICF  
informed consent form
IEC  
independent ethics committee
INI 
integrase
IRB  
Institutional Review Board
ITT  
intent-to-treat
IWRS  
interactive web response system
NAFLD  
non-alcoholic fatty liver disease
NRTI 
nucleoside reverse transcriptase inhibitor
PGIC  
patient global impression of change
PGIC-S 
patient global impression of change–Satiety
PI 
protease inhibitor
PQC 
product quality complaint
PK 
pharmacokinetic
PR 
protease
PRO  
patient reported outcomes
RAM  
resistance-associated mutations
RT  
reverse transcriptase
SAEs 
serious adverse events
SAP  
statistical analysis plan
SBP 
systolic blood pressure
SSR  
sample size re-estimation
SUSARs 
suspected unexpected serious adverse reactions
TAF  
tenofovir alafenamide
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
82
10.2. Appendix 2: Clinical Laboratory Tests and Calculations
The following tests will be performed according to the Schedule of Activities (SoA) by the central
laboratory:
NCT04442737


NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
84
Calculations
Body Mass Index (BMI)
(kg/m2 )
Weight (kg) / [Height (m)]2
Child Pugh Class
eGFRcr (Cockcroft-Gault 
Formula) 
CrCl (male) = ([140-age] × weight in kg)/(serum creatinine × 72)
CrCl (female) = ([140-age] × weight in kg)/(serum creatinine × 72) × 0.85
Note: If a participant’s actual body weight is greater than 20% over their Ideal
Body Weight, the participant’s Adjusted BodyWeight will be used for eGFRcr
(Cockcroft-GaultFormula):
Ideal Body Weight (IBW):
Male: 50kg + 0.9kg x (height(cm) –152)
Female: 45.5kg + 0.9kg x (height(cm) –152)
Adjusted Body Weight:
IBW (kg) + 0.4 x (Weight(kg) –IBW (kg))
HOMA-IR (mg/dL) 
Fasting insulin x Fasting glucose / 405
Non-Alcoholic Fatty Liver 
-1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG/diabetes (yes =
Disease (NAFLD) Fibrosis 
Score1 
1, no = 0) + 0.99 × AST/ALT ratio –0.013 × platelet (×109/l) –0.66 × albumin
(g/dl)
NAFLD Score <-1.455 = F0-F2
NAFLD Score -1.455 –0.675 = indeterminate score
NAFLD Score >0.675 = F3-F4
NASH: HAIR Scores12
HAIR score (0–3) is calculated by adding Hypertension = 1, ALT >40 IU
=1, and IR index >5.0 = 1
A score of ≥2 is high risk for NASH.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
85
10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by the
sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must be
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of amendment
approval by the investigator and IEC/IRB must be provided to the sponsor. When the change(s)
involve only logistic or administrative aspects of the study, the IEC/IRB (where required) only needs
to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, the
investigator or other physician in attendance will contact the appropriate sponsor representative listed
in the Contact Information page(s), which will be provided as a separate document. Except in
emergency situations, this contact should be made before implementing any departure from the
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the
situation and agree on an appropriate course of action. The data recorded in the CRF and source
documents will reflect any departure from the protocol, and the source documents will describe this
departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities in
each respective country, if applicable. A study  may not be initiated until all local regulatory
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention to
the study site:
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
86
 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if applicable,
participant compensation programs. This approval must clearly identify the specific protocol by
title and number and must be signed (or sealed, where appropriate per local regulations) by the
chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the applicable
laws and regulations. If accompanied by a letter of explanation, or equivalent, from the IEC/IRB,
a general statement may be substituted for this list. If an investigator or a member of the study-
site personnel is a member of the IEC/IRB, documentation must be obtained to state that this
person did not participate in the deliberations or in the vote/opinion of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where required
 
Signed and dated clinical trial agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
Investigator's Brochure (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
87
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented by
the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting materials,
and participant compensation programs, and the sponsor has received a copy of this approval. This
approval letter must be dated and must clearly identify the IEC/IRB and the documents being
approved.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and accurate
financial certification or disclosure statements to the appropriate regulatory authorities. Investigators
are responsible for providing information on financial interests during the course of the study and for
1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
INFORMED CONSENT PROCESS
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any study- related
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing
IEC/IRB and be in a language that the participant can read and understand. The informed consent
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site personnel
must explain to potential participants the aims, methods, reasonably anticipated benefits, and potential
hazards of the study, and any discomfort participation in the study may entail. Participants will be
informed that their participation is voluntary and that they may withdraw consent to participate at any
time. They will be informed that choosing not to participate will not affect the care the participant
will receive for the treatment of his or her disease. Participants will be told that alternative treatments
are available, or they can remain on their current ARV regimen if they refuse to take part and that
such refusal will not prejudice future treatment. Finally, they will be told that the investigator will
maintain a participant identification register for the purposes of long-term follow up if needed and
that their records may be accessed by health authorities and authorized sponsor personnel without
violating the confidentiality of the participant, to the extent permitted by the applicable law(s) or
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
88
regulations. By signing the ICF the participant is authorizing such access, which includes permission
to obtain information about his or her survival status. It also denotes that the participant agrees to
allow his or her study physician to recontact the participant for the purpose of obtaining consent for
additional safety evaluations, and subsequent disease-related treatments, if needed.
The participantwill be givensufficienttime to readthe ICF andthe opportunityto askquestions. After
this explanation and before entry into the study, consent should be appropriately recorded by means
of the participant's personally dated signature. After having obtained the consent, a copy ofthe ICF
must be given to the participant.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be limited
to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality and
compliance with applicable data privacy protection laws and regulations. Appropriate technical and
organizational measures to protect the personal data against unauthorized disclosures or access,
accidental or unlawful destruction, or accidental loss or alteration must be put in place. Sponsor
personnel whose responsibilities require access to personal data agree to keep the identity of
participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator/institution to allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory
inspection. This consent also addresses the transfer of the data to other entities and to other countries.
The participant has the right to request through the investigator access to his or her personal data and
the right to request rectification of any data that are not correct or complete. Reasonable steps will be
taken to respond to such a request, taking into consideration the nature of the request, the conditions
of the study, and the applicable laws and regulations.
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH
Blood samples collected in this study may be stored for up to 15 years (or according to local
regulations) for additional research. Samples will only be used to understand D/C/F/TAF FDC tablet,
to understand HIV-1 infection and to understand differential intervention responders. The research
may begin at any time during the study or the poststudy storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
89
COMMITTEES  STRUCTURE
The DRC will consist of two medical experts in the relevant therapeutic area and one statistician,
independent to the study team. The DRC responsibilities, authorities, and procedures will be provided
in the DRC charter.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding D/C/F/TAF FDC tablet or the
sponsor's operations (eg, patent application, formulas, manufacturing processes, basic scientific data,
prior clinical data, formulation supplied by the sponsor to the investigator and not previously
published, and any data, including research data, generated as a result of this study, are considered
confidential and remain the sole property of the sponsor. The investigator agrees to maintain this
information in confidence and use this information only to accomplish this study, and will not use it
for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the sponsor
in connection with the continued development of D/C/F/TAF FDC tablet, and thus may   be disclosed
as required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all data
obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and will
contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the study
will be used to determine a coordinating investigator for the study. Results of analyses performed
after the Clinical Study Report has been issued will be reported in a separate report and will not
require a revision of the Clinical Study  Report.
Study participant identifiers will not be used in publication of results. Any work created in connection
with performance of the study and contained in the data that can benefit from copyright protection
(except any publication by the investigator as provided for below) shall be the property of the sponsor
as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal Editors
(ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter) data and
information without approval from the investigator. The investigator has the right to publish study
site-specific data after the primary data are published. If an investigator wishes to publish information
from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days
before submission for publication or presentation. Expedited reviews will be arranged for abstracts,
poster presentations, or other materials.  If requested by the sponsor in writing, the investigator will
withhold such publication for up to an additional 60 days to allow for filing of a patent application.
In the event that issues arise regarding scientific integrity or regulatory compliance, the sponsor will
review these issues with the investigator. The sponsor will not mandate modifications to scientific
content and does not have the right to suppress information. For multicenter study designs and
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
90
substudy approaches, secondary  results generally  should not be published before the primary
endpoints of a study have been published. Similarly, investigators will recognize the integrity of a
multicenter study by not submitting for publication data derived from the individual study site until
the combinedresults from the completed study have been submitted for publication, within 18 months
after the study end date, or the sponsor confirms there will be no multicenter study publication.
Authorship of publications resulting from this study will be based on the guidelines on authorship,
such as  those described in the International Committee of Medical Journal Editors (ICMJE)
Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical
Journals, which state that the named authors must have made a significant contribution to the
conception or design of the work; or the acquisition, analysis, or interpretation of the data for the
work; and drafted the work or revised it critically for important intellectual content; and given final
approval of the version to be published; and agreed to be accountable for all aspects  of the work in
ensuring that questions related to the accuracy or integrity of any part of the work are appropriately
investigated andresolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order to
ensure the statistical analyses are relevant.
DATA QUALITY ASSURANCE
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, periodic monitoring visits by the sponsor, direct transmission
of clinical laboratory data from a central laboratory into the sponsor's data base, and electronic
transmission of electronic PRO data to the electronic PRO vendor data base then to the Sponsor’s
clinical data base. Written instructions will be provided for collection, handling, storage, and
shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before the
start of the study. The sponsor will review eCRFs for accuracy and completeness during on- site
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with the
investigator or designee, as appropriate. After upload of the data into the study data base they will be
verified for accuracy and consistency with the data sources.
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in electronic format.
All data relating to the study must be recorded in eCRF. All eCRF entries, corrections, and alterations
must be made by the investigator or authorized study-site personnel. The investigator must verify that
all data entries in the eCRF are accurate and correct.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
91
The study data will be transcribed by study-site personnel from the source documents onto an eCRF,
if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any such
worksheets will become part of the participant's source documents. Data must be entered into eCRF
in English. The eCRF must be completed as soon as possible after a participant visit and the forms
should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be completed
by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed    after
the initial entry into the eCRF, this can be done in either of the following ways:
 
Investigator and study-site personnel can make corrections in the eDC tool at their own initiative
or as a response to an auto query (generated by the eDC tool).
 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the protocol;
record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of  study
completion and reason for early discontinuation of study intervention or withdrawal from the study,
ifapplicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines (or
other equivalent document).
The following data will be recorded directly into the electronic device to collect PROs and will be
considered source data:
 
HIV-SI
 
BSQ-8D
 
DAILY EATS
 
PGIC, PGIC-S
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
92
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical study-
specific data fields as determined by the protocol. This data is electronically extracted for    use by
the sponsor. If eSource is utilized, references made to the eCRF in the protocol include       the eSource
system, but information collected through eSource may not be limited to that found       in the eCRF.
MONITORING
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
postinitiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor   will   compare   the   data   entered   into   the   eCRF   with   the   source   documents (eg,
hospital/clinic/physician’s office medical records). The nature and location of all source documents
will be identified to ensure that all sources of original data required to complete the eCRF are known
to the sponsor and study-site personnel and are accessible for verification by the sponsor study-site
contact.  If electronic records are maintained at the study site, the method of verification must be
discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will be
discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a suitable
environment will be provided for review of study-related documents. The monitor will meet with the
investigator on a regular basis during the study to provide feedback on the studyconduct.
ON-SITE AUDITS
Representatives of the sponsor's clinical quality assurance department may visit the study site at   any
time during or after completion of the study to conduct an audit of the study in compliance    with
regulatory guidelines and company policy. These audits will require access to all study records,
including source documents, for inspection. Participant privacy must, however, be respected. The
investigator and study-site personnel are responsible for being present and available for consultation
during routinely scheduled study-site audit visits conducted by the sponsor or its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as     part
of a national GCP compliance program or to review the results of this study in support of a regulatory
submission. The investigator should immediately notify the sponsor if he or she has     been contacted
by a regulatory agencyconcerning an upcoming inspection.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
93
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF    and
all source documents that support the data collected from each participant, as well as all       study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period if
required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility
of keeping the study records, custody must be transferred to a person who will accept the
responsibility. The sponsor must be notified in writing of the name and address of the new custodian.
Under no circumstance shall the investigator relocate or dispose of any study documents before
having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any reason
at the sole discretion of the sponsor. Study sites will be closed upon study completion. A study site
is considered closed when all required documents and study supplies have been collected and a study-
site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
94
 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or local
health authorities, the sponsor's procedures, or GCP guidelines
 
Inadequate recruitment of participants by the investigator
 
Discontinuation of further study intervention development
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
95
10.4. Appendix 4: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a clinical study participant
administered a medicinal (investigational or non-investigational) product. An AE does not
necessarily have a causal relationship with the intervention. An AE can therefore be any unfavorable
and unintended sign (including an abnormal finding), symptom, or disease temporally associated with
the use of a medicinal (investigational or non-investigational) product, whether or not related to that
medicinal (investigational or non-investigational) product. (Definition per International Conference
on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AE starting with the signing of the ICF (refer to All Adverse Events under
Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious Adverse Events
Information, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event (SAE) based on ICH and EU Guidelines on Pharmacovigilance for Medicinal
Products for Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is also
appropriate in other situations, such as important medical events that may not be immediately life
threatening or result in death or hospitalization but may jeopardize the participant or may require
intervention to prevent one of the other outcomes listed in the definition above. These should usually
be considered serious.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
96
If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention and the event (eg, death from anaphylaxis), the event must be reported
as a serious and unexpected suspected adverse reaction even if it is a component of the study endpoint
(eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For D/C/F/TAF FDC tablet, the expectedness of an AE will be
determined by whether or not it is listed in the applicable full Prescribing Information current at the
time the event is reported.
ATTRIBUTION DEFINITIONS
Assessment of Causality
The causal relationship to study treatment is determined by the Investigator. The following selection
should be used to assess all adverse events (AE).
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
SEVERITY CRITERIA
An assessment of severity grade will be made using the general categorical descriptors outlined in
the DAIDS toxicity grading table in Appendix 7: DAIDS Table for Grading the Severity of Adult
and Pediatric Adverse Events. The investigator should use clinical judgment DAIDS Table for
Grading the Severity of Adult and Pediatric Adverse Events.in  assessing the severity of events not
directly experienced by the participant (eg, laboratory abnormalities).
A distinction should be made between seriousness and severity of adverse events. An AE assessed
as Grade 4 (potentially  life-threatening) should not be confused with  a serious adverse event.
Severity is a category utilized for rating the intensity of an event, and both AEs and SAEs can  be
assessed as Grade 4. An  event is defined as ‘serious’ when  it meets one of the predefined
outcomes listed above.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or
Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or serious adverse events. However,
laboratory abnormalities independent of the underlying medical condition that require medical or
surgical intervention or lead to study intervention interruption or discontinuation must be recorded
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
97
as an AE as well as a SAE, if applicable. Laboratory or other abnormal assessments (eg, vital signs)
that are associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the
definitions as described above. If the laboratory abnormality is part of a syndrome, the
syndrome/diagnosis (ie, anemia) must be recorded and not the laboratory result (ie, decreased
hemoglobin).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study intervention
 
Unexpected therapeutic or clinical benefit from use of a sponsor study intervention
 
Medication error, intercepted medication error, or potential medication error involving a Johnson
& Johnson medicinal product (with or without patient exposure to the Johnson & Johnson
medicinal product, eg, product name confusion, product label confusion, intercepted prescribing
or dispensing errors)
 
Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that meets
the criteria of a serious adverse event should be recorded on the serious adverse event page of the
CRF.
PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must be
recorded using medical terminology in the source document and the eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, runny
nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory infection").
Investigators must record in the eCRF their opinion concerning the relationship of the AE to study
therapy. All measures required for AE management must be recorded in the source document and
reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be provided
with a "wallet (study) card" and instructed to carry this card with them for the duration of the study
indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
98
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical staff only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the participant's participation in the study, must be followed until any of the
following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated to
study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs
during the course of a participant's participation in a study must be reported as a serious adverse
event, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such
as pending placement in long-term care facility).
 
Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the underlying
condition for which the hospitalization was planned has not worsened, will not be considered
serious adverse events. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new serious adverse event.
Disease progression should not be recorded as an AE or SAE term; instead, signs and symptoms of
clinical sequelae resulting from disease progression/lack of efficacy will be reported if they fulfill the
SAE definition (refer to Adverse Event Definitions and Classifications in Appendix 4: Adverse
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting).
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information page(s),
which will be provided as a separate document.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
99
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, or reliability of a product, including its labeling or package integrity. A PQC may have an
impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of participants, investigators,
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting of
PQC information; all studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
If the defect is combined with a SAE, the study-site personnel must report the PQC to the sponsor
according to the SAE reporting timelines (refer to Section 8.3.1, Time Period and Frequency for
Collecting Adverse Event and Serious Adverse Event Information). A sample of the suspected
product should be maintained for further investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be provided
as a separate document.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
100
10.5. Appendix 5: Contraceptive and Barrier Guidance and Collection of
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.4, Pregnancy, and
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in female participants not
using hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months of amenorrhea, a single FSH measurement is insufficient.
 permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal
occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal female
participant experiences menarche) or the risk of pregnancy changes (eg, a female participant who is
not heterosexually active becomes active), a female participant must begin a highly effective method
of contraception, as described throughout the inclusion criteria. If reproductive status is questionable,
additional evaluation should be considered.
Contraceptive (birth control) use by male or female participants should be consistent with local
regulations regarding the acceptable methods of contraception for those participating in clinical
studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
101
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of ≤1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Bilateral tubal occlusion
 Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not,
additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately
74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 
Estrogen-based hormonal contraception may  not be reliable when  taking the study  drug.
Therefore, to be eligible for this study, women ofchildbearing potential should either use:
 a double-barrier method (male condom + either diaphragm or cervical cap);OR
 non-estrogen  hormonal based contraceptives in combination with a barrier contraceptive (male
condom, diaphragm or cervical cap, or female condom);OR
 intrauterine device in combination with a barrier contraceptive (male condom, diaphragm or
cervical cap, or female condom).
Note: A male condom and female condom should not be used together due to risk ofbreakage or
damage caused by latex friction.
 Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle
of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of >1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of
action.
 Male or female condom with or without spermicidec
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier
methods)c
 Periodic abstinence (calendar, symptothermal, postovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for participants in clinical
studies.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
102
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
103
10.6. Appendix 6: Management of Clinically Significant Laboratory Toxicities
a Mandatory confirmation is not warranted for asymptomatic Grade 3 or Grade 4 glucose elevations in participants with pre-existing
diabetes, and asymptomatic Grade 3 or Grade 4 triglyceride or cholesterol elevations.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
104
10.7. Appendix 7: DAIDS Table for Grading the Severity of Adult and Pediatric
Adverse Events
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (v
2.1, July 2017), or 'DAIDS grading table', is a descriptive terminology to be utilized for adverse
event reporting in this study. A grading (severity) scale is provided for each adverse event term.
General Considerations
The Division  ofAIDS (DAIDS) Table for Grading  the Severity ofAdult andPediatric Adverse
Events, Version  2.1 consists ofparameters, or AEs, with severity grading guidance that are to be
used in DAIDS  clinical trials for safety data reporting to maintain  accuracy  and consistency  in
the evaluation  of AEs. The term “severe” is not the same as the term “serious” in classifying
AEs. The severity ofa specific event describes its intensity, and it is the intensity which is graded.
Seriousness, which is not graded, relates to an outcome ofan AE and is a regulatory definition.
Clinical sites are encouraged to report parameters in the DAIDS  grading table as they are written
to maintain  data consistency  across clinical trials. However, since some parameters can  be
reported with  more specificity, clinical sites are encouraged to report parameters that convey
additional clinical information. For example, diarrhea could be reported as neonatal diarrhea;
seizures, as febrile seizures; and pain, as jaw pain.
The DAIDS  grading table provides an AE severity grading scale ranging from grades 1 to 5 with
descriptions for each AE based on the following general guidelines:
• 
Grade 1 indicates a mild event
• 
Grade 2 indicates a moderate event
• 
Grade 3 indicates a severe event
• 
Grade 4 indicates a potentially life-threatening event
• 
Grade 5 indicates death (Note: This grade is not specifically  listed on  each  page of the
grading table).
Other points to consider include:
• 
Use age and sex values as applicable.
• 
Unless noted, laboratory values are for term neonates. Preterm neonates should be assessed
using local laboratory normal ranges.
• 
Where applicable, Standard International (SI) units are included in italics.
Selecting and Reporting a Primary AE Term
When selecting a primary  AE term to report, sites should select the term that best describes what
NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
111
Gastrointestinal
PARAMETER  
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Anorexia  
Loss ofappetite
without decreased
oral intake
Loss ofappetite
associated with
decreased oral intake
without significant
weight loss
Loss ofappetite
associated with
significant weight
loss
Life threatening
consequences OR
Aggressive intervention
indicated (e.g., tube
feeding, total parenteral
nutrition)
Ascites 
No symptoms 
Symptoms AND
Intervention
indicated (e.g.,
diuretics, therapeutic
paracentesis)
Symptoms recur or
persist despite
intervention
Life threatening
consequences
Bloating or Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing
greater than minimal
interference with
usual social &
functional activities
Symptoms causing
inability to perform
usual social &
functional activities
NA
Cholecystitis 
NA  
Symptoms AND
Medical intervention
indicated
Radiologic,
endoscopic, or
operative
intervention indicated
Life threatening
consequences (e.g.,
sepsis, perforation)
Constipation  
NA  
Persistent
constipation
requiring regular use
ofdietary
modifications,
laxatives, or enemas
Obstipation with
manual evacuation
indicated
Life threatening
consequences (e.g.,
obstruction)
Diarrhea
≥ 1 year ofage 
Transient or 
intermittent 
episodes of 
unformed stools OR  
Increase of≤ 3 
stools over baseline 
per 24 hour period
Persistent episodes
ofunformed to
watery stools OR
Increase of4 to 6
stools over baseline
per 24 hour period
Increase of ≥ 7
stools per 24 hour
period OR IV fluid
replacement
indicated
Life threatening
consequences (e.g.,
hypotensive shock)
< 1 year ofage 
Liquid stools (more 
unformed than 
usual) but usual 
number ofstools 
Liquid stools with
increased number of
stools OR Mild
dehydration
Liquid stools with
moderate dehydration
Life threatening
consequences (e.g.,
liquid stools resulting in
severe dehydration,
hypotensive shock)
Dysphagia or
Odynophagia
Report only one and
specify location
Symptoms but able
to eat usual diet
Symptoms causing
altered dietary intake
with no intervention
indicated
Symptoms causing
severely altered
dietary intake with
intervention indicated
Life threatening
reduction in oral intake
Gastrointestinal
Bleeding
Not requiring
intervention other
than iron
supplement
Endoscopic
intervention
indicated
Transfusion indicated Life threatening
consequences (e.g.,
hypotensive shock)
AIDS AE GradingTable Corrected Version 2.1 July 2017
Page 37
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
112
Gastrointestinal
PARAMETER  
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-
THREATENING
Mucositis or Stomatitis
Report only one and
specify location
Mucosal erythema 
Patchy
pseudomembranes or
ulcerations
Confluent
pseudomembranes or
ulcerations OR
Mucosal bleeding
with minor trauma
Life threatening
consequences (e.g.,
aspiration, choking) OR
Tissue necrosis OR
Diffuse spontaneous
mucosal bleeding
Nausea 
Transient (< 24
hours) or
intermittent AND
No or minimal
interference with
oral intake
Persistent nausea
resulting in
decreased oral intake
for 24 to 48 hours
Persistent nausea
resulting in minimal
oral intake for > 48
hours OR
Rehydration
indicated (e.g., IV
fluids)
Life threatening
consequences (e.g.,
hypotensive shock)
Pancreatitis 
NA  
Symptoms with
hospitalization not
indicated
Symptoms with
hospitalization
indicated
Life threatening
consequences (e.g.,
circulatory failure,
hemorrhage, sepsis)
Perforation
(colon or rectum)
NA  
NA  
Intervention
indicated
Life threatening
consequences
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing
greater than minimal
interference with
usual social &
functional activities
OR Medical
intervention
indicated
Symptoms causing
inability to perform
usual social &
functional activities
OR Operative
intervention indicated
Life threatening
consequences (e.g.,
perforation)
Rectal Discharge 
Visible discharge 
Discharge requiring
the use ofpads
NA  
NA
Vomiting 
Transient or 
intermittent AND  
No or minimal 
interference with
oral intake
Frequent episodes
with no or mild
dehydration
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR
Aggressive
rehydration indicated
(e.g., IV fluids)
Life threatening
consequences (e.g.,
hypotensive shock)
NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
121
Serum Sickness10 
Mild signs and
symptoms
Moderate signs and
symptoms AND
Intervention
indicated (e.g.,
antihistamines)
Severe signs and
symptoms AND
Higher level
intervention indicated
(e.g., steroids or IV
fluids)
Life threatening
consequences (e.g.,
requiring pressor or
ventilator support)
Underweight11
> 5 to 19years of
age
WHO BMI z score
< 1 to 2
WHO BMI z score
< 2 to 3
WHO BMI z score
< 3
WHO BMI z score
< 3 with life threatening
consequences
2 to 5 years ofage 
WHO Weight for
height z score
< 1 to 2
WHO Weight for
height z score
< 2 to 3
WHO Weight for
height z score < 3
WHO Weight for height z
score < 3 with life
threatening consequences
< 2 years ofage 
WHO Weight for
length z score
< 1 to 2
WHO Weight for
length z score
< 2 to 3
WHO Weight for
length z score < 3
WHO Weight for length z
score < 3 with life
threatening consequences
Unintentional Weight
Loss (excludes
postpartum weight
loss)
NA  
5 to < 9% loss in
body weight from
baseline
≥ 9 to < 20% loss in
body weight from
baseline
≥ 20% loss in body
weight from baseline OR
Aggressive intervention
indicated (e.g., tube
feeding, total parenteral
nutrition)
10 
Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort,
and/or dyspnea.
11 
WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs:
http://www.who.int/growthref/who2007 bmi for age/en/ for participants > 5 to 19 years ofage and
http://www.who.int/childgrowth/standards/chart catalogue/en/ for those ≤ 5 years ofage.
NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
132
10.8. Appendix 8: Patient Reported Outcomes Questionnaires
10.8.1. 
HIV-Symptom Index (HIV-SI)
INSTRUCTIONS: Please answer the following questions by placing a (../) in the appropriate box.
A) The following questions ask about symptoms you might have had during the past four weeks. Please check the box that
describes how much you have been bothered by each symptom
(Check one.) 
1. Fatigue or loss of energy?
2. Fever, chills or sweats?
3. Feeling dizzy or lightheaded?
4. Pain, numbness or tingling in the
hands or feet?
5. Trouble remembering?
6. Nausea or vomiting?
7. Diarrhea or loose bowel
movements?
8. Felt sad, down or depressed?
9. Felt nervous or anxious?
10. Difficulty falling or staying
asleep?
11. Skin problems, such as rash,
dryness or itching?
I DO NOT HAVE  
I HAVE THIS SYMPTOM AND…
It bothers me It bothers me a
little
☐ 
☐ 
2 
3 
☐ 
☐
2 
3
☐ 
☐ 
2 
3
☐ 
☐
2 
3
☐ 
☐
2 
3
☐ 
☐
2 
3
☐ 
☐ 
2 
3
☐ 
☐ 
2 
3
☐ 
☐ 
2 
3
☐ 
☐
2 
3
☐ 
☐
2 
3
THIS SYMPTOM
It doesn’t 
It bothers 
bother me 
me alot 
☐ 
☐ 
☐
0 
1 
4
☐ 
☐ 
☐ 
0 
1 
4 
☐ 
☐ 
☐
0 
1 
4
☐ 
☐ 
☐
0 
1 
4
☐ 
☐ 
☐
0 
1 
4
☐ 
☐ 
☐ 
0 
1 
4 
☐ 
☐ 
☐
0 
1 
4 
☐ 
☐ 
☐
0 
1 
4
☐ 
☐ 
☐
0 
1 
4
☐ 
☐ 
☐
0 
1 
4
☐ 
☐ 
☐
0 
1 
4
US:ENG (United States/English)
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
133
(Check one.) 
I DO NOT HAVE
THIS SYMPTOM
It doesn’t
bother me
I HAVE THIS SYMPTOM AND…
It bothers me It bothers me a
little
It bothers
me alot
12. Cough or trouble catching your
breath?
13. Headache?
14. Loss of appetite or a change in
the taste of food?
15. Bloating, pain or gas in your
stomach?
16. Muscle aches or joint pain?
17. Problems with having sex, such
as loss of interest or lack of
satisfaction?
18. Changes in the way your body
looks such as fat deposits or
weight gain?
19. Problems with weight loss or
wasting?
20. Hair loss or changes in the way
your hair looks?
☐
0
☐
0
☐
0
☐
0
☐
0
☐
0
☐
0
☐
0
☐
0
☐ 
☐ 
☐ 
☐
1 
2 
3 
4
☐ 
☐ 
☐ 
☐
1 
2 
3 
4
☐ 
☐ 
☐ 
☐
1 
2 
3 
4
☐ 
☐ 
☐ 
☐
1 
2 
3 
4
☐ 
☐ 
☐ 
☐
1 
2 
3 
4
☐ 
☐ 
☐ 
☐
1 
2 
3 
4
☐ 
☐ 
☐ 
☐
1 
2 
3 
4
☐ 
☐ 
☐ 
☐
1 
2 
3 
4
☐ 
☐ 
☐ 
☐
1 
2 
3 
4
Thank you very much for completing this questionnaire.
US:ENG (United States/English)
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
134
10.8.2. 
Body Shape Questionnaire (BSQ-8D)
BSQ-8D
We should like to know how you have been feeling about your appearance over the PAST FOUR
WEEKS. Please read each question and circle the appropriate number to the right. Please answer all
the questions.
OVER THE PAST FOUR WEEKS:
Never
|   Rarely
| 
|  Sometimes
| 
| 
|  Often
| 
| 
| 
|    Veryoften
| 
| 
| 
| 
| 
| 
| 
| 
| 
| 
Always
|
1. Have you been so worried about your shape that you have been feeling
you ought to 
i
?
1 
2 
3 
4 
5 
6
2. Have you noticed the shape of other women and felt that your own
shape   compared  
f
l ?
1 
2 
3 
4 
5 
6
3. Has being naked, such as when taking a bath, made you feel fat?.......... 1 
2 
3 
4 
5 
6
4. Have you not gone out to social occasions (e.g. parties) because you
have felt bad about your 
h
?
1 
2 
3 
4 
5 
6
5. Have you worried about other people seeing rolls of fat around your
waist or 
h?
1 
2 
3 
4 
5 
6
6. When in company have your worried about taking up too much room
(e.g. sitting on a sofa, or a bus 
t)?
1 
2 
3 
4 
5 
6
7. Have you pinched areas of your body to see how much fat there is?..... 
1 
2 
3 
4 
5 
6
8. Have you avoided situations where people could see your body (e.g.
communal changing rooms or swimming 
1 
2 
3 
4 
5 
6
BSQ-8D © Evans & Dolan, 1993.  Non-profit-making reproduction unchanged authorised, see   http://www.psyctc.org/tools/bsq/
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
135
BSQ-8D (Men)
We should like to know how you have been feeling about your appearance over the PAST FOUR
WEEKS. Please read each question and circle the appropriate number to the right. Please answer  all
the questions.
OVER THE PAST FOUR WEEKS:
Never
|   Rarely
| 
|  Sometimes
| 
| 
|  Often
| 
| 
| 
|    Veryoften
| 
| 
| 
| 
| 
| 
| 
| 
| 
| 
Always
|
1. Have you been so worried about your shape that you have been feeling
you ought to 
di
?
1 
2 
3 
4 
5 
6
2. Have you noticed the shape of other men and felt that your own shape
compared    unfavourably?............................................................... 
1 
2 
3 
4 
5 
6
3. Has being naked, such as when taking a bath, made you feel fat?.......... 1 
2 
3 
4 
5 
6
4. Have you not gone out to social occasions (e.g. parties) because you
have felt bad about your 
?
1 
2 
3 
4 
5 
6
5. Have you worried about other people seeing rolls of fat around your
waist or 
?
1 
2 
3 
4 
5 
6
6. When in company have your worried about taking up too much room
(e.g. sitting on a sofa, or a bus seat)?...................................................... 1 
2 
3 
4 
5 
6
7.  Have you pinched areas of your body to see how much fat there is?..... 1 
2 
3 
4 
5 
6
8. Have you avoided situations where people could see your body (e.g.
communal changing rooms or swimming 
1 
2 
3 
4 
5 
6
BSQ-8D © Evans & Dolan, 1993.   Non-profit-making reproduction unchanged authorised, see  http://www.psyctc.org/tools/bsq/
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
136
10.8.3. 
DAILY EATS
DAILY EATS V2.0 7-Day  Diary
General Instructions
 Please answer every question at approximately the same time each evening (e.g., just before
bedtime) for the next 7days.
 You are being asked to complete this questionnaire as part of the study to find out more
information about how your weight affects your life, ifat all?
 Please read eachquestion carefully and do not skip any questions.
 Please answereach question withoutinputfromanyone else.
 There are no right or wrong answers so use your best judgment based on what you think the
question is asking.
 Please bring the device to your next scheduled visit
THANKYOU
NCT04442737


NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
138
DAY2
For the following questions, please select the one response that best describes your answer.
A. Overall, how hungry did you feel in the past 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
Not 
Extremely
hungry 
hungry
at all
B. What was the hungriest you felt in the past 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
Not 
Extremely
hungry 
hungry
at all
C. How was your appetite (desire to eat) in the past 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
No 
Extremely
appetite 
big
at all 
appetite
D. How strong were your cravings for unhealthy foods in the past 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
No 
Extremely
cravings 
strong
at all 
cravings
E. How satisfied (comfortably full) did you feel after eating your meals in the past 24 hours?
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10
Not at all 
satisfied  
Completely
satisfied
NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
144
10.8.4. 
Patient Global Impression of Change (PGIC)
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC)
Compared to before starting the study, my overall status is:
[1] ☐Very Much Improved
[2] ☐Much Improved
[3] ☐Minimally Improved
[4] ☐No Change
[5] ☐Minimally Worse
[6] ☐Much Worse
[7] ☐Very Much Worse
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC)
Compared to the Week 24 visit, my overall status is:
[1] ☐Very Much Improved
[2] ☐Much Improved
[3] ☐Minimally Improved
[4] ☐No Change
[5] ☐Minimally Worse
[6] ☐Much Worse
[7] ☐Very Much Worse
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
145
10.8.5. 
Patient Global Impression of Change-Satiety (PGIC-S)
Patient Global Impression of Change - Satiety (PGIC-S)
Compared to before starting the study, how would you rate your
satisfaction (fullness) after meals in the past 7 days?
[1] ☐Much more satisfied (full)
[2] ☐Moderately more satisfied (full)
[3] ☐A little more satisfied (full)
[4] ☐No change
[5] ☐A little less satisfied (full)
[6] ☐Moderately less satisfied (full)
[7] ☐Much less satisfied (full)
Compared to the Week 24 visit, how would you rate your satisfaction (fullness) after
meals in the past 7 days?
[1] ☐Much more satisfied (full)
[2] ☐Moderately more satisfied (full)
[3] ☐A little more satisfied (full)
[4] ☐No change
[5] ☐A little less satisfied (full)
[6] ☐Moderately less satisfied (full)
[7] ☐Much less satisfied (full)
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
146
10.9. Appendix 9: Characteristics, Prevention, and Management of
Cardiovascular Diseases in People Living with HIV by American Heart
Association
Feinstein MJ, Hsue PY, Benjamin LA, et al. Characteristics, Prevention, and Management of
Cardiovascular Disease in People Living With HIV: A Scientific Statement From the American Heart
Association. Circulation. 2019;140(2):e98 e124.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
147
10.10. Appendix 10: 2017 American College of Cardiology (ACC) Guideline for the
Prevention, Detection, Evaluation, and Management of High Blood
Pressure in Adults
Whelton PK, Carey RM, et al. 2017 Guideline for the Prevention, Detection, Evaluation, and
Management of High Blood Pressure in Adults. A Report of the American College of
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll
Cardiol. Sep 2017, 23976; DOI: 10.1016/j.jacc.2017.07.745.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
148
10.11. Appendix 11: Management of Hyperglycemia in Type 2 Diabetes, 2018. A
Consensus Report by the American Diabetes Association (ADA) and the
European Association for the Study of Diabetes (EASD)
Davies JD, D’Alession DR, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the
American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. Dec 2018; 41(12):
2669 2701.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
149
10.12. Appendix 12: WHO Clinical Staging of HIV/AIDS
The clinical stages of HIV infection for adults and adolescents are defined as follows. (Adapted from:
1993 Revised classification system for HIV infection and expanded surveillance case definition for
AIDS among adolescents and adults. MMWR 1992;41(RR-17):1-19; and WHO 2007 Case definitions
of HIV for surveillance and revised clinical staging and immunological classification of HIV-related
disease in adults and children [Table 3]).31,41
Clinical Stage 1
Clinical Stage 1 consists of one or more of the conditions listed below in adolescents or adults (13
years) with documented HIV infection. Conditions listed in Clinical Stages 2, 3 or 4 must not have
occurred.
 Asymptomatic HIV infection
 Persistent generalized lymphadenopathy
Clinical Stage 2
Clinical Stage 2 consists ofsymptomatic conditions in an HIV-infected adolescents or adults that are
not included among conditions listed in Clinical Stage 3, and that meet one or more ofthe following
criteria:
a) the conditions are attributed to HIV infection or are indicative ofa defect in cell-mediated immunity; or
b) the conditions are considered by physicians to have a clinical course or to require management that
is complicated by HIV infection. Examples ofconditions in Clinical Stage 2 include, but are not limited
to the following.
 Moderate unexplained weight loss (<10% of presumed or measured body weight)
 Recurrent respiratory tract infections sinusitis, tonsillitis, otitis media and pharyngitis)
 Herpes zoster
 Angular cheilitis
 Recurrent oral ulceration
 Papular pruritic eruptions
 Seborrhoeic dermatitis
 Fungal nail infections
Clinical Stage 3
Clinical Stage 3 includes the clinical conditions listed in  the AIDS  surveillance case definition.
For classification purposes, once a Clinical Stage 3 condition has occurred, the person will remain in
Clinical Stage 3. Conditions in Clinical Stage 3 include the following.
 
Unexplained (not explained by other causes) severe weight loss (>10% of presumed or measured
body weight)
 
Unexplained chronic diarrhea for longer than 1 month
 
Unexplained persistent fever (above 37.6°C intermittent or constant, for longer than 1 month)
 
Persistent oral candidiasis
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
150
 
Oral hairy leukoplakia
 
Pulmonary tuberculosis (current)
 
Severe bacterial infections (such as pneumonia, empyema, pyomyositis, bone or joint infection,
meningitis or bacteremia)
 
Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
 
Unexplained anemia (<8 g/dL), neutropenia (<0.5x109/L) or chronic thrombocytopenia
(<50x109/L)
Clinical Stage 4
 
HIV wasting syndrome:
 
Pneumocystis pneumonia
 
Recurrent severe bacterial pneumonia
 
Chronic herpes simplex infection (orolabial, genital or anorectal of more than one month’s
duration or visceral at any site)
 
Esophageal candidiasis (or candidiasis of trachea, bronchi or lungs)
 
Extrapulmonary tuberculosis
 
Kaposi’s sarcoma
 
Cytomegalovirus infection (retinitis or infection of other organs)
 
Central nervous system toxoplasmosis
 
HIV encephalopathy
 
Extrapulmonary cryptococcosis including meningitis
 
Disseminated non-tuberculous mycobacterial infection
 
Progressive multifocal leukoencephalopathy
 
Chronic cryptosporidiosis (with diarrhea)
 
Chronic isosporiasis
 
Disseminated mycosis (coccidiomycosis or histoplasmosis)
 
Recurrent non-typhoidal Salmonella bacteremia
 
Lymphoma (cerebral or B-cell non-Hodgkin) or other solid HIV-associated tumors
 
Invasive cervical carcinoma
 
Atypical disseminated leishmaniasis
 
Symptomatic HIV-associated nephropathy or symptomatic HIV-associated cardiomyopathy
NCT04442737


NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
152
10.14. Appendix 14: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 2 (21-May-2021)
Overall Rationale for the Amendment:  The overall reason for this amendment is to account for new data
and investigator feedback indicating 10% weight gain may not occur within 12 months but could occur
more gradually over a longer period of time.
Section number
and Name
Description of Change 
Brief Rationale
1.1. Synopsis (Overall
Design); 1.2 Schema;
4.1. Overall Design;
5.1. Inclusion Criteria
#4
Eligible patients could have a rapid and significant 
body weight gain which is defined as a ≥10% 
increase within a 12-to-36-month time period.
To account for new data and
investigator feedback.
5.5. 
Criteria for
Temporarily Delaying
Enrollment,
Randomization,
Administration of
Study Intervention;
8.7. Immunogenicity
Assessments
Sections were added to align with the template. 
To adapt/follow the new protocol
template.
6.5 Dose
Modification;
6.6 Continued Access
to Study Intervention
After the End of the
Study;
6.7. Treatment of
Overdose
8.6.1.
Pharmacodynamics
Moved the Section to align with the template 
To adapt/follow the new protocol
template.
6.7. Treatment of
Overdose
The text was modified (new  text in bold and 
deletion in strike through) to: 
For D/C/F/TAF FDC anything any dose greater
than 1 tablet within a 24-hour period ±12 hours.
This is considered an overdose as per Prescribing
information of D/C/F/TAF FDC tablet.
The sentences defining an overdose
were revised for better clarity.
8.3 Adverse Events,
Serious Adverse
Events, and Other
Safety Reporting
The title of the Section 8.3 was changed from 
'Adverse Events and Serious Adverse Events' to 
Adverse Events, Serious Adverse Events, and
Other Safety Reporting'.
To adapt/follow the new protocol
template.
8.7 Immunogenicity
Assessments
Added the section to align with the new template 
To adapt/follow the new protocol
template.
9.3. Population for
Analysis Sets
The title of the Section 9.3 was changed from 
'Population for Analyses' to 'Population for 
Analysis Sets'.
To adapt/follow the new protocol
template.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
153
Section number 
and Name
Description of Change 
Brief Rationale
Appendices 
Updated the Appendices per the new protocol 
template. 
To adapt/follow the new protocol
template.
Throughout the 
protocol 
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted
Amendment 1 (24-April-2020)
Overall Rationale for the Amendment:  The overall reason for this amendment is to eliminate the need
to monitor and analyze anticipated events and to remove the Anticipated Events Safety Monitoring Plan
included in Appendix 2 of the protocol, and to evaluate the proportion of participants with >3% change in
body weight at Week 24 and Week 48.
Section number 
and Name
Description of Change 
Brief Rationale
8.3. Adverse Events and
Serious Adverse Events;
8.3.3. Regulatory Reporting
Requirements for Serious
Adverse Events
Deleted text related to anticipated adverse
events and removed cross-reference to
Appendix 2 (Anticipated Events) from the
protocol.
To delete the non-applicable
formal Anticipated Events Safety
Monitoring Plan. As the current
study TMC114FD2HTX4004 has
unblinded study design and the
study population consist of
virologically suppressed patients,
the number of suspected
unexpected serious adverse
reactions (SUSARS) is expected
to be low and there is no need to
monitor and analyze the
anticipated events.
Appendix 2: Anticipated
Events
Appendix 2 has been removed from the
protocol and subsequent appendices have
been renumbered.
1.1. Synopsis (Week 24
Objectives and Endpoints);
3.1. Week 24 Objectives
and Endpoints; 3.2. Week
48 Objectives and
Endpoints
Added new secondary endpoints, ‘Proportion
of participants with % change in body weight
>3% at Week 24’ and ‘Proportion of
participants with % change in body weight
>3% at Week 48’.
To identify participants with 3%
to 5% changes in body weight, as
sustained body weight loss of as
little as 3%-5% may lead to
clinically meaningful reductions
in some cardiovascular risk
factors
1.1. Synopsis (Overall
Design, Efficacy
Assessments);
1.3. Schedule of Activities
(SoA);
4.1. Overall Design; 7.1.
Discontinuation of Study
Intervention;
8.1.3.2. Resistance
Determinations; 8.1.3.3.
Management of Virologic
Rebound;
9.4.3.2. Resistance/Efficacy
Analyses
Specified PhenoSense GT® Plus Integrase as
the test to be utilized for human
immunodeficiency virus (HIV)-1 genotypic
and phenotypic resistance testing in
participants with confirmed virologic
rebound.
To ensure that nucleoside reverse
transcriptase inhibitor (NRTI),
non-nucleoside reverse
transcriptase inhibitor (NNRTI),
protease inhibitor (PI) and
integrase (INI) drug class
resistance in participants with
confirmed virologic rebound is
reported
Appendix 14 (now
Appendix 13)
Footnote b was updated by adding
‘PhenoSense GT® Plus Integrase’.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
154
Section number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of Activities; 
8.1.3.2. Resistance 
Determinations 
Specified Genosure Archive® as the test to 
be utilized to characterize archived viral 
resistance of the whole blood sample 
collected at Baseline Day 1.
To clarify the type of assay that
will be used to assess baseline
resistance if needed
Appendix 3 (now Appendix  
2): Clinical Laboratory  
Tests and Calculations 
Added footnote that International normalized 
ratio (INR) will only be assessed at 
Screening.
To specify that INR will be
assessed at Screening only
Appendix 3 (now Appendix  
2): Clinical Laboratory  
Tests and Calculations 
Added formula for calculation of Ideal Body  
Weight and Adjusted Body Weight. 
To specify that if a participant’s
actual body weight is greater than
20% of their Ideal Body Weight,
the participant’s Adjusted Body
Weight will be used for eGFRcr
(Cockcroft-Gault Formula)
5.1. Inclusion Criteria 
The text ‘Contraceptive (birth control) use by  
men or women should be consistent with  
local regulations regarding the acceptable 
methods of contraception for those 
participating in clinical studies. Typical use 
failure rates may differ from those when used
consistently and correctly. Use should be
consistent with local regulations regarding the
use of contraceptive methods for participants
in clinical studies’ originally included under
inclusion criterion 10 was removed.
To remove the duplicate text
related to contraception from
inclusion criterion 10 because it is
also included in inclusion
criterion 13
Title page (Confidentiality 
Statement); Running footer 
Replaced 
the 
original 
Confidentiality  
Statement with a new statement, and added 
a running footer to note exemptions. 
Updated Confidentiality
Statement in accordance with
clinical trial protocol template
change
Throughout the protocol 
Minor grammatical and formatting changes 
were made
References were updated..
Minor errors were noted.
1.1. Synopsis (Objectives 
and Endpoints); 2.1. Study 
Rationale; 3.1. Week 
24 Objectives and
Endpoints; 3.2. Week 48
Objectives and Endpoints;
Appendix 1
Full form of ‘BMI’ was corrected from ‘basal
metabolic rate’ and ‘body metabolic index’ to
‘body mass index’.
Appendix 14 (now 
Appendix 13) 
The text ‘and bring back study medication for
pill count’ was deleted.
The word ‘counsellation’ was replaced by
‘counseling’ in the following statement
‘Contact the patient within 48 hours, assess
potential causes and provide adherence
counseling as appropriate or take any other
action as deemed appropriate’.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
155
REFERENCES
1. 
Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score A noninvasive system that identifies liver
fibrosis in patients with NAFLD Hepatology 2007;45(4):846-854.
2. 
Bakal D, Coelho LE, Luz PM, et al. Obesity Following ART Initiation is common and influenced by Both
Traditional and HIV-/ART-specific Risk Factors. J Antimicrob Chemother. 2018;73(8):2177-2185.
3. 
Bhaduri S, Roberts. M. “Weight gain in patients using integrase inhibitors: An emerging class side effect.”
HIV Medicine. 2017;18(Supplement 1):48.
4. 
BIKTARY® [package insert]. Foster City, CA: Gilead Sciences, Inc; August 2019.
5. 
Bourgi K, Rebeiro PF, Turner M, et al. Greater Weight Gain Among Treatment-Naïve Persons Starting
Integrase Inhibitors.  Clin Infect Dis. 2019 May 17.
6. 
Cahn P, Fourie J, Grinsztejn B, et al. Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in
treatment-experienced HIV-1-infected patients. AIDS 2011,25:929-939.
7. 
Castilhos JK, Sprinz E, Lazzaretti RK, et al. Polymorphisms in adiponectin receptor genes are associated
with lipodystrophy-related phenotypes in HIV-infected patients receiving antiretroviral therapy. HIV
Medicine 2015;16:494-501.
8. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron.
1976;16:31-41.
9. 
Cooper PJ, Taylor MJ, Cooper Z, Fairburn CG. The development and validation of the Body Shape
Questionnaire. International Journal of Eating Disorders 1986,6:485-494.
10. DESCOVY® [package insert]. Foster City, CA: Gilead Sciences, Inc; October 2019.
11. Development Safety Update Report No.5: Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide.
Period Covered:7 December 2017 to 20 September 2018. Janssen Research & Development. Approved: 2
November 2018.
12. Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic
steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121(1):91-100.
13. Edelman EJ, Gordon K, Rodriguez-Barradas MC, Justice AC, Vacs Project T. Patient-reported symptoms on
the antiretroviral regimen efavirenz/emtricitabine/tenofovir. AIDS Patient Care STDS. 2012;26:312-319.
14. EMTRIVA® [package insert]. Foster City, CA: Gilead Sciences, Inc; November 2012.
15. Eron J, Orkin C, Gallant J, et al. A week-48 randomized phase-3 trial of
darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS.
2018,32:1431-1442.
16. Evans C, Dolan B.  International Journal of Eating Disorders, 1993;13(3),315-321.
17. GENVOYA® [package insert]. Foster City, CA: Gilead Sciences, Inc; February 2019.
18. Hill A, Waters L, Pozniak A. Are New Antiretroviral Treatments Increasing the Risks of Clinical Obesity?
Journal of Virus Eradication. 2019;5(1):41-43.
19. Investigator’s Brochure: D/C/F/TAF. Edition 6. Janssen Research & Development (6 November 2019).
20. ISENTRESS®[package insert]. Whitehouse Station, NJ: Mercj & Co, Inc; January 2019.
21. Justice A, Holmes W, Giford A, et al. Development and validation of a self-completed HIV symptom index.
J Clin Epidemiol. 2001;(54):S77-90.
22. Lake JE, Kunling W, Kristine M, et al. Risk Factors for Excess Weight Gain Following Switch to Integrase
Inhibitor-Based ART. Poster 669. Seattle,WA, CROI 2019.
23. McComsky G, Eron JJ, Santiago S, et al. Weight Gain During Treatment Among 3,468 Treatment-
Experienced Adults with HIV. Poster 671. Seattle, WA, CROI 2019.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
156
24. Menard A. Dolutegravir and Weight Gain: An Unexpected Bothering Side Effect? AIDS 2017;31:1499-
1502.
25. Mounzer K, Brunet L, Hsu R, et al. Changes in BMI Associated with Antiretroviral Regimens in Treatment-
Experienced Virologically Suppressed Individuals Living with HIV. IDWeek 2019. Oral Presentation 978
26. NAMSAL ANRS 12313 Study Group. Dolutegravir-Based or Low-Dose Efavirenz-Based Regimen for the
Treatment of HIV-1. N Engl J Med. 2019;381:816-826.
27. Norwood J, Turner M, Bofill C, et al. Brief Report: Weight Gain in Persons with HIV Switched From
Efavirenz-Based to Integrase Strand Transfer Inhibitor-Based Regimens. Jn Acquir Defic Syndr.
2017;76(5):527-531.
28. ODEFSEY® [package insert]. Foster City, CA: Gilead Sciences, Inc; March 2016.
29. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir
compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV
Medicine. 2013;14:49-59.
30. Orkin C, Molina J, Negredo E, et al. Efficacy and safety of switching from boosted protease inhibitors plus
emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine,
and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase
3, randomised, non-inferiority trial. Lancet HIV. 2018;5:e23-34.
31. Revised classification system for HIV infection and expanded surveillance case definition for AIDS among
adolescents and adults. MMWR. 1992;41(RR-17):1-19.
32. Rodriguez F, Harrison RW, Wojdyla D, Mahaffey KW. Lost to Follow-up and Withdrawal of Consent in
Contemporary Global Cardiovascular Randomized Clinical Trials. Crit Pathways in Cardiol. 2015;14:150-
153.
33. Schulz C, Paulus K, Lobmann R, et al. Endogenous ACTH, not only α-melanocyte-stimulating hormone,
reduces food intake mediated by hypothalamic mechanisms. Am J Physiol Endocrinol Metab
2010;298:E237-E244.
34. STRIBILD® [package insert]. Foster City, CA: Gilead Sciences, Inc; January 2019.
35. SYMTUZA® [package insert]. Titusville, NJ: Janssen Therapeutics; July 2018.
36. Symtuza: EPAR –Product Information; May 2018; https://www.ema.europa.eu/documents/product-
information/symtuza-epar-product-information en.pdf.
37. Tiliscan C, Arama V, Mihailescu R, et al. Leptin expression in HIV-infected patients during antiretroviral
therapy. Germs 2015; 5(3):92-98.
38. US Department of Health and Human Services, FDA, CDER. FDA Guidance for Industry on the Nonclinical
Safety Evaluation of Drug or Biologic Combinations. March 2006. Available at:
https://www.fda.gov/OHRMS/DOCKETS/98fr/05d-0004-gdl0002.pdf. Accessed 15 January 2018.
39. Venter WDF, Moorhouse M, Sokhela S et al. Dolutegravir plus Two Different Prodrugs of Tenofovir to
Treat HIV. N Engl J Med 2019;381:803-815.
40. Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data, Springer, 2000.
41. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification
of HIV-related disease in adults and children, 2007. Available at
http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf?ua=1. Accessed 13 October 2016.
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA
(darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S.
Status: Approved, Date: 29 April 2022 
157
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Scientific Affairs, LLC
Signature: [electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04442737


Signature
User 
Date 
Reason
29-Apr-2022
14:04:07
(GMT)
Document Approval
PPD
NCT04442737


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 03 June 2020
Janssen Scientific Affairs
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Phase 4, Randomized, Active-Controlled, Open-label Study to Evaluate the Safety and 
Tolerability of Switching to Once-Daily Darunavir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (D/C/F/TAF) Fixed-dose Combination (FDC) Regimen in Virologically-
suppressed Human Immunodeficiency Virus Type 1 (HIV-1) Infected Participants 
Experiencing Rapid Weight Gain with an INI + TAF/FTC ARV Regimen
DEFINE
D/C/F/TAF FDC Evaluated as a Fixed Dose Combination Regimen in Participants 
Switching from an Integrase Inhibitor who have Experienced Rapid Weight Gain
Protocol TMC114FD2HTX4004; Phase 4
TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA (darunavir 800 
mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Status:
Approved
Date:
03 June 2020
Prepared by:
Janssen Scientific Affairs, LLC  
EDMS number:
EDMS-RIM-75905, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04442737


COVID-19 Appendix
TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA (darunavir 800 mg/cobicistat 150 
mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 03 June 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study-
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgment of the 
investigator to protect the health and well-being of participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention will be discontinued, and study 
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key metabolic and efficacy endpoint 
assessments should be performed if required and as feasible. Participants will also be questioned 
regarding general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, and 
the sponsor. Missed assessments/visits will be captured in the clinical trial management system 
for protocol deviations. Discontinuations of study interventions and withdrawal from the study 
should be documented with the prefix “COVID-19-related” in the case report form (CRF).
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.
The below emergency provisions are meant to ensure participant safety on study while site 
capabilities are compromised by COVID-19-related restrictions. As restrictions are lifted and the 
acute phase of the COVID-19 pandemic resolves, sites should revert to original protocol conduct 
as soon as feasible. If at any time during the course of the study the status of the pandemic resurges 
these provisions may need to be enacted again.

To safely maintain participants on study intervention while site capabilities are compromised 
by COVID-19-related restrictions, participants for whom there is no safety concern may have 
tele-health contacts (conducted via phone or video conversation as per local regulation) for 
NCT04442737


COVID-19 Appendix
TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA (darunavir 800 mg/cobicistat 150 
mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 03 June 2020
the study visits at Weeks 4, 12, 28 and 36 until such time that on-site visits can be resumed. 
Whenever possible, the study visits at Weeks 24 and 48 should be on-site visits, conducted 
within the protocol window of ± 7 days; if on-site visits are not possible, tele-health contacts 
can be used. Normal study procedures should be followed for the applicable study visits as 
closely as possible. The reasons for visits and/or procedures not being conducted should be 
entered in the CRF. The CRF completion guidelines should be consulted for details.

At each contact, participants will be interviewed to collect safety data. Key metabolic and 
efficacy endpoint assessments should be performed if required and as feasible. Participants
will also be questioned regarding general health status to fulfill any physical examination
requirement.

If home health visits are conducted, arrangements should be made to weigh the participant 
using the same scale at previous visits at the study site. Each site will be provided with a 
portable scale that should be used for the duration of the study. Participants should be weighed 
wearing underwear and a gown; they will be instructed to take off their shoes and to empty 
their bladders before being weighed.

Central laboratory testing should be performed according to the current Schedule of 
Activities (SoA) as outlined in the protocol. If central laboratory tests cannot be performed,
the use of a local laboratory is allowed for protocol-specified laboratory assessments. A 
copy of the local laboratory report should be reviewed for safety by the investigator and
retained, along with reference ranges, for source documentation. Results from key metabolic 
parameters including leptin, adiponectin (if available) and fasting metabolic profile (total, 
high-density lipoprotein [HDL] and low-density lipoprotein [LDL], cholesterol, triglycerides, 
glucose) and efficacy parameters (HIV-1 RNA viral load and CD4+ cell counts) from the local 
laboratory testing for Week 24 and Week 48/ESID will be entered in the CRF. In anticipation 
of this possibility, study sites should consider proactively adding a local laboratory to the 
Form FDA 1572 and providing the sponsor with supporting documentation (eg, Clinical 
Laboratory Improvement Amendments [CLIA], CV of the laboratory head, etc.).

If a participant is found to have abnormal laboratory findings, including Grade 3 or 4 
abnormalities, suspected virologic rebound (HIV-1 RNA value ≥200 copies/mL), or other 
laboratory findings that in the judgment of the investigator warrant confirmation, a 
concerted effort should be made to have the participant seen at an unscheduled visit at the 
study site or in person home visit for examination and applicable laboratory testing using 
the central laboratory.

At Weeks 24 and 48, the PROs (BSQ-8D, HIV-SI, PGIC and PGIC-S) should be completed 
by the participant during the on-site study visit using the sponsor-provided electronic device. 
If the Week-24 or Week 48-visit is conducted remotely, the PROs will be collected using the 
sponsor-provided electronic device, if possible. If remote completion of the PROs is not 
possible, the PRO assessments will not collected at these visits and the reason recorded in the 
CRF.

The SoA window for the completion of the DEXA scan at Week 24 and 48/ESID is ±10 days. 
If the DEXA scan cannot be performed within this window due to COVID-19 related 
restrictions, this should be documented as a deviation related to COVID-19 and should be 
conducted as soon as possible.
NCT04442737


COVID-19 Appendix
TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA (darunavir 800 mg/cobicistat 150 
mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 03 June 2020

Study intervention should be continued if, in the assessment of the investigator, it does not
result in risk to the participant. Remote medical consultation and clinical safety laboratory
assessments (including home health visits) will allow continued study participation for
participants in this trial. If at any time a participant's safety is considered to be at risk due
to study intervention, study intervention will be temporarily or permanently discontinued,
while every effort should be made to maintain follow-up on study.

The benefit of continuing study intervention should be considered by the investigator for
each individual participant, considering the potential impact of reduced direct clinical
supervision on participant safety. A temporary interruption of study intervention might be
considered based on investigator´s discretion and documented.

If study procedures cannot be performed per study protocol and are delayed, participants
should stay on the assigned study intervention until these procedures can be performed.

If a participant develops SARS-CoV-2 infection or related disease, the investigator should
contact the sponsor to discuss plans for study intervention and follow-up. An interruption
of study intervention should be considered by the investigator, depending on symptoms and
concomitant medication used for the treatment of COVID-19. Treatment must be interrupted
if prohibited medication is used. Standard Adverse Event/Serious Adverse Event reporting
requirements apply.

When a participant, for whom study intervention has been interrupted, recovers from
suspected or confirmed SARS-CoV-2 infection or related disease and all toxicities improve
to Grade ≤1, the investigator should discuss with the sponsor about resuming study
intervention. If the study intervention has been interrupted for more than 4 weeks, the
participant should be withdrawn from the study.

Dispensing of D/C/F/TAF:

For participants unable to visit the study site, handover to a caregiver or delegate of
D/C/F/TAF or direct-to-participant (DTP) shipment may be implemented, where allowed
per local regulations and if requested by the principal investigator. Where handover
to delegates or DTP shipments are deemed necessary, the process must be coordinated
between the site staff and sponsor following standard DTP procedures for arranging
shipment and adhering to associated approvals and documentation requirements.

For participants who are able to visit the study site, but who request to reduce visit
frequency or for whom limited access to the site is expected, an additional supply of
D/C/F/TAF can be provided using an Unscheduled Visit in the IWRS system.

In the unlikely event that there is a need to communicate new important safety information to
the participant during the study, participants will be reconsented at the next on-site or home
visit.
NCT04442737


COVID-19 Appendix
TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA (darunavir 800 mg/cobicistat 150 
mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX4004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 03 June 2020
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. 
I will conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study intervention, the conduct of the study, and the obligations 
of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Institution:
Janssen Scientific Affairs, LLC
Signature:
electronic signature appended at the end of the protocol
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
NCT04442737


Signature
User
Date
Reason
03-Jun-2020
17:59:41
(GMT)
Document Approval
PPD
NCT04442737

SAP_001.pdf: 
1
Approved, Date: 24 March 2023
Janssen Scientific Affairs, LLC
Statistical Analysis Plan
AMENDMENT 1
Protocol Title: A Phase 4, Randomized, Active-Controlled, Open-label Study to Evaluate 
the Tolerability of Switching to Once-Daily Darunavir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (D/C/F/TAF) Fixed-dose Combination (FDC) Regimen in Virologically-
suppressed Human Immunodeficiency Virus Type 1 (HIV-1) Infected Participants 
Experiencing Rapid Weight Gain with an INI + TAF/FTC ARV Regimen 
DEFINE
Short Title
D/C/F/TAF FDC Evaluated as a Fixed Dose Combination Regimen in Participants 
Switching from an Integrase Inhibitor who have Experienced Rapid Weight Gain
Protocol TMC114FD2HTX4004; Phase 4
AMENDMENT 3
TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA (darunavir 
800mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Status:
Approved
Date:
24 March 2023
Prepared by:
Janssen Scientific Affairs, LLC
Document No.: EDMS-RIM-989506
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
NCT04442737


2
Approved, Date: 24 March 2023
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................2
AMENDMENT HISTORY..............................................................................................................................4
ABBREVIATIONS.........................................................................................................................................5
1.
INTRODUCTION..................................................................................................................................7
1.1.
Trial Objectives.................................................................................................................................7
1.1.1.
Primary Objective..........................................................................................................................7
1.1.2.
Secondary Objectives ...................................................................................................................8
1.1.2.1.
Week 24 Objectives...................................................................................................................8
1.1.2.2.
Week 48 Secondary Objectives.................................................................................................9
1.1.2.3.
Consistency of Effect of Baseline to Week 24 (Immediate Switch) versus Week 24 to Week 48
(Delayed Switch)........................................................................................................................10
1.2.
Hypothesis......................................................................................................................................11
1.3.
Trial Design ....................................................................................................................................11
1.4.
Statistical Hypotheses for Trial Objectives.....................................................................................15
1.5.
Sample Size Justification ...............................................................................................................15
1.6.
Randomization and Blinding...........................................................................................................17
1.6.1.
Procedures for Randomization ...................................................................................................17
1.6.2.
Blinding .......................................................................................................................................17
2.
GENERAL ANALYSIS DEFINITIONS...............................................................................................17
2.1.
Treatment Arms..............................................................................................................................17
2.2.
Visit Windows .................................................................................................................................18
2.3.
Pooling Algorithm for Analysis Centers..........................................................................................20
2.4.
Analysis Sets..................................................................................................................................20
2.4.1.
All Subjects .................................................................................................................................20
2.4.1.1.
Intent-to-Treat Analysis Set .....................................................................................................20
2.4.1.2.
Per-Protocol Analysis Set ........................................................................................................20
2.4.2.
Safety Analysis Set .....................................................................................................................20
2.5.
Definition of Subgroups..................................................................................................................20
2.6.
Study Day and Relative Day ..........................................................................................................22
2.7.
Baseline and Endpoint ...................................................................................................................22
2.8.
Imputation Rules for Missing AE Date of Onset/Resolution...........................................................22
3.
INTERIM ANALYSIS AND, DATA MONITORING COMMITTEE REVIEW......................................23
4.
SUBJECT INFORMATION ................................................................................................................23
4.1.
Demographics and Baseline Characteristics .................................................................................23
4.2.
Disposition Information...................................................................................................................25
4.3.
Treatment Compliance (Adherence) ..............................................................................................26
4.4.
Extent of Exposure .........................................................................................................................26
4.5.
Protocol Deviations ........................................................................................................................26
4.6.
Prior and Concomitant Medications ...............................................................................................27
4.7.
Medical History...............................................................................................................................27
5.
METABOLIC/WEIGHT.......................................................................................................................28
5.1.
Analysis Specification.....................................................................................................................28
5.2.
Primary Endpoint............................................................................................................................28
5.2.1.
Definition .....................................................................................................................................28
5.2.2.
Primary Estimand........................................................................................................................28
5.2.3.
Analysis Methods........................................................................................................................29
NCT04442737


3
Approved, Date: 24 March 2023
5.2.4.
Sensitivity Estimator....................................................................................................................30
6.
EFFICACY/VIROLOGY .....................................................................................................................30
6.1.
Analysis Specifications...................................................................................................................30
6.1.1.
Data Handling Rules ...................................................................................................................30
6.1.2.
Virologic Response Definitions ...................................................................................................30
6.2.
Secondary Endpoints and Analysis Methods.................................................................................32
6.2.1.
Weeks 24 and 48 Endpoints.......................................................................................................32
6.2.1.1.
Consistency of Effect of Baseline to Week 24 (Immediate Switch) versus Week 24 to Week 48
(Delayed Switch)........................................................................................................................34
6.2.2.
Secondary Analysis Methods......................................................................................................37
6.2.2.1.
Metabolic Analyses..................................................................................................................37
6.2.2.2.
Efficacy Analyses.....................................................................................................................37
Genotype and Phenotype.....................................................................................................38
6.2.2.3.
Adherence Analyses................................................................................................................38
6.2.2.4.
Exploratory Analyses ...............................................................................................................38
7.
SAFETY .............................................................................................................................................38
7.1.
Adverse Events ..............................................................................................................................38
7.1.1.
Definitions ...................................................................................................................................38
7.1.2.
Analysis Methods........................................................................................................................39
7.2.
Clinical Laboratory Tests................................................................................................................40
7.2.1.
Definitions ...................................................................................................................................40
7.2.2.
Analysis Methods........................................................................................................................40
7.3.
Vital Signs and Physical Examination Findings .............................................................................41
7.3.1.
Definitions ...................................................................................................................................41
7.3.2.
Analysis Methods........................................................................................................................42
8.
PATIENT REPORTED OUTCOMES (PROs)....................................................................................42
8.1.
PROs..............................................................................................................................................42
8.1.1.
HIV-SI..........................................................................................................................................42
8.1.2.
BSQ-8D.......................................................................................................................................42
8.1.3.
DAILY EATS ...............................................................................................................................43
8.1.4.
PGIC and PGIC-S.......................................................................................................................43
8.2.
PRO Analysis Methods ..................................................................................................................43
9.
PHARMACOKINETICS/PHARMACODYNAMICS............................................................................44
9.1.
Pharmacokinetics ...........................................................................................................................44
9.1.1.
Evaluations..................................................................................................................................44
9.1.2.
Pharmacokinetic Parameters and Evaluations...........................................................................45
9.2.
Pharmacodynamics........................................................................................................................45
REFERENCES............................................................................................................................................46
ATTACHMENT 1. ADVERSE DRUG REACTION (ADR) ..........................................................................47
ATTACHMENT 2. CLINICAL LABORATORY TESTS AND CALCULATIONS ........................................50
NCT04442737


4
Approved, Date: 24 March 2023
AMENDMENT HISTORY
Status 
and 
Version
Release Date
Change Description
Reason/Comment
Final Version 1.0
08-Dec-2020
Amendment 1 
09-Feb-2022
!
Change of inclusion criteria 
#4 definition. Eligible patients 
could have a rapid and 
significant body weight gain 
which is defined as a ≥10% 
increase within a 12-to-36-
month time period.
!
Treatment phase end date was 
changed from visit date +1 day 
to visit date + 7 days for 
ongoing and early withdrawal 
subjects
!
Some 
Demographic 
and 
baseline characteristic label 
modification and additional 
information
!
To account for 
new 
data,
investigator 
feedback
and 
protocol 
amendment. The 
window 
was 
extended from 12 
month to 12-to-36 
month.
!
Clinical feedback 
from 
 
interim 
analysis outputs
24-Feb-2023
!
Description 
of 
Primary 
analysis and Final Analysis
!
Scope of subgroup analysis 
!
Table of visit window
!
Table of trial phase
!
Removal of tipping point 
analysis
!
Genotype/phenotype session
!
Clarify the range 
of 
 
data 
for 
Primary Analysis 
and 
Final 
Analysis 
!
Study 
team 
feedback
!
Formatting 
!
To account for 
scrambled data
!
Not applicable 
!
According to data 
availability
NCT04442737


5
Approved, Date: 24 March 2023
ABBREVIATIONS
ACC
American College of Cardiology
ADR
Adverse Drug Reaction
AE
adverse event
AEOI
Adverse events of interest
ALP
Alkaline phosphatase
ALT/SGPT
alanine aminotransferase
ANCOVA
analysis of covariance
ART
antiretroviral therapy
ARV
antiretroviral
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic Class
BCO
biological cut-off
BMI
body mass index
BSA
body surface area
BSQ
body shape questionnaire
CBC
complete blood count
CCO
clinical cut-off
CD4
cluster of differentiation 4
CD8
cluster of differentiation 8
CDC
Centers for Disease Control and Prevention
CI
confidence interval
COBI
cobicistat
CRF
case report form
CSR
Clinical Study Report
D/C/F/TAF
darunavir/cobicistat/emtricitabine/tenofovir alafenamide
DAIDS
Division of AIDS
DBP
diastolic blood pressure
DEXA
dual- energy X-ray absorptiometry
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
DRC
Data Review Committee 
DRV
darunavir
EAS
Efficacy analysis set
EC50
50% effective concentration
ECG
electrocardiogram
eCRF
electronic case report form
eGFRcr
creatinine-based estimated glomerular filtration rate
EOI
events of interest
ESID
Early Study Intervention Discontinuation
ES
effect size
FC
fold change
FDA
Food and Drug Administration
FDC
Fixed-dose Combination
FU
Follow up
HAIR
hypertension, age, insulin, resistance
HbA1c
Hemoglobin A1c
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
high density lipoprotein
HIV-1
Human Immunodeficiency Virus Type 1
HIV-SI
HIV-Symptom Index
HOMA-IR
homeostatic model assessment of insulin resistance
NCT04442737


6
Approved, Date: 24 March 2023
IA
interim analysis
INI
Integrase inhibitor 
IN
Integrase
ITT
intent-to-treat
IWRS
interactive web response system
LDL
low-density lipoprotein
LME
linear mixed- effects
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MMRM
mixed model for repeated measures 
MSM
men who have sex with men
NAFLD
non-alcoholic fatty liver disease
NNRTI
Non- Nucleoside Reverse Transcriptase Inhibitor
NRTI
Nucleoside Reverse Transcriptase Inhibitor
PGIC
patient global impression of change
PGIC-S
patient global impression of change for satiety
PI
protease inhibitor
PK
pharmacokinetic(s)
PP
per protocol
PR
protease
PRO
patient report outcome
RAM
Resistance-Associated Mutation
RNA
Ribonucleic acid
RPV
rilpivirine
RT
reverse transcriptase
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
standard deviation
SoA
Schedule of Activities
SOC
System organ class
SSR
sample size re-estimation
T2DM
Type 2 diabetes mellitus
TEAE
treatment-emergent adverse event
VAT
Visceral Adipose Tissue
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
NCT04442737


7
Approved, Date: 24 March 2023
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables and statistical 
methods for the analysis of metabolic (the percent change in body weight), efficacy and safety.
The
primary
study
intervention
is
the
darunavir/cobicistat/emtricitabine/tenofovir
alafenamide
(D/C/F/TAF) fixed-dose combination (FDC). D/C/F/TAF FDC is a 4-agent tablet for oral once-daily use
for the treatment of human immunodeficiency virus (HIV)-1 infection in adults. This tablet contains the
protease inhibitor (PI) darunavir (D or DRV) (800 mg), the pharmacokinetic (PK) enhancer cobicistat
(COBI or C) (150 mg), the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC or F)
(200 mg), and the tenofovir (TFV) prodrug tenofovir alafenamide (TAF) (10 mg). The D/C/F/TAF FDC
tablet (SYMTUZA®) was approved by the US Food and Drug Administration as a complete regimen for
the treatment of HIV-1 infection in adults and pediatric patients weighing ≥40 kg who have no
prior
antiretroviral
(ARV)
treatment
history
or
who
are virologically-suppressed
(human 
immunodeficiency virus type 1 ribonucleic acid [HIV-1 RNA] less than 50 copies per mL) on a stable
ARV regimen for at least 6 months and have no known substitutions associated with resistance to 
DRV or TFV. Participants not initially randomized to receive treatment with the D/C/F/TAF FDC will
be assigned to maintain treatment on their baseline ARV regimen. The baseline ARV regimen in this
study will be comprised of an INI + TAF/FTC ARV regimen.
The following analyses will be performed: 
!
An interim analysis at week 12 for monitoring purpose including an unblinded sample size re-
estimation and futility analysis (see also Section 3) 
!
The primary analysis: once all participants have completed the Week 24 assessments or 
discontinued earlier. The primary hypothesis will be tested at an overall significance level of 0.05, 
2-sided in a longitudinal data with repeated measures model (Section 5.2.3). In this analysis, 
primary and other endpoints up to week 24 will be presented. Additionally, patient data collected 
beyond week 24 at this time, including metabolic, adverse events (AEs) and other pertinent data, 
will be descriptively summarized
!
The Week 48 analysis: once all participants have completed the Week 48 assessments or 
discontinued earlier. Descriptive statistics will be conducted
1.1.
Trial Objectives
1.1.1.
Primary Objective
The primary objective of this study is to assess the percent change in body weight at Week 24 from 
Baseline when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to continuing the current 
INI + TAF/FTC ARV regimen (Delayed Switch Arm) in virologically-suppressed (HIV-1 RNA <50 
copies/mL) HIV-1 infected participants who have experienced rapid and significant body weight gain.
NCT04442737


8
Approved, Date: 24 March 2023
1.1.2.
Secondary Objectives
1.1.2.1.
Week 24 Objectives
Metabolic:
!
To assess changes in body weight when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to
continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
!
To assess changes in body composition when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared
to continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
!
To assess change in blood pressure when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to 
continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
!
To assess changes in clinical laboratory tests when switching to D/C/F/TAF FDC (Immediate Switch Arm) 
compared to continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
!
To assess changes in liver biomarkers when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to 
continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
!
To assess changes in concomitant medications of interest (including anti- hypertensive, anti-hyperglycemic, and 
lipid lowering agents) when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to continuing the 
current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
Safety:
!
To evaluate the safety of switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to continuing the
current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
Efficacy:
!
To evaluate the virologic outcomes when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to
continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
!
To evaluate immunological changes when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to
continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
Resistance:
!
To assess viral resistance in participants with confirmed HIV-1 RNA rebound for participants switching to
D/C/F/TAF FDC (Immediate Switch Arm) compared to continuing the current INI + TAF/FTC ARV regimen
(Delayed Switch Arm)
PROs:
!
To assess changes in the burden of common symptoms associated with HIV treatment or disease for
participants switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to continuing the current INI +
TAF/FTC ARV regimen (Delayed Switch Arm)
!
To describe responses on the PGIC in participants switching to D/C/F/TAF FDC (Immediate Switch Arm) and
in participants continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
Adherence:
!
To evaluate adherence in participants switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to
continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
Exploratory:
NCT04442737


9
Approved, Date: 24 March 2023
Exploratory clinical biomarker: Alpha melanocyte stimulating hormone
!
To assess changes in alpha-melanocyte stimulating hormone when switching to D/C/F/TAF FDC (Immediate
Switch Arm) compared to continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
Exploratory PROs
!
To assess changes in eating-related concepts (hunger, appetite, cravings, and satiety) for participants switching 
to D/C/F/TAF FDC (Immediate Switch Arm) compared to continuing the current INI + TAF/FTC ARV regimen 
(Delayed Switch Arm)
!
To assess changes in concerns about body shape for participants switching to D/C/F/TAF FDC (Immediate 
Switch Arm) compared to continuing the current INI + TAF/FTC ARV regimen (Delayed Switch Arm)
1.1.2.2.
Week 48 Secondary Objectives
Metabolic:
!
To assess the percent change in body weight when switching to D/C/F/TAF FDC (Immediate Switch Arm)
!
To assess changes in body weight when switching to D/C/F/TAF FDC (Immediate Switch Arm)
!
To assess changes in body composition when switching to D/C/F/TAF FDC (Immediate Switch Arm)
!
To assess change in blood pressure when switching to D/C/F/TAF FDC (Immediate Switch Arm) 
!
To assess changes in clinical laboratory tests when switching to D/C/F/TAF FDC (Immediate Switch Arm) 
!
To assess changes in liver biomarkers when switching to D/C/F/TAF FDC (Immediate Switch Arm) 
!
To assess changes in concomitant medications of interest (including anti- hypertensive, anti-hyperglycemic, and 
lipid lowering agents) when switching to D/C/F/TAF FDC (Immediate Switch Arm) 
Safety:
!
To evaluate the safety of switching to D/C/F/TAF FDC (Immediate Switch Arm)
Efficacy:
!
To evaluate the virologic outcomes when switching to D/C/F/TAF FDC (Immediate Switch Arm)
!
To evaluate immunological changes when switching to D/C/F/TAF FDC (Immediate Switch Arm)
Resistance:
!
To assess viral resistance in participants with confirmed HIV-1 RNA rebound for participants switching to
D/C/F/TAF FDC (Immediate Switch Arm) 
PROs:
!
To assess changes in the burden of common symptoms associated with HIV treatment or disease for
participants switching to D/C/F/TAF FDC (Immediate Switch Arm)
!
To describe responses on the PGIC in participants switching to D/C/F/TAF FDC (Immediate Switch Arm)
Adherence:
NCT04442737


10
Approved, Date: 24 March 2023
!
To evaluate adherence in participants switching to D/C/F/TAF FDC (Immediate Switch Arm)
Exploratory:
Exploratory clinical biomarker: Alpha melanocyte stimulating hormone
!
To assess changes in alpha-melanocyte stimulating hormone when switching to D/C/F/TAF FDC (Immediate
Switch Arm) 
Exploratory PROs
!
To assess changes in eating-related concepts (hunger, appetite, cravings, and satiety) for participants switching 
to D/C/F/TAF FDC (Immediate Switch Arm) 
!
To assess changes in concerns about body shape for participants switching to D/C/F/TAF FDC (Immediate 
Switch Arm) 
1.1.2.3.
Consistency of Effect of Baseline to Week 24 (Immediate Switch) versus Week 24 to
Week 48 (Delayed Switch)
Metabolic:
!
To assess consistency of effect in changes in body weight in participants switching to D/C/F/TAF FDC
(Immediate Switch Arm) compared to participants switching to D/C/F/TAF FDC after 24 weeks on INI +
TAF/FTC ARV regimen (Delayed Switch Arm)
!
To assess consistency of effect in body composition changes when switching to D/C/F/TAF FDC (Immediate
Switch Arm) compared to participants switching to D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV
regimen (Delayed Switch Arm)
!
To assess consistency of effect in change in blood pressure when switching to D/C/F/TAF FDC (Immediate Switch
Arm) compared to participants switching to D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV regimen
(Delayed Switch Arm)
!
To assess changes in clinical laboratory tests when switching to D/C/F/TAF FDC (Immediate Switch Arm)
compared to participants switching to D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV regimen (Delayed
Switch Arm)
!
To assess changes in liver biomarkers when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared
to participants switching to D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV regimen (Delayed Switch
Arm)
!
To assess consistency of effect in change of concomitant medications of interest when switching to D/C/F/TAF
FDC (Immediate Switch Arm) (including anti-hypertensive, anti-hyperglycemic, and lipid lowering agents)
compared to participants switching to D/C/F/TAF FDC after 24  weeks on INI + TAF/FTC ARV Regimen
(Delayed Switch Arm)
Safety:
!
To evaluate the safety of switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to participants   
switching to D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV regimen (Delayed Switch Arm)
Efficacy:
!
To evaluate the virologic outcomes when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to
participants switching to D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV regimen (Delayed Switch
Arm)
NCT04442737


11
Approved, Date: 24 March 2023
!
To evaluate immunological changes when switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to
participants switching to D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV regimen (Delayed Switch
Arm)
Resistance:
!
To assess viral resistance in participants with confirmed HIV-1 RNA rebound when switching to D/C/F/TAF
FDC compared to participants switching to D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV regimen
(Delayed Switch Arm)
PROs:
!
To assess changes in the burden of common symptoms associated with HIV treatment or disease for
participants switching to D/C/F/TAF FDC (Immediate Switch Arm) compared to participants switching to
D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV regimen (Delayed Switch Arm)
!
To describe responses on the PGIC in participants switching to D/C/F/TAF FDC (Immediate Switch Arm) and
in participants switching to D/C/TAF FDC after 24 weeks on INI + TAF/FTC ARV regimen (Delayed Switch
Arm)
Adherence:
!
To evaluate adherence in participants switching to D/C/F/TAF FDC (Immediate Switch
Arm) compared
to
participants switching to D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV regimen (Delayed Switch
Arm)
Exploratory:
Exploratory clinical biomarker: Alpha melanocyte stimulating hormone
!
To assess changes in alpha melanocyte stimulating hormone when switching to D/C/F/TAF FDC (Immediate
Switch Arm) after 24 weeks compared to participants switching to D/C/F/TAF FDC after 24 weeks on INI +
TAF/FTC ARV regimen (Delayed Switch Arm)
Exploratory PROs
!
To assess changes in eating-related concepts (hunger, appetite, cravings, and satiety) for participants switching 
to D/C/F/TAF FDC (Immediate Switch Arm) compared to participants switching to D/C/F/TAF FDC after 24
weeks on INI + TAF/FTC ARV regimen (Delayed Switch Arm)
!
To assess changes in concerns about body shape for participants switching to D/C/F/TAF FDC (Immediate 
Switch Arm) compared to participants switching to D/C/F/TAF FDC after 24 weeks on INI + TAF/FTC ARV
regimen (Delayed Switch Arm)
1.2.
Hypothesis
Based on the primary endpoint, the percent change in body weight at Week 24 from Baseline in the 
Immediate Switch Arm (D/C/F/TAF FDC) is less than that of the Delayed Switch Arm (INI + TAF/FTC 
ARV).
1.3.
Trial Design
This is a randomized, 48 week, active-controlled, open-label, prospective, multicenter, Phase 4 study to 
evaluate the tolerability of switching to D/C/F/TAF FDC compared to continuing the current INI +
TAF/FTC ARV regimen in virologically-suppressed HIV-1 infected adult participants who have
experienced rapid and significant body weight gain while receiving an INI + TAF/FTC ARV regimen.
Figure 1 described three phases conducted in this study: Screening (approximately 30 days [up to a
NCT04442737


12
Approved, Date: 24 March 2023
maximum of 6 weeks]), Open-Label Treatment (48 weeks), and Follow-up (for any participant who has
an ongoing adverse event (AE) or serious adverse event (SAE) at the time of his/her last study visit).
Figure 1:
Schematic Overview of the Study
Approximately 110 subjects will participate in this study. A maximum enrollment of approximately
70% male participants will be utilized to ensure adequate recruitment of female participants. A
maximum enrollment of approximately 70% non-black participants will be utilized to ensure adequate 
recruitment of diverse races. 
After obtaining the informed consent form (ICF) from the participant, selection criteria will be reviewed
to confirm the participant’s eligibility. At baseline (Day 1), participants who meet all eligibility criteria
will be randomized in a 1:1 ratio to one of the following two treatment arms in an open-label
manner. Randomization will be stratified by sex (Male or Female) and race (Black/African American
or Non- Black/African American) at Baseline.
Eligible participants are to:
!
have documented HIV-1 infection currently treated with a stable ARV regimen consisting of an
INI combined with TAF/FTC for ≥6 consecutive months preceding the screening visit,
!
body mass index (BMI) of ≥18 kg/m2 at the time of starting an INI + TAF/FTC ARV regimen,
!
have a rapid and significant weight gain, defined as a ≥10% increase in body weight within a 
12-to-36month time period while on the current INI + TAF/FTC ARV regimen,
!
be virologically suppressed, with at least 1 plasma HIV-1 RNA measurement <50 copies/mL
occurring between 12 and 2 months prior to screening while being on the stable INI + TAF/FTC
ARV regimen and having HIV-1 RNA<50 copies/mL at the screening visit,
!
Not have had previous failure on DRV treatment or known documented history of ≥1 DRV
resistance associated mutations (RAMs).
NCT04442737


13
Approved, Date: 24 March 2023
The study will consist of three phases:
!
Screening (approximately 30 days [up to a maximum of 6 weeks])
!
Open-Label Treatment (48 weeks)
!
Follow-up (for any participant who has an ongoing AE or SAE at the time of his/her last study
visit).
Screening Phase
The informed consent form (ICF) must be signed before any study-specific procedures at the start of
the Screening Phase. After obtaining the ICF from the participant, selection criteria will be reviewed
to confirm the participant’s eligibility. At baseline (Day 1), participants who meet all eligibility
criteria will be randomized in a 1:1 ratio to one of the following two treatment arms. Randomization
will be stratified by sex (Male or Female) and race (Black/African American or Non-Black/African
American) at Baseline. All enrolled participants will be assigned randomized treatments in an open-
label manner.
!
D/C/F/TAF FDC Arm (Immediate Switch): Switch to a regimen of DRV 800 mg +
COBI 150 mg + FTC 200 mg + TAF 10 mg FDC once daily, (n=55) for 48 weeks;
!
Active-Control Arm (Delayed Switch): Continue current INI + TAF/FTC ARV regimen,
(n=55) for 24 weeks. After 24 weeks participants will switch to a regimen of DRV 800 mg + 
COBI 150 mg + FTC 200 mg + TAF 10 mg FDC once daily for an additional 24 weeks.
Treatment Phase
Participants randomized to the Immediate Switch Arm must start D/C/F/TAF FDC within 24 hours of 
the Baseline visit and will continue to receive D/C/F/TAF treatment for a total of 48 weeks.
Participants randomized to the Delayed Switch Arm will continue their current INI + TAF/FTC ARV
regimen for 24 weeks. After Week 24, all participants in the Delayed Switch Arm will be given the option
to receive the D/C/F/TAF tablet and will be followed for an additional 24 weeks.
!
D/C/F/TAF FDC Arm (Immediate Switch): Switch to a regimen of DRV 800 mg +
COBI 150 mg + FTC 200 mg + TAF 10 mg FDC once daily, (n=55) for 48 weeks;
!
Active-Control Arm (Delayed Switch): Continue current INI + TAF/FTC ARV regimen,
(n=55) for 24 weeks. After 24 weeks participants will switch to a regimen of DRV 800 mg + 
COBI 150 mg + FTC 200 mg + TAF 10 mg FDC once daily for an additional 24 weeks.
Participants will return for study visits at Weeks 4, 12, 24, 36, and 48. Additionally, participants
randomized to the Delayed Switch Arm will have an additional study visit at Week 28 (i.e., 4 weeks after 
switching from the INI + TAF/FTC ARV regimen to D/C/F/TAF FDC).
Key metabolic assessments include body weight measurements, body composition assessed via dual-
energy
X-ray
absorptiometry (DEXA) scan,
waist circumference
measurements,
vital
sign
measurements, select clinical laboratory tests (including fasting lipids, fasting glucose, homeostatic
NCT04442737


14
Approved, Date: 24 March 2023
model assessment of insulin resistance [HOMA-IR], HbA1c, leptin, adiponectin), and liver biomarkers. 
Key efficacy assessments
include HIV-1 viral load,
CD4+/CD8+ cell count, and HIV-1 
genotype/phenotype resistance testing, if necessary.
Key safety assessments include AEs, physical examinations, standard clinical laboratory tests, and 
pregnancy testing. Concomitant medications will be recorded. D/C/F/TAF FDC study intervention
accountability and reasons for non-adherence will be monitored. 
Patient Reported outcomes (PROs), including body shape questionnaire [BSQ-8D], DAILY EATS, HIV-
Symptom Index [HIV-SI], and patient global impression of change [PGIC]), will be completed.
Unscheduled visits can be conducted as needed based on individual tolerability issues, or virologic
reasons (i.e., suspected virologic rebound) that occur between scheduled visits.
HIV-1 genotypic and phenotypic resistance testing (PhenoSense GT® Plus Integrase1) will be performed
for participants with confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥200 copies/mL at 
a scheduled or unscheduled visit) and an HIV-1 RNA >400 copies/mL at the time of confirmed rebound.
The confirmatory testing should be conducted 2 to 4 weeks after the initial HIV-1 RNA value ≥200
copies/mL. If genotypic/phenotypic resistance to study intervention is determined, study intervention
may be discontinued, and the participant will be referred for continued medical care outside of the study
if the decision is made to discontinue study intervention.
Plasma concentrations of DRV and COBI may be determined in participants experiencing virologic
rebound using stored blood samples collected throughout the study, if deemed necessary. Plasma 
concentrations of INIs for the Delayed Switch Arm may be determined in participants experiencing
virologic rebound using stored blood samples collected throughout the study, if deemed necessary.
The end of the study is defined as completion of the last data collection visit for the last participant
participating in the study. For the purpose of the primary analysis, a participant will be considered to
have completed the study if data collection as required per protocol through the complete course of 24 
weeks of ART has been completed. The primary analysis of this study will be performed once all
participants have completed the Week 24 visit or discontinued earlier. Additionally, data collected 
beyond Week 24 visit, including metabolic data, adverse events and other pertinent data, will also be 
summarized in the primary analysis. An interim analysis (IA) will be performed when approximately
60% of the planned 110 participants have completed the Week 12 visit and approximately 30% of
participants have completed the Week 24 visit to assess sample size re-estimation (SSR) unblinded to 
ensure adequate power for the hypothesis testing for the primary endpoint.
Early Study Intervention Discontinuation (ESID): Participants who prematurely discontinue study
intervention but have not withdrawn consent will be required to complete ESID assessments as soon as 
possible but within no later than 1 week of discontinuing study intervention.
At the end of the study (or at ESID), participants will resume routine clinical care with the care
provider who will determine their future care. In anticipation of transitioning the participant to routine
clinical care at the end of the study (or early discontinuation), the investigator should take steps to
NCT04442737


15
Approved, Date: 24 March 2023
ensure that the participants’ ART is not interrupted.
Follow-up Phase
A follow-up visit is required for any participant who has an ongoing AE or SAE after completion of
the last study-related visit (unless consent is withdrawn). These participants are required to return to
the site 30 days (±7 days) after completion of the last study-related visit (unless consent is withdrawn)
and complete all procedures indicated in the Schedule of Activities (SoA).
1.4.
Statistical Hypotheses for Trial Objectives
The primary goal of this study is to assess the percent change in body weight at Week 24 from Baseline
of D/C/F/TAF FDC (Immediate Switch arm) in HIV-1 infected participant who are virologically-
suppressed (HIV-1 RNA <50 copies/mL) and have experienced rapid and significant body weight gain in 
combination with an INI + TAF/FTC ARV regimen (Delayed Switch arm). The statistical hypothesis is 
the following: 
H0: Dt-Dc=0 versus H1: Dt-Dc≠0.
Where H0 is the null hypothesis, H1 is the alternative hypothesis; Dt= percent change in body weight at 
Week 24 from baseline for treatment D/C/F/TAF (Immediate Switch arm), Dc for the Delayed Switch 
arm.
The statistical hypothesis will be tested using repeated measures longitudinal method (linear mixed- effects 
(LME) model) at 0.05 significance level, 2-sided.
For all participants who receive at least 1 dose of study intervention, the descriptive statistics will be 
provided. Participant information will be analyzed based on the Intent-to-treat (ITT) population, unless
otherwise specified.
Primary Endpoint Analyses: Percent change in body weight at Week 24 from Baseline. The primary
endpoint analyses will be based on the ITT population. It will be evaluated using LME model with
participant as random effect adjusted by baseline BMI and stratification factors (sex and race) in a
longitudinal data with repeated measures (percent change in body weight measured at multiple visits).
1.5.
Sample Size Justification
Using a T-test with 80% power to detect a difference of 3% at the significance level of 0.05, 2-sided, the
sample size per treatment arm is a simple function of effect size (ES): narm=16/(ES)2. The effect size is
the standardized difference: ES=Δ/σ, where Δ is the difference between the two arms, and σ2 is the 
common variance. Since there was no direct data on the study population to assume the observed 
difference, Δ =3% is considered a clinical meaningful difference. Internal data from 2 Phase 3
studies2, 3 on D/C/F/TAF FDC arm from different HIV patient populations (naive, switch) have
shown the %body weight change in the range of 1.5% to 1.8% and standard deviation from 4.0 to 4.6
(Table 1 and Figure 2), resulting a range of ES and corresponding sample size3.
NCT04442737


16
Approved, Date: 24 March 2023
Table 2
Phase 3 Studies on D/C/F/TAF FDC Arm
Study
AMBER
D/C/F/TAF arm
EMERALD
D/C/F/TAF arm
N
347
738
% body weight change from baseline at week 24 (SD)
1.5 (4.6)
1.8 (4.0)
N
340
728
% body weight change from baseline at week 48 (SD)
2.3 (5.0)
1.9 (5.1)
(Data on file)
Figure 2:
Sample Size Estimation by Treatment Effect Size
Given the uncertainty of either the Δ or the variability, an adaptive unblinded SSR is planned to re-
estimate the sample size in an IA to ensure adequate power in the hypothesis testing for the primary
endpoint using the conditional power approach. An initial sample size of 55 participants per treatment
arm (110 participants total) will be used for treatment effect size of 0.54 (ADDPLAN version 6). The IA
is planned when approximately 60% of the initial planned 110 participants have completed the Week
12 visit and approximately 30% of participants have completed the Week 24 visit to re-estimate the
sample size to ensure adequate power for the hypothesis testing. All cumulative data will be used for
the IA. The planned maximum total sample size after SSR is 150 participants. Details for the SSR,
NCT04442737


17
Approved, Date: 24 March 2023
threshold for the conditional power, and protection of overall significance level will be provided in the 
statistical plan for the IA and monitoring.
1.6.
Randomization and Blinding
1.6.1.
Procedures for Randomization
Participants will be randomly assigned to one of two intervention arms based on a computer-generated
randomization schedule prepared before the study
by
or under the supervision of the sponsor.
Randomization will be based on a computer-generated schedule, constructed via random permuted
blocks to ensure balance across treatment arms in each strata of the stratification factors (sex and race),
and prepared before the start of the study by the sponsor.
Central randomization will be implemented in this study. Participants will be randomized in a 1:1
ratio to the Immediate Switch Arm (D/C/F/TAF FDC starting on Day 1 for 48 weeks), or the
Delayed Switch Arm (continue current INI + TAF/FTC ARV regimen for 24 weeks then switch to
D/C/F/TAF for an additional 24 weeks).
Randomization will be stratified by sex (Male or Female) and race (Black/African American or
Non-Black/African American) at Baseline. A maximum enrollment of approximately 70% male
participants will be utilized to ensure adequate recruitment of female participants. A maximum
enrollment of approximately 70% non-black participants will be utilized to ensure adequate recruitment
of diverse races.
The randomization and baseline visit (Day 1) cannot proceed until the investigator has received all
results of the screening visit and participant eligibility has been confirmed in interactive web response
system (IWRS), which should occur within approximately 30 days after the screening visit (for further
details, see Section 8 in Protocol). It is the responsibility of the investigator to ensure that the
participant is eligible for the study prior to enrollment. Randomization should be performed on the
same day as the baseline visit (Day 1), provided that all screening procedures have been completed
and participant eligibility has been confirmed.
The IWRS will assign open-label kit numbers at each study visit. Study drug will be dispensed to
the participant in an open-label fashion. The requestor must use his or her own user identification and
personal identification number when contacting the IWRS, and then will give the relevant participant 
details to uniquely identify the participant.
1.6.2.
Blinding
As this is an open-label study, blinding procedures are not applicable.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Treatment Arms
Following notations for the treatment arms will be used:
NCT04442737


18
Approved, Date: 24 March 2023
!
D/C/F/TAF FDC Arm (Immediate Switch): Switch to a regimen of DRV 800 mg + COBI 
150 mg + FTC 200 mg + TAF 10 mg FDC once daily, (n=55) for 48 weeks.
!
Active-Control Arm (Delayed Switch): Continue current INI + TAF/FTC ARV regimen,
(n=55) for 24 weeks. After 24 weeks participants will switch to a regimen of DRV 800 mg + 
COBI 150 mg + FTC 200 mg + TAF 10 mg FDC once daily for an additional 24 weeks.
2.2.
Visit Windows
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to assign 
actual visits to analysis visits. Listed below are the visit windows and the target days for each visit. The 
reference day is Study Day 1. If a subject has 2 or more actual visits in one visit window, the visit closest 
to the target day will be used as the protocol visit for that visit window. The other additional visit(s) will 
not be used in the summaries or analyses, but they can be used for determination of clinically important 
endpoints. If 2 actual visits are equidistant from the target day within a visit window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit window, it 
will no longer be used for a later time point except for the endpoint. Listed below (Table 2) are the analysis 
time points (week), visit windows and the target days for each visit defined in the protocol during the 
treatment phase. The time intervals will be used for reporting of metabolic/weight, efficacy, and safety 
data.
Table 2. Visit Windows
a For subjects discontinuing treatment early, data collected at that visit will count towards the time interval based on days relative 
to baseline.
b The baseline visit (Day 1) cannot proceed until the investigator has received all results of the screening visit and participant
eligibility has been confirmed.
Note: Target Time Point (Day)=Week x×7 +1; Time Interval (Day), for example, Start day=127=(85+169)/2 and then obtain 
the previous interval End day=127-1=126. Similarly, for other intervals’ Start day and End day.
Phases will be constructed for each subject as follows for adverse events, concomitant therapies, and for 
the determination of the worst-case/toxicity/change in the cross-tabulations.
Analysis 
Time Point a
Immediate Switch 
Arm - Time 
Interval
(Day)
Delayed Switch 
Arm - Time 
Interval
(Day)
Target Time 
Point (Day)
Screening
Day-42 - <Day 0
Day-42 - <Day 0
-∞
Baseline b
≤Day 1
≤Day 1
1
Week 4
Day 2 – Day 56
Day 2 – Day 56
29
Week 12
Day 57 – Day 126
Day 57 – Day 126
85
Week 24
Day 127 – Day 210
Day 127 – Day 182
169
Week 28
NA
Day 183 – Day 224
197
Week 36
Day 211 – Day 294
Day 225 – Day 294
253
Week 48
Day 295 – Day 378
Day 295 – Day 378
337
NCT04442737


19
Approved, Date: 24 March 2023
Trial phase
Start date
End date
Screening
Minimum of date of signing the 
informed consent and date of 
the screening visit, no early than 
Day -42
1 day before start of treatment or day 1 of treatment 
whichever the last before first dose. 
Treatment
Phase I
Date of the first intake (after 
randomization)
For ongoing/completed subjects, in order of priority: 
-
For delayed switched arm, use first 
D/C/F/TAF intake date – 1;
-
For immediate switch arm, use Week 24 visit 
date; if missing then
-
Projected Week 24 visit date
Projected Week 24 visit date = first dose date 
+ (7×24).
In case of withdrawal before Week 24 visit:  Date of 
last intake +7 days. If the last dose date is missing, 
use the following date in order of priority:
-
The date of treatment termination + 7 days;
-
The first available follow-up visit date-1 day;
-
The earlier of projected Week 24 visit date +7 
and Trial discontinuation date + 7, where 
projected Week 24 visit date = first dose date 
+ (7×24).
Treatment
Phase II
Treatment Phase I end date +1 
day
For ongoing/completed subjects, in order of priority: 
-
Week 48 visit date + 7; if missing then
-
Projected Week 48 visit date +7, where 
projected Week 48 visit date = first dose date  
+ (7×48).
In case of withdrawal after Week 24 visit:  Date of 
last intake +7 days. If the last intake date is missing, 
use the following date in order of priority:
-
The date of withdrawal + 7 days;
-
The first available follow-up visit date-1 day;
-
The earlier of projected Week 48 visit date +7 
and trial discontinuation date + 7, where 
projected Week 48 visit date = first dose date 
+ (7×48).
*Follow-up
End of the last treatment phase 
+1 day
Trial termination date for all groups (date of last 
contact)
*30 day follow-up visit required for any subject who has ongoing AE or SAE at the time of his last study visit.
NCT04442737


20
Approved, Date: 24 March 2023
2.3.
Pooling Algorithm for Analysis Centers
Not applicable.
2.4.
Analysis Sets
2.4.1.
All Subjects
All subject analysis set population includes subjects who were screened. 
2.4.1.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all the subjects who were randomized and received at 
least 1 dose of treatment subsequent to randomization in the study. Subjects will be grouped according to 
the treatment arm (D/C/F/TAF FDC or Active-Control) to which they were randomized. 
The ITT analysis set is the primary analysis set for primary endpoint (percent change in body weight)
analysis. The ITT analysis set is also used for efficacy analysis. Efficacy data up to the last dose date of 
the randomized study treatment will be included.
2.4.1.2.
Per-Protocol Analysis Set
Since an analysis on the ITT population may not be conservative in certain analysis settings, an analysis 
based on the per-protocol (PP) population will also be performed to investigate the impact of excluding 
subjects with major protocol violations and to evaluate the robustness of the primary and major secondary 
analysis results. 
2.4.2.
Safety Analysis Set
The safety analysis set includes all randomized subjects who received at least 1 dose of study intervention
(i.e., ITT analysis set). The safety analysis (including all data collected up to 30-day follow-up visit) is 
also performed on the ITT analysis set. Participants will be assessed according to the actual intervention
they received.
2.5.
Definition of Subgroups
The pre-specified subgroups are summarized in the table below. Selected subgroup analyses will be 
performed for baseline and demographic characteristics tables. Additional subgroup analyses may be 
performed, if requested and deemed necessary.
Subgroup
Definition
Race a*
!
Black/African American
!
Non-Black/African American
Sex*
!
Female
!
Male
Race:Sex*
!
Black/African American Female
!
Black/African American Male
NCT04442737


21
Approved, Date: 24 March 2023
Subgroup
Definition
!
Non-Black/African American 
Female
!
Non-Black/African American Male
Ethnicity*
!
Hispanic or Latino
!
Non-Hispanic or Latino
!
Others (Unknown/Not Reported)
Race/Ethnicity  
!
Black/African American Hispanic or 
Latino
!
Black/African American Non-
Hispanic or Latino
!
Non-Black/African American 
Hispanic or Latino
!
Non-Black/African American Non-
Hispanic or Latino
Baseline CD4+ categories
!
>200
!
≤ 200
Age Group*
Adults
!
18-25
!
26-50
!
51-64
!
≥65
BMI*
!
normal 18 - <25 kg/m2
!
overweight 25 - <30 kg/m2
!
obese ≥30 kg/m2
Waist circumference (inch) *
!
Male WC ≥ 40”
!
Males WC < 40”
!
Female WC ≥ 35”
!
Female WC < 35”
ARV Treatment Regimen at Time of Screening
!
BIC/FTC/TAF 
!
DTG + FTC/TAF
!
RAL + FTC/TAF
!
EVG/C/FTC/TAF
Delayed Switch Regimen
!
DTG+FTC/TAF vs SYM 
!
BIC/FTC/TAF vs SYM
!
RAL+FTC/TAF vs SYM
!
EVG/C/FTC/TAF vs SYM
Presence of one or more primary and/or DRV 
Resistance-Associated Mutation (RAMs),
!
Yes/No
Presence of one or more NRTI RAMs
!
Yes/No
Presence of one or more NNRTI RAMs
!
Yes/No
Presence of one or more Primary INI RAMs
!
Yes/No
Presence of one or more Secondary INI RAMs
!
Yes/No
HIV Acquisition Risk Factor b*
!
Heterosexual contact 
!
MSM
!
Others
NCT04442737


22
Approved, Date: 24 March 2023
Subgroup
Definition
NAFLD fibrosis score*
!
F0-F2
!
Indeterminate
!
F3-F4
HAIR scores *
!
>=2
!
<2
Baseline Co-morbid conditions (defined by 
Medical History)
!
Diabetes Y/N
!
HTN Y/N
!
Hyperlipidemia Y/N
a Non-Black/African American=White, American Indian or Alaska Native, Asian, Native Hawaiian or other Pacific Islander,
Multiple, Other, Unknown, and Not reported.
b Others= Intravenously injectable drug use, Blood transfusion, Hemophilia-associated injections, Occupational exposure, 
Mother to child transmission and other.
* Subgroup analyses will be performed for these subgroups only
2.6.
Study Day and Relative Day
Study Day 1 or Day 1 refers to the start of the first study agent administration or randomization date. If 
subjects start medication a day after baseline/screening visit, actual treatment administration date will be 
used as Day 1 instead of screening/baseline visit date.
All metabolic, efficacy and safety assessments at all visits will be assigned a day relative to this date.
2.7.
Baseline and Endpoint
Baseline is defined as the last observation prior to the start of the first study agent administration or 
randomization date.
Endpoint is defined as the last available postbaseline result within the analysis period. Unscheduled visit 
results are included in this definition and will be considered as the endpoint value if the unscheduled visit 
result is the last postbaseline result available within the analysis period.
2.8.
Imputation Rules for Missing AE Date of Onset/Resolution
Partial AE onset dates will be imputed as follows:
!
If the onset date of an adverse event is missing day only, it will be set to:
∀
First day of the month that the AE occurred, if month/year of the onset of AE is different than the 
month/year of the study treatment start.
∀
The day of the study treatment start, if the month/year of the onset of AE is the same as 
month/year of the study treatment start and month/year of the AE resolution date is different
∀
The day of the study treatment start or day of AE resolution date, whichever is earliest, if 
month/year of the onset of AE and month/year of the study treatment start and month/year of the 
AE resolution date are same
!
If the onset date of an adverse event is missing both day and month, it will be set to the earliest of:
NCT04442737


23
Approved, Date: 24 March 2023
∀
January 1 of the year of onset, as long as this date is on or after the study treatment start date
∀
Month and day of the study treatment start date, if this date is the same year that the AE occurred
∀
Last day of the year if the year of the AE onset is prior to the year of the study treatment start 
date,
∀
The AE resolution date.
!
Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:
!
If the resolution date of an adverse event is missing day only, it will be set to the earliest of the last 
day of the month of occurrence of resolution or the day of the date of death, if the death occurred in 
that month.
!
If the resolution date of an adverse event is missing both day and month, it will be set to the earliest 
of December 31 of the year or the day and month of the date of death, if the death occurred in that 
year.
!
Completely missing resolution dates will not be imputed.
3.
INTERIM ANALYSIS AND, DATA MONITORING COMMITTEE REVIEW
An interim analysis (IA) is planned when approximately 60% of the initial planned 110 participants
have completed the Week 12 visit and approximately 30% of participants have completed the Week 24
visit to re-estimate the sample size to ensure adequate power for the hypothesis testing. All cumulative 
data will be used for the interim analysis. Details for the sample size re-estimation (SSR), threshold for 
the conditional power, and protection of overall significance level will be provided in DRC charter for
the IA and monitoring. The planned maximum total sample size after SSR is 150 participants. IA 
contents will be defined in DPS.
The Data Monitoring Committee (DMC) is not applicable. Instead, a data review committee (DRC) is used 
for the interim analysis. Details are included in the DRC charter.
4.
SUBJECT INFORMATION
The number of subjects in each analysis set will be summarized and listed by treatment group, and overall. 
In addition, the distribution of subjects by site ID will be presented unless otherwise noted.
4.1.
Demographics and Baseline Characteristics
Table 3 presents a list of the demographic variables that will be summarized by treatment group, and 
overall for the ITT, safety, and PP analysis sets. Additionally, baseline disease characteristics data are
listed in Table 4. Demographics and baseline disease characteristics will also be summarized and analyzed
by study subgroups listed in Section 2.5 using the ITT analysis set.
NCT04442737


24
Approved, Date: 24 March 2023
Table 3: Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum])
Weight (kg)/(pounds)
Percent weight gained on current INI+TAF/FTC regimen at screening
Duration of virologic suppression on current INI+TAF/FTC regimen
(month)
Duration of infection (month)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Waist circumference (cm)
Categorical Variables
Age (18-25 years, 26-50 years, 51-64 years, and ≥65 years)
Frequency distribution with the 
number and percentage of subjects 
in each category.
Baseline history of hypertension (yes/no)
Baseline history of diabetes (yes/no)
Baseline history of dyslipidemia (yes/no)
Baseline active neurologic comorbidities (yes/no)
Baseline active psychiatric comorbidities (yes/no)
Number of active neurologic/psychiatric comorbidity (1, 2, 3, 4, >/=5) 
Baseline HbA1c > 6.5% (yes/no)
Antihypertensives, antihyperglycemic agents or lipid lowering agents
(yes/no)
Sex (male, female)
Gender (male, female, male-to-female, female-to-male, non-binary/other)
Race (Black/African American, Non-Black/African American)
Race:Sex (Black/African American Female, Black/African American 
Male, Non-Black/African American Female, Non-Black/African American 
Male)
Racea (Black/African American, White, American Indian or Alaska 
Native, Asian, Native Hawaiian or other Pacific Islander, Other, Unknown, 
Not reported)
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Unknown, Not 
reported)
BMI (normal 18-<25 kg/m2, overweight 25-<30 kg/m2, obese ≥30 kg/m2)
Woman of childbearing potential (Of childbearing potential/Permanently 
Sterilized/ Postmenopausal/ NA)
Nicotine use (Never used, current user, former user)
Alcohol consumption (Never used, current user, former user)
Drug Use (Never used, current user, former user)
Highest education level (Less than high school, …)
Marital status (Single- newer married, married, …)
Employment status (Employed full time for wages, …)
State belongs to (Alabama, …) 
Social support of the subject (Friend, Family member, …)
Current housing situation
a If multiple race categories are indicated, the Race is recorded as 'Multiple'
Table 4: Baseline HIV disease characteristics
Continuous Variables:
Summary Type
Baseline CD4+ (absolute count and %)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
Baseline-screening eGFRcra
Baseline HIV-1 viral load (absolute count)
NCT04442737


25
Approved, Date: 24 March 2023
Duration of INI + TAF/FTC treatment at baseline (years)
and range [minimum and 
maximum]).
Duration of TAF use (years)
Duration of ART (years)
Categorical Variables:
Frequency distribution with the 
number and percentage of subjects 
in each category.
Type of INI regimen at baseline
Number of previous ART regimens
Switched previous regimens for AE, VF, Convenience and Other
HIV Acquisition Risk Factor (Heterosexual contact, MSMs, Others b)
Baseline viral load (<50, ≥ 50 HIV-1 RNA copies/mL)
Baseline CD4 cell count (≤200, 200<x≤350, 350< x≤500, >500)
cells/mm3)
HIV-1 subtype (B, Non-B)
Historical evidence of DRV RAM
!
yes/no
!
V11I
!
V32I
!
etc.
Historical evidence of FTC RAM
!
yes/no
!
K65R
!
K65E
!
etc.
Historical Evidence of TFV RAM
!
yes/no
!
K65N
!
K70E
!
etc.
Historical Evidence of INI RAM
!
yes/no
!
T66A
!
T66I
!
etc.
a If a participant’s actual body weight is greater than 20% over their Ideal Body Weight (IBW), the participant’s Adjusted 
Body Weight (ABW) will be used for eGFRcr (Cockcroft-Gault Formula).  IBW(male) = 50kg + 0.9kg x (height(cm) – 152). 
IBW (female) = 45.5kg + 0.9kg x (height(cm) – 152. ABW= IBW(kg) + 0.4 x (Weight(kg) – IBW(kg)).
bOthers=Intravenously injectable drug use, Blood transfusion, Hemophilia-associated injections, Occupational exposure, 
Mother to child transmission, and Other
4.2.
Disposition Information
A tabulation of the total number (with percentages) of subjects screened (and reason for screen failures), 
randomized and not treated, and randomized and treated will be provided.
Tabulation per treatment arm and overall of the number of subjects who have completed the treatment 
phase, who are ongoing, and who have discontinued the trial before Week 48 visit, with the reason for 
discontinuation will be provided.
A Kaplan-Meier graph for the time to Discontinuation (any reason) will be included.
The number of subjects in the following disposition categories will be summarized throughout the study:
!
Subjects receiving study intervention
NCT04442737


26
Approved, Date: 24 March 2023
!
Subjects completing the study
!
Subjects who discontinued study intervention
!
Reasons for discontinuation of study intervention
The above categories will include summaries. A listing of subjects will be provided for the following 
categories:
!
Subjects who discontinued study intervention
4.3.
Treatment Compliance (Adherence)
Treatment adherence defined based on participant self-report using a 4-day recall as collected Drug 
Adherence page of eCRF for the study will be assessed at all study visits by participant self-report using
a 4-day recall.
Adherence rates will be reported according to the proportion of participants missing 0, 1, 2, 3 or 4 doses
using participant self-report 4-day recall at Weeks 4, 12, 24, 36, and 48.
4.4.
Extent of Exposure
The number and percentage of subjects who receive study drug of both D/C/F/TAF FDC arm and active-
control arm will be summarized by treatment group.
Descriptive statistics, (N, mean, SD, median, and range (minimum, maximum)), will be tabulated for the 
duration of treatment of both D/C/F/TAF and control, in weeks, during the respective active treatment phases,
up to the Week 48 visit, or in case of early discontinuation, last study medication intake for the ITT analysis 
set. In addition,
!
subject-years of exposure will be shown, derived as mean of treatment duration ((in weeks) x N) x 7 / 
365.25..
!
subject-weeks of exposure are calculated as (days of exposure)/7. Subject-weeks will be presented.
!
treatment duration (in weeks) is defined as follows for each of the two treatment arms:
(End of phase – start of phase + 1) / 7
Treatment interruptions will not be taken into account for the above definition.
!
total dose days of exposure is defined as the total number of days that study intervention was 
administered to the subject (excluding days of known study treatment interruption). If dates of study 
treatment interruptions are not fully known, in terms of start and end date of interruption, these 
interruptions will not be excluded from total days of exposure.
4.5.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact subjects’ rights, 
safety or well-being, or the integrity and/or result of the clinical study. Subjects with major protocol 
deviations will be identified prior to database lock and the subjects with major protocol deviations will be 
summarized by category.
!
Developed withdrawal criteria but not withdrawn
NCT04442737


27
Approved, Date: 24 March 2023
!
Entered but did not satisfy inclusion/exclusion criteria
!
Received a disallowed concomitant treatment
!
Received incorrect dose
!
Other
4.6.
Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD). Prior medications are defined as any therapy used before the Baseline Day 1. Concomitant 
medications are defined as any therapy used on or after the same day as the Baseline Day 1.
Summaries of concomitant medications will be presented by treatment group. The proportion of subjects 
who receive each concomitant medication and the proportion of subjects who receive at least one 
concomitant medication will be summarized. 
Summaries of concomitant medications will be presented by ATC term. A summary of participants with 
changes in medications of interest at Week 48 will be reported.
Prior and concomitant therapies will be summarized and grouped as follows by treatment group for specific 
drugs, using a list of dictionary derived terms provided as metadata. These groups will be tabulated (n, %) 
per treatment group and analysis phase:
!
lipid lowering drugs
!
antidiabetic drugs
!
antihypertensive drugs
!
drugs for cardiovascular disease
!
antiosteoporotic drugs
!
antidepressants
!
antipsychotics
!
steroids
!
thyroid medications
Prior medications will be summarized by ATC term.
4.7.
Medical History
Subjects past and/or concomitant diseases will be tabulated by medical history categories, general medical 
history, and family history, separately by treatment group. Tabulation (n, %) will be done by body system 
and medical term. Additionally, all medical history will be listed by medical history category.
NCT04442737


28
Approved, Date: 24 March 2023
5.
METABOLIC/WEIGHT
5.1.
Analysis Specification
In general, continuous variables will be summarized using descriptive statistics including the number of 
participants, mean, standard deviation (SD), two-sided 95% confidence interval (CI), median, and range. 
Binary or categorical variables will be summarized using the number and percentage of participants in 
each category. Descriptive summaries will be provided by stratification factors (sex and race). Graphic 
displays will also be used to summarize the data.
5.2.
Primary Endpoint
5.2.1.
Definition
The primary endpoint is defined as the percent change in body weight at Week 24 from Baseline.
5.2.2.
Primary Estimand
The main analysis of the primary endpoint will be conducted by using the following estimand attributes:
A) Study Intervention:
o
Arm 1: D/C/F/TAF FDC Arm (Immediate Switch)
o
Arm 2: Active-Control Arm (Delayed Switch)
B) Study population: Type 1 (HIV-1) infection currently treated subjects with a stable ARV 
regimen consisting of an INI combined with TAF/FTC for ≥ 6 consecutive months preceding the 
screening visit and experiencing a ≥10% increase in body weight within 12 months’ time period 
C) Variable: Percent change in body weight at Week 24 from Baseline
D) Intercurrent events:
o
Treatment discontinuation prior to Week 24: if the participant discontinued treatment
prior to Week 24 but weight assessments are available at that time point,
all data will be used regardless of occurrence of the intercurrent event (treatment policy
strategy).
o
Major protocol deviations: all data are used regardless of the occurrence of major
protocol deviations (treatment policy strategy).
o
Deaths prior to Week 24: participants who die prior to Week 24 will be included with the 
weight data available prior death.
NCT04442737


29
Approved, Date: 24 March 2023
E) Population-level summary: Mean difference in %weight change at Week 24 between study 
intervention arms.
5.2.3.
Analysis Methods
The statistical hypothesis is the following: 
H0: Dt-Dc=0 versus H1: Dt -Dc≠0.
Where H0 is the null hypothesis, H1 is the alternative hypothesis; Dt= percent change in body weight at
Week 24 from Baseline for D/C/F/TAFFDC (Immediate Switch Arm), Dc = percent change in body
weight at Week 24 from Baseline for active control (Delayed Switch Arm).
The statistical hypothesis will be tested using mixed model for repeated measures (MMRM) below.
Y = Baseline BMI + Sex + Race + Time + Treatment + Treatment*Time + Subject + Ɛ
In this model, Y is the %change in body weight from baseline at time week 4, week 12, and week 24; 
baseline BMI, sex, race, time, treatment and treatment*time are fixed effects; subject is a random effect; 
and Ɛ is the random error. Subject is treated as a random effect to incorporate the variability and correlation 
among repeated measures (time).
The statistical hypothesis will be tested by estimating the treatment LSmeans for the %change in body 
weight corresponding to the time measurement at week 24. The significance level p-value and 95% 
confidence interval for the difference will be provided.
To control for the overall Type I error rate at the 2-sided 0.05 significance level, the weighted inverse-
normal p-value combination test will be used to combine p-values from interim stage and primary 
analysis stage4 . The overall p value will be calculated by the combination statistic below
Z(p1, p2) = w1 Φ−1(1−p1) + w2 Φ−1(1−p2)
where w1=√ (n1/N), w2=√ (n2/N), n1 and n2 are number of subjects in IA stage and remaining primary 
stage.
All available data from randomized participants that have received at least one dose is included (ITT 
analysis set) will be used for the analysis, regardless of the occurrence of intercurrent events.
Missing Data for body weight is assumed as Missing At Random (MAR). In addition, as a sensitivity 
analysis, a control-based multiple imputation will be applied to the MMRM model, assuming weight 
data is not missing at random.
NCT04442737


30
Approved, Date: 24 March 2023
5.2.4.
Sensitivity Estimator
A sensitivity analysis will be performed for primary endpoint (percent change in body weight Week 24) 
analysis based on modified ITT population (mITT) which will exclude those ITT subjects who are 
impacted specifically by COVID-19 with missing important study visits and/or discontinuation. The 
mITT analysis set will be pre-specified before the database lock.
A second sensitivity analysis will be performed to evaluate outlier effect on the primary endpoint. 
Outliers of percent weight change, which is defined as more than three standard deviations from the 
mean percent change in body weight from baseline at Week 24, will be excluded from modified ITT 
population 2 (mITT2) for this analysis.
The same MMRM model described in methods for the primary estimand will be used for the sensitivity 
analyses described above.
6.
EFFICACY/VIROLOGY
6.1.
Analysis Specifications
6.1.1.
Data Handling Rules
Plasma viral load will be measured using a validated assay at a central laboratory.  
Imputation of left censored HIV-1 RNA values: viral load results recorded as “< 20 copies/mL HIV RNA 
detected”, “< 20 copies/mL HIV RNA copies/mL Not Detected” and “NO HIV-1 RNA DETECTED” will 
be scored at 19.
If there are retesting, repeating the same analysis from same collected sample, last or retested results will 
be used in analysis. 
6.1.2.
Virologic Response Definitions
The following imputation methods will be used to calculate virologic response at a given time point
addition with applying 50/200 copies/mL as threshold.
Two imputation mechanisms are considered:
1. Observed
2. FDA Snapshot 
The first mechanism, Observed, does not require an imputation procedure. Subjects with a missing value 
are disregarded in the analysis for that time point.
The second mechanism FDA snapshot approach: The snapshot mechanism is based on the last available 
plasma HIV-1 RNA level within the window of an analysis time point. This does not necessarily 
coincide with the HIV-1 RNA assessment with USE = ‘Y’.
The snapshot approach will classify subjects into 3 outcome categories: “virologic response”, “virologic 
failure”, or “no viral load data in the Week 24 and Week 48 visit windows”. Several subcategories of the 
outcome will also be presented in the analysis and are shown below. The categories below are mutually 
exclusive such that a subject will be included in one category. If a subject discontinues in the time window 
NCT04442737


31
Approved, Date: 24 March 2023
but also has an HIV-RNA value in the time window, then the viral load data will be used to classify the 
subject’s category. 
!
Virologic response: 
o
HIV RNA <50/200 copies/mL in the Week 24 visit window (Week 18-30) and Week 48 visit 
window (Week 42-54)
!
Virologic failure:
o
HIV RNA ≥50/200 copies/mL in the Week 24 visit window (Week 18-30) and Week 48 visit 
window (Week 42-54)
o
Virologic failure leading to discontinuation
o
Discontinued due to other reason (i.e., other than AE/death or virologic failure) and last available 
HIV RNA ≥50/200 copies/mL
!
No viral load data in the Week 24 visit window (Week 18-30) and Week 48 visit window (Week 42-
54):
o
Discontinued due to AE/death (subjects will be classified in this category if discontinued prior to 
Week 24 visit window and Week 48 visit window regardless of HIV RNA level).
o
Discontinued due to other reason (i.e., other than AE/death or virologic failure) and the last 
available HIV RNA <50/200 copies/mL (or missing)
o
Missing data during the Week 24 visit window and Week 48 visit window but on study.
Virologic failure leading to discontinuation will be determined by a medical assessment of the comment 
fields and other specification reasons for discontinuation to determine if anyone discontinued the trial 
due to lack of efficacy reasons. Upon further clinical evaluation additional comments or other 
specification reasons might need to be added, and these will be documented in the DPS. An identified 
subject will be classified to the snapshot categories as follows:
!
Data within window: If an identified subject has HIV RNA data within the window, the HIV RNA 
data will be used to classify the subject as either at or above the threshold or below the threshold.
!
No data within window: If an identified subject does not have HIV RNA data in window, then 
regardless of the last HIV RNA value the subject will be classified as “Virologic failure leading to 
discontinuation”.
Virologic response will then be categorized as follows: Yes (virologic response), or No (virologic failure 
and no viral load data in the Week 24 visit window and Week 48 visit window).
The snapshot approach will also be displayed over time by analysis time points and will follow the same 
logic as defined above weeks 24 and 48 time point. (Please see Section 2.2. Visit Windows for visit 
intervals).
Subjects will also be classified as confirmed virologic rebounds if they meet the criteria below:
!
Two consecutive HIV RNA ≥200 copies/mL at a scheduled or unscheduled visit after maintaining 
HIV-1 RNA <50 copies/mL).
NCT04442737


32
Approved, Date: 24 March 2023
6.2.
Secondary Endpoints and Analysis Methods
6.2.1.
Weeks 24 and 48 Endpoints
In the following, the secondary endpoints at Week 24 are defined for D/C/F/TAF FDC regimen 
(Immediate Switch Arm) versus INI + TAF/FTC ARV regimen (Delayed Switch Arm), while the 
secondary endpoints at Week 48 are related to D/C/F/TAF FDC (Immediate Switch Arm) only.  
Metabolic:
!
Change from Baseline in absolute body weight over time
!
Proportion of participants with % change from baseline in body weight >5% over time.
!
Proportion of participants with % change from baseline in body weight >3% over time.
!
Change from Baseline in BMI over time.
!
Change from Baseline in body composition as measured by DEXA scan at Week 24 and Week 
48, respectively.
!
Change from Baseline in waist circumference over time.
!
Change in SBP and DBP from Baseline over time.
!
Change from Baseline in fasting lipids over time.
!
Change from Baseline in fasting glucose over time.
!
Change from Baseline in HOMA-IR at Week 24 and Week 48, respectively.
!
Change from Baseline in HbA1c at Week 24 and Week 48, respectively.
!
Change from Baseline in leptin and adiponectin at Week 24 and Week 48, respectively.
!
Change from Baseline in the proportion of participants with advanced fibrosis according to the 
NAFLD fibrosis score at Week 24 and Week 48, respectively.
!
Change from Baseline in the proportion of participants at high risk of NASH according to the 
HAIR score at Week 24 and Week 48, respectively.
!
Proportion of participants having a dose-reduction or complete withdrawal of anti-hypertensive, 
anti- hyperglycemic, or lipid lowering agents in the Immediate Switch Arm from Baseline to 
Week 24 and Week 48, respectively or Delayed Switch Arm from Baseline to Week 24.
!
Proportion of participants initiating an anti-hypertensive, anti-hyperglycemic, or lipid lowering
agent in the Immediate Switch Arm from Baseline to Week 24 and Week 48, respectively or
Delayed Switch Arm from Baseline to Week 24.
Safety:
!
Incidence of any Grade AEs (related and not related) through Week 24 and Week 48, 
respectively.
!
Incidence of Grade 3 and 4 AEs (related and not related) through Week 24 and Week 48, 
NCT04442737


33
Approved, Date: 24 March 2023
respectively.
!
Incidence of discontinuations due to AEs through Week 24 and Week 48, respectively.
!
Incidence of SAEs (related and not related) through Week 24 and Week 48, respectively.
!
Change from Baseline in clinical laboratory tests over time .
!
Incidence of Grade 3 and 4 laboratory abnormalities over time .
Efficacy:
!
Proportion of participants with confirmed virologic rebound through Week 24 and Week 48, 
respectively.
!
Proportion of participants with virologic response (HIV-1 RNA<50 copies/mL) at Week 24
and Week 48, respectively, according to the FDA snapshot algorithm
!
Proportion of participants with virologic failure (HIV-1 RNA ≥50 copies/mL) at Week 24 and 
Week 48, respectively, according to the FDA snapshot algorithm
!
Proportion of participants having virologic response (HIV-1 RNA<200 copies/mL) at Week 
24 and Week 48, respectively, according to the FDA snapshot algorithm
!
Proportion of participants having virologic failure (HIV-1 RNA ≥200 copies/mL) at Week 24
and Week 48, respectively, according to the FDA snapshot algorithm
!
Change from Baseline in CD4+ cell count at Week 24 and Week 48 respectively.
Resistance:
!
Proportion of participants with baseline DRV,  FTC, TFV and INI resistance-associated mutations
(RAMs) based on historical genotypes .
!
Incidence of observed genotypic and phenotypic ARV resistance for participants meeting HIV-
1 RNA rebound criteria through Weeks 24 and 48, respectively.
!
Proportion of participants with newly identified post-baseline RAMs and phenotypic resistance 
compared to pre-baseline resistance tests when available, upon meeting confirmed virologic
rebound through Weeks 24 and 48, respectively.
PROs:
!
Change from Baseline in the proportion of participants who have bothersome symptoms (scores
of 2, 3 or 4) across all items of the HIV-SI at Week 24 and Week 48, respectively.
!
Change from Baseline in the proportion of participants who have any symptoms (scores of 1, 2,
3 or 4) across all items of the HIV-SI at Week 24 and Week 48, respectively.
!
Association between treatment arm and each bothersome symptom of the HIV-SI adjusting for
Baseline variables at Week 24 and Week 48, respectively.
!
PGIC and PGIC-S at Week 24 and Week 48, respectively.
Adherence:
!
Adherence rates by participant self-report using 4-day recall at Weeks 4, 12, 24, 36 and 48, 
respectively.
Exploratory:
Exploratory clinical biomarker:
!
Change from Baseline in alpha melanocyte-stimulating hormone at Week 24 and Week 48, 
respectively.
NCT04442737


34
Approved, Date: 24 March 2023
Exploratory PROs:
!
Change from Baseline in the scores on the DAILY EATS at Week 24 and Week 48, respectively.
!
Change from Baseline in the scores on the BSQ-8D at Week 24 and Week 48, respectively.
!
Change from Baseline in the proportion of participants who have no concern (<19), mild concern
(19-25), moderate concern (26-33) or marked concern (>33) with their body shape on the BSQ-
8D at Week 24 and Week 48, respectively.
6.2.1.1.
Consistency of Effect of Baseline to Week 24 (Immediate Switch) versus Week 24
to Week 48 (Delayed Switch)
Metabolic:
!
Change in absolute body weight from Baseline to Week 24 (Immediate Switch Arm) compared
to the change in absolute body weight from Week 24 to Week 48 (Delayed Switch Arm)
!
The proportion of participants having a >5% change in body weight from Baseline to Week 24
(Immediate Switch Arm) compared to the proportion of participants having a >5% change in
body weight from Week 24 to Week 48 (Delayed Switch Arm)
!
The proportion of participants having a >3% change in body weight from Baseline to Week 24
(Immediate Switch Arm) compared to the proportion of participants having a >3% change in
body weight from Week 24 to Week 48 (Delayed Switch Arm)
!
Change in BMI from Baseline through Week 24 (Immediate Switch Arm) compared to the
change in BMI from Week 24 through Week 48 (Delayed Switch Arm)
!
Change in BMI categories from Baseline through Week 24 (Immediate Switch Arm) compared
to the change in BMI categories from Week 24 through Week 48 (Delayed Switch Arm)
!
Percent change in body weight from Baseline to Week 24 (Immediate Switch Arm) compared
to the percent change in body weight from Week 24 to Week 48 (Delayed Switch Arm).
!
Percent change in Visceral Adipose Tissue from Baseline to Week 24 (Immediate Switch Arm)
compared to the percent change in Visceral Adipose Tissue from Week 24 to Week 48 (Delayed
Switch Arm).
!
Change in body composition as measured by DEXA from Baseline through Week 24
(Immediate Switch Arm) compared to the change in body composition from Week 24 through 
Week 48 (Delayed Switch Arm)
!
Change in waist circumference from Baseline to Week 24 (Immediate Switch Arm) compared
to the change in waist circumference from Week 24 to Week 48 (Delayed Switch Arm)
!
The proportion of participants having a waist circumference of > 40 inches for men and > 35 inches for 
women at Week 24 (Immediate Switch Arm) compared to the proportion of participants having waist 
circumference of > 40 inches for men and > 35 inches for women at Week 48 (Delayed Switch Arm)
!
Change in SBP and DBP from Baseline to Week 24 (Immediate Switch Arm) compared to the
change in SBP and DBP from Week 24 to Week 48 (Delayed Switch Arm)
!
Change in fasting lipids from Baseline to Week 24 (Immediate Switch Arm) compared to the
change in fasting lipids from Week 24 to Week 48 (Delayed Switch Arm)
!
Change in fasting glucose from Baseline to Week 24 (Immediate Switch Arm) compared to the
change in fasting glucose from Week 24 to Week 48 (Delayed Switch Arm)
NCT04442737


35
Approved, Date: 24 March 2023
!
Change in in HOMA-IR from Baseline to Week 24 (Immediate Switch Arm) compared to the
change in HOMA-IR from Week 24 to Week 48 (Delayed Switch Arm)
!
Change in HbA1c from Baseline to Week 24 (Immediate Switch Arm) compared to the change
in HbA1c from Week 24 to Week 48 (Delayed Switch Arm)
!
Change in leptin and adiponectin from Baseline to Week 24 (Immediate Switch Arm) compared
to the change in leptin and adiponectin from Week 24 to Week 48 (Delayed Switch Arm)
!
Change in the proportion of participants from Baseline to Week 24 with advanced fibrosis
according to the NAFLD fibrosis score (F0-F1, Indeterminate, and F3-F4) (Immediate Switch
Arm) compared to the change in the proportion of participants from Week 24 to Week 48 with
advanced fibrosis according to the NAFLD fibrosis score (Delayed Switch Arm)
!
Change in the proportion of participants from Baseline to Week 24 at high risk of NASH according
to the HAIR score (<2 and ≥2) (Immediate Switch Arm) compared to the change in the proportion
of participants from Week 24 to Week 48 at high risk of NASH according to the HAIR score
(Delayed Switch Arm)
!
Proportion of participants having a dose-reduction or complete withdrawal of anti-hypertensive,
anti- hyperglycemic, or lipid lowering agents from Baseline to Week 24 (Immediate Switch
Arm) compared to Week 24 to Week 48 (Delayed Switch Arm)
!
Proportion of participants starting an anti- hypertensive, anti-hyperglycemic, or lipid lowering
agent from Baseline to Week 24 (Immediate Switch Arm) compared to Weeks 24 to Week 48
(Delayed Switch Arm)
Safety:
!
Incidence of any Grade AEs (related and not related) through Week 24 (Immediate Switch Arm)
compared to the incidence of any grade AEs (related and not related) through Week 48 (Delayed
Switch Arm)
!
Incidence of Grade 3 and 4 AEs (related and not related) through Week 24 (Immediate Switch
Arm) compared to the incidence of Grade 3 and 4 AEs (related and not related) through Week
48 (Delayed Switch Arm)
!
Incidence of discontinuations due to AEs through Week 24 (Immediate Switch Arm) compared
to discontinuations due to AEs through Week 48 (Delayed Switch Arm)
!
Incidence of SAEs (related and not related) through Week 24 (Immediate Switch Arm)
compared to Incidence of SAEs (related and not related) through Week 48 (Delayed Switch
Arm)
!
Change in clinical laboratory tests over time (Baseline to Week 24 for Immediate Switch Arm)
compared to the change in clinical laboratory tests over time (Week 24 to Week 48 (Delayed
Switch Arm)
!
Incidence of Grade 3 and 4 laboratory abnormalities through Week 24 (Immediate Switch
Arm) compared to Grade 3 and 4 laboratory abnormalities through Week 48 (Delayed Switch
Arm)
Efficacy:
!
The proportion of participants with confirmed virologic rebound at Week 24 (Immediate Switch
Arm) compared to the proportion of participants with confirmed virologic rebound from Week
24 to Week 48 (Delayed Switch Arm)
NCT04442737


36
Approved, Date: 24 March 2023
!
The proportion of participants with virologic response (HIV-1 RNA<50 copies/mL) at Week
24 according to the FDA snapshot algorithm (Immediate Switch Arm) compared to the
proportion of participants with virologic response (HIV-1 RNA<50 copies/mL) at Week 48
according to the FDA snapshot algorithm (Delayed Switch Arm)
!
The proportion of participants with virologic failure (HIV-1 RNA ≥50 copies/mL) at Week 24
according to the FDA snapshot algorithm (Immediate Switch Arm) compared to the proportion
of participants with virologic failure (HIV-1 RNA ≥50 copies/mL) at Week 48 according to the
FDA snapshot algorithm (Delayed Switch Arm)
!
The proportion of participants having virologic response (HIV-1 RNA<200 copies/mL) at Week
24 according to the FDA snapshot algorithm (Immediate Switch Arm) compared to the
proportion of participants having virologic response (HIV-1 RNA<200 copies/mL) at Week 48
according to the FDA snapshot algorithm (Delayed Switch Arm)
!
The proportion of participants having virologic failure (HIV-1 RNA ≥200 copies/mL) at Week
24 according to the FDA snapshot algorithm (Immediate Switch Arm) compared to the
proportion of participants having virologic failure (HIV-1 RNA ≥200 copies/mL) at Week 48
according to the FDA snapshot algorithm (Delayed Switch Arm)
!
Change in CD4+ cell count from Baseline to Week 24 (Immediate Switch Arm) compared to
the change in CD4+ cell count from Week 24 to Week 48 (Delayed Switch Arm)
Resistance:
!
Incidence of observed genotypic and phenotypic resistance for participants meeting HIV-1
RNA rebound criteria at Week 24 (Immediate Switch Arm) compared to the incidence of
observed genotypic and phenotypic resistance for participants meeting HIV-1 RNA rebound
criteria from Week 24 to Week 48 (Delayed Switch Arm)
!
Proportion of participants with baseline DRV, FTC, TFV and INI RAMs based on historical
genotypes
!
Proportion of participant with identified post-baseline RAMs
and
loss
of
phenotypic
susceptibility,
when available, upon meeting confirmed virologic rebound at
Week
24
(Immediate Switch Arm) compared to proportion of participant with identified post-baseline
RAMs and loss of phenotypic susceptibility, when available, upon meeting confirmed virologic
rebound from Week 24 to Week 48 (Delayed Switch Arm)
PROs:
!
Change in the proportion of participants who have bothersome symptoms (scores of 2, 3 or 4)
across all items of the HIV-SI from Baseline to Week 24 (Immediate Switch Arm) compared
to the Change in the proportion of participants who have bothersome symptoms (scores of 2, 3
or 4) across all items of the HIV-SI from Week 24 to Week 48 (Delayed Switch Arm)
!
Change in the proportion of participants who have any symptoms (scores of 1, 2, 3 or 4) across 
all items of the HIV-SI from Baseline to Week 24 (Immediate Switch Arm) compared to the
change in the proportion of participants who have any symptoms (scores of 1, 2, 3 or 4) across
all items of the HIV-SI from Week 24 to Week 48 (Delayed Switch Arm)
!
PGIC and PGIC-S at Week 24 (Immediate Switch Arm) and PGIC and PGIC-S at Week 48
(Delayed Switch Arm)
Adherence:
!
Adherence rates by participant self-report using 4-day recall at Weeks 12 and 24 (Immediate
NCT04442737


37
Approved, Date: 24 March 2023
Switch Arm) compared to the Adherence rates by participant self- report using 4-day recall at
Weeks 36 and 48 (Delayed Switch Arm).
Exploratory:
Exploratory clinical biomarker:
!
Change in alpha stimulating-melanocyte hormone from Baseline to Week 24 (Immediate Switch
Arm) compared to the change in alpha stimulating melanocyte hormone from Week 24 to Week
48 (Delayed Switch Arm).
Exploratory PROs:
!
Change in the scores on the DAILY EATS from Baseline to Week 24 (Immediate Switch Arm)
compared to the change in the scores on the DAILY EATS from Week 24 to Week 48 (Delayed
Switch Arm)
!
Change in the scores on the BSQ-8D from Baseline to Week 24 (Immediate Switch Arm)
compared to the change in the scores on the BSQ-8D from Week 24 to Week 48 (Delayed Switch
Arm)
!
Change in the proportion of participants who have no concern (<19), mild concern (19-25),
moderate concern (26-33) or marked concern (>33) with their body shape on the BSQ-8D from
Baseline to Week 24 (Immediate Switch Arm) compared to the change in the proportion of
participants who have no concern (<19), mild concern (19-25), moderate concern (26-33) or
marked concern (>33) with their body shape on the BSQ-8D from Week 24 to Week 48
(Delayed Switch Arm).
6.2.2.
Secondary Analysis Methods
6.2.2.1.
Metabolic Analyses
Secondary metabolic endpoints will be analyzed using descriptive statistics and frequency tabulations.
6.2.2.2.
Efficacy Analyses
Tabulations (numbers and proportions) per time point will be provided for the categorical parameters 
(virologic rebounders, responses, FDA snapshot response outcomes) for secondary endpoints at Weeks 
24 and 48, respectively. The treatment arms will be compared by 2-sided 95% CIs constructed using 
Clopper-Pearson method.
Descriptive statistics (n, mean (SD), median, and ranges) per time point will be provided for the continuous 
parameters, CD4 cell count actual values and the change from baseline in CD4+ cell count at Weeks 24 
and 48. 95% CIs for the means and mean changes will be calculated. 
NCT04442737


38
Approved, Date: 24 March 2023
Genotype and Phenotype
As all patients are expected to be virologically suppressed at time of study entry, standard resistance testing 
will not be performed. Historical genotypic testing results will be collected and tabulated if available prior 
to study entry. 
For subjects with confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥200 copies/mL at a 
scheduled or unscheduled visit) and with a HIV-1 RNA value ≥400 copies/mL, HIV-1 
genotypic/phenotypic resistance testing (using PhenoSense GT® Plus Integrase1) will be performed on the 
confirmed rebound sample if HIV-1 RNA ≥400 copies/mL or on a following visit with HIV-1 RNA ≥400 
copies/mL. Other time points may still be analyzed if deemed necessary. The analysis method is described 
in Section 6.2.1.
6.2.2.3.
Adherence Analyses
Adherence rates will be reported according to the proportion of participants missing 0, 1, 2, 3 or 4
doses using participant self-report 4-day recall at Weeks 4, 12, 24, 36, and 48.
Treatment adherence based on participant self-report using a 4-day recall will be summarized
descriptively and frequency tabulations for both D/C/F/TAF FDC and the INI + TAF/FTC ARV 
regimen. Cumulative treatment adherence through Week 48 will be determined. Additionally, all self-
reported adherence will be listed.
6.2.2.4.
Exploratory Analyses
Descriptive statistics and frequency tabulations, when available, will be presented for all exploratory 
endpoints.
In addition, for the Alpha melanocyte stimulating hormone, the association analysis whether increases in 
concentrations of alpha melanocyte stimulating hormone induce a satiety response will be conducted.
7.
SAFETY
7.1.
Adverse Events
7.1.1.
Definitions
Reported AE parameters and grades are based on the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events ("DAIDS AE grading table"). All AEs will be coded using 
MedDRA version 25.0.
Adverse Drug Reaction (ADR) 
ADRs will be presented. A current list of all ADRs is in Attachment 1, and upon further clinical evaluation, 
additional (grouped) terms might need to be added.  The medical assessment of the safety data will be 
performed according to a pre-specified algorithm (attached to the DPS) and will lead to the final list of 
ADRs. In case multiple lists are available (US definition), ADRs will be tabulated separately per list. 
Events of interest 
NCT04442737


39
Approved, Date: 24 March 2023
The events of interest (EOI) groups include a broad list of terms to identify potential cases. The  
preferred terms belonging to each adverse events of interest (AEOI) group will be coded using MedDRA 
version 25.0.
Since many of the terms used to identify potential cases are clinically non-specific, only those retrieved 
cases that upon medical review are specifically suggestive of /compatible with the AEs of special interest 
will be commented on in the CSR. 
AEOI groups used for the safety analyses are listed as follows.
!
Severe skin reactions
!
Rash
!
Hepatotoxicity
!
Hyperglycaemia
!
Lipid abnormalities 
!
Coronary artery events
!
Renal toxicity
!
Bone events due to potential PRT/loss of BMD
!
Ocular effects (posterior uveitis)
!
Lipodystrophy 
Incidence of treatment-emergent adverse events (TEAEs) of interest will be summarized as AE summary 
tables.
A listing of subjects who died will be provided.
7.1.2.
Analysis Methods
All safety analyses will be made on the Safety Population. For all safety endpoints descriptive
statistics will be used to summarize the endpoints.
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial 
administration of study drug through the day of last dose plus 7 day is considered to be treatment emergent. 
If the event occurs on the day of the initial administration of study drug, then the event will be assumed to 
be treatment emergent. If the event date is recorded as partial or completely missing, then the event will 
be considered to be treatment emergent unless it is known to be prior to the first administration of study 
drug based on partial onset date or resolution date. All reported treatment-emergent adverse events will be 
included in the analysis.  For each adverse event, the number and percentage of subjects who experience 
at least 1 occurrence of the given event will be summarized by treatment group. In addition, comparisons 
between treatment groups will be provided.
A summary will be provided for the following TEAEs: 
!
any adverse events, 
!
serious adverse events, 
NCT04442737


40
Approved, Date: 24 March 2023
!
deaths due to AE, 
!
adverse events by toxicity grade (as well as AEs with toxicity grade at least 2 and AEs with toxicity 
grades 3 or 4), 
!
AEs at least possibly related to study medication,
!
AEs for which the medication was temporarily/permanently stopped, 
!
serious adverse events that were at least possibly related to the medication. 
Incidences of AEs for above mentioned analyses will also be presented by SOC and preferred term. A 
listing of all AEs will be provided. There will be no formal statistical testing.
Summary of adverse events and incidence tabulations for individual AE will be provided for AEOIs and 
ADRs.
AIDS defining illness based on WHO clinical staging will be tabulated.
AE listings will be provided for subjects who
!
had SAEs
!
had AEs leading to discontinuation of study drug.
!
had grade 3 or 4 AE
!
had each AEOI category?
7.2.
Clinical Laboratory Tests
7.2.1.
Definitions
All clinical laboratory tests will be displayed for the subjects included in the ITT analysis set. Laboratory 
parameters of the lab subcategories and calculations are listed in Attachment 2. 
Number and percentage of subjects with postbaseline clinically important laboratory values and/or 
markedly abnormal postbaseline values will be presented by treatment group.
7.2.2.
Analysis Methods
Descriptive statistics will be presented for all chemistry, hematology, and urinalysis laboratory tests at 
scheduled time points. If there are retesting, repeating the same analyze from same collected sample, last 
or retested results will be used in analysis.
Change from baseline to each scheduled time points will be summarized descriptively for chemistry, 
hematology, and urinalysis (pH, and specific gravity) tests. A box plot of change from baseline to analysis
timepoints will be provided for the following laboratory tests: eGFR, ALT and AST.
Cross-tabulations for the worst toxicity grades through Weeks 24 and 48, respectively, versus reference per 
laboratory test, and cross-tabulations of the worst toxicity grades at Weeks 24 and 48, respectively, versus reference 
will also be provided if applicable. Subject listings of abnormal laboratory values will be provided.
NCT04442737


41
Approved, Date: 24 March 2023
Descriptive statistics by Division of AIDS (DAIDS) toxicity grade over time will be presented. Shift 
summaries from baseline DAIDS toxicity grade to the worst on-treatment toxicity grade will also be 
presented.
If the DAIDS grading is not available, shift tables will be provided summarizing the shift in laboratory 
values from baseline to weeks 24 and 48 analysis time points with respect to abnormality criteria (low, 
normal, high). 
7.3.
Vital Signs and Physical Examination Findings
7.3.1.
Definitions
The following vital signs parameters will be analyzed.
!
Pulse (bpm)
!
Systolic blood pressure, SBP (mmHg)
!
Diastolic blood pressure, DBP (mmHg)
A listing of subjects with treatment-emergent clinically important vital signs will be presented, along with 
a listing of all vital sign measurements.
Table 5: Pulse, SBP and DBP are classified in the following abnormality codes.
Abnormality Code
Pulse 
(bpm)
DBPa
(mmHg)
SBPa
(mmHg)
Abnormally low
#50 
#50
#90 
Grade 1 or mild
-
>90 - <100 
>140 - <160 
Grade 2 or moderate
-
∃100 - <110 
∃160 - <180 
Grade 3 or severe
-
∃110 
∃180 
Abnormally high
∃120 
-
-
a
Classification of adverse events related to hypotension/hypertension should be done according to the DAIDS grading table 
(Appendix 7 at protocol).
In determining abnormalities, the following rules are applied:
!
worst grades/abnormalities are determined over the whole observational period for each trial period
separately, including post-reference scheduled and unscheduled measurements of that phase.
!
The abnormalities ‘abnormally low’ and ‘abnormally high’/grades are considered equally important, 
i.e. if a subject has as well an abnormally low as an abnormally high or graded value post-reference, 
both abnormalities are shown in the tables. (This means that the sum of the percentages can be more 
than 100%).
Definition treatment-emergent:
An abnormality will be considered treatment-emergent in a particular period if it is worse than the 
reference corresponding to this period. If the reference is missing, the abnormality is always considered as 
treatment-emergent. A shift from ‘abnormally low’ at reference to ‘abnormally high’ or ‘grade’ post 
reference (or vice versa) is also treatment-emergent.
NCT04442737


42
Approved, Date: 24 March 2023
7.3.2.
Analysis Methods
Continuous vital sign parameters including height, weight, pulse, blood pressure (systolic and diastolic),
and Body Mass Index (BMI) will be summarized at each assessment time point by descriptive statistics 
(mean, standard deviation, median, minimum and maximum) per treatment arm.
Cross-tabulations for the worst abnormalities versus reference per vital signs test will be produced by
treatment arm.
Descriptive statistics for the actual values and changes from baseline (including BMI, weight) per timepoint will be 
presented. The only reference time point that will be used to calculate these changes is the timepoint closest to the 
first drug intake after randomization.
BMI will be calculated as weight (kg)/(height (m2)), at each time point that body weight is measured. The height 
measurement collected at screening will be used in the calculation. The frequency tabulations will be presented for 
BMI as a categorical variable and the descriptive statistics will be summarized for BMI as a continuous variable.
Physical examination findings and changes from baseline at each scheduled time point will be tabulated 
per treatment arm. Abnormal physical examination findings will also be listed.
8.
PATIENT REPORTED OUTCOMES (PROs)
8.1.
PROs
Following PROs will be assessed at the time points indicated in the Schedule of Activities (SoA). 
Appendix 8 in the Protocol provided all information of PROs questionnaires. Participants will complete 
the PROs using the sponsor-provided electronic devices.
8.1.1.
HIV-SI
The HIV-Symptom Index (HIV-SI) is a validated PRO instrument that assesses the burden of 20
common symptoms associated with HIV treatment or disease.5 Respondents are asked about their
experience with each of 20 symptoms during the past 4 weeks using a 5-point, Likert-type scale.
Response options and scores are as follows: (0) “I don’t have this symptom;” (1) “I have this symptom
and it doesn’t bother me;” (2) “I have this symptom and it bothers me a little;” (3) “I have this
symptom and it bothers me;” (4) “I have this symptom and it bothers me a lot.” The 20 symptoms
comprising the HIV-SI are fatigue/loss of energy, difficulty sleeping, nervous/anxious, diarrhea/loose
bowels, changes in body composition, feeling sad/down/depressed, bloating/pain/gas in stomach, 
muscle aches/joint pain, problems with sex, trouble remembering, headaches, pain/numbness/tingling in
hands/feet,
skin
problems/rash/itching,
cough/trouble
breathing,
fever/chills/sweats,
dizzy/lightheadedness, body weight loss/wasting, nausea/vomiting, hair loss/changes, and loss of
appetite/food taste. Symptoms scores can be dichotomized into not bothersome (scores of 0 or 1) or
bothersome (scores of 2, 3 and 4) and overall bothersome symptom count at baseline can be generated
by counting the number of individual symptoms scored as bothersome.6
8.1.2.
BSQ-8D
The Body Shape Questionnaire (BSQ-8D) is an 8-item version of the 34-item self-report questionnaire
NCT04442737


43
Approved, Date: 24 March 2023
that was developed and validated to measure concerns about body shape; in particular, it focused on the
phenomenal experience of “feeling fat”.7, 8 Respondents are asked about how they have been feeling
about their appearances over the past four weeks. Each item from this questionnaire is answered using
a 6-point Likert scale: 1 (never), 2 (rarely), 3 (sometimes), 4 (often), 5 (very often), and 6 (always)
and the overall score is the total across the 8 items.
8.1.3.
DAILY EATS
The DAILY EATS will be administered to measure eating-related concepts such as hunger, appetite,
cravings, and satiety. The home-based DAILY EATS should be completed daily, preferably in the
evening, and, whenever possible, in the same setting for 7 consecutive days. The site should contact
participants approximately 7 days prior to the Baseline (Day 1), Week 24 and Week 48 visits,
preferably by telephone, to remind the completion of the DAILY EATS for 7 consecutive days prior to
the applicable visit. For participants who discontinue early from study intervention, no DAILY EATS 
completion is required at the ESID visit.
8.1.4.
PGIC and PGIC-S 
The Patient Global Impression of Change (PGIC) is a global index that is used to rate the overall
status of the participant related to the participant’s condition. It is rated by the participant and is based
on the single question, “Compared to before starting the study or compared to the Week 24 visit, my
overall status is, where 1=very much improved, 2=somewhat improved, 3=a little improved, 4=no
change, 5=a little worse, 6=somewhat worse, and 7=very much worse.”
The single-item PGIC for satiety (PGIC-S), with question, “Compared to before starting the study or
compared to the Week 24 visit, how would you rate your satisfaction (fullness) after meals in the past 7
days?” and where 1=much more satisfied, 2=moderately more satisfied, 3=a little more satisfied, 4=no
change, 5=a little less satisfied, 6=moderately less satisfied, and 7=much less satisfied, will also be 
used. The content validity of the PGIC-S has been demonstrated in overweight and obese patients with and 
without T2DM, although the psychometric properties of the PGIC-S were not evaluated.
8.2.
PRO Analysis Methods
Descriptive statistics for absolute values, including total scores, will be calculated for each PRO measure
including HIV-SI, BSQ-8D, DAILY EATS, PGIC (PGIC-S) at each timepoint.
The changes from baseline in the proportion of participants who have bothersome symptoms (scores
of 2, 3 or 4) across all items of the HIV-SI at Weeks 24 and 48 will be summarized by treatment arm; the
changes from baseline in the proportion of participants who have any symptoms (scores of 1, 2, 3 or
4) across all items of the HIV-SI at Weeks 24 and 48 will be summarized by treatment arm.
The changes from baseline in the scores on the BSQ-8D and proportion of participants who have no
concern (<19), mild concern (19-25), moderate concern (26-33) or marked concern (>33) with their
body shape at Weeks 24 and 48 will be summarized.
The changes from baseline in the scores on the DAILY EATS at Weeks 24 and 48 will be summarized.
Further, descriptive statistics will be presented for item-level weekly scores on the DAILY EATS, item-
level weekly change scores on the DAILY EATS, Eating Drivers Index (EDI) weekly scores, and EDI 
NCT04442737


44
Approved, Date: 24 March 2023
weekly change scores, respectively. Item-level weekly scores are computed as the average of the non-
missing item-level scores over the 7-day (weekly) diary period.  EDI is computed as the average of the 
item-level weekly scores for Worst Hunger (Item 2), Appetite (Item 3), and Cravings (Item 4).
Change in the proportion of participants who have bothersome symptoms (scores of 2, 3 or 4) across
all items of the HIV-SI from Baseline to Week 24 (Immediate Switch Arm) compared to the Change
in the proportion of participants who have bothersome symptoms (scores of 2, 3 or 4) across all items
of the HIV-SI from Week 24 to Week 48 (Delayed Switch Arm will be summarized descriptively.
Change in the proportion of participants who have any symptoms (scores of 1, 2, 3 or 4) across all 
items of the HIV-SI from Baseline to Week 24 (Immediate Switch Arm) compared to the change in the
proportion of participants who have any symptoms (scores of 1, 2, 3 or 4) across all items of the HIV-
SI from Week 24 to Week 48 (Delayed Switch Arm) will be presented 
Descriptive statistics for PGIC and PGIC-S at Week 24 (Immediate Switch Arm) and PGIC and PGIC-S
at Week 48 (Delayed Switch Arm) will be calculated.
Association between treatment arm and each bothersome symptoms of the HIV-SI adjusting for
baseline variables at Weeks 24 will be calculated. For each symptom we can consider using stepwise 
variable selection criterion to choose statistically significant covariates at baseline. To understand
meaningful change in scores on PRO measures, PGIC-S will be used as an anchor to determine
meaningful change scores for the DAILY EATS in participants living with HIV.
Association of the specific item of the HIV-SI with body weight loss/wasting at Weeks 24 and 48 will be 
evaluated. Association between BSQ-8D scores and percent change in body weight and/or >5% in change 
in weight will be presented.
9.
PHARMACOKINETICS/PHARMACODYNAMICS
9.1.
Pharmacokinetics
Plasma concentrations of DRV and COBI may be determined in subjects for the Immediate Switch arm
experiencing confirmed virologic rebound, using stored blood samples collected throughout the study 
period at the discretion of the sponsor, if deemed necessary. Plasma concentrations of INIs for the Delayed
Switch arm may be determined in participants experiencing confirmed virologic rebound using stored
blood samples collected throughout the study, if deemed necessary by the sponsor. Genetic analyses will
not be performed on these serum samples. Participant confidentiality will be maintained.
Plasma concentration will be listed if available.
9.1.1.
Evaluations
Venous blood samples of approximately 3mL will be collected for measurement of plasma
concentrations of DRV and COBI in participants experiencing confirmed virologic rebound using
stored blood samples collected throughout the study at the discretion of the sponsor. Plasma 
concentrations of INIs for the Delayed Switch arm may be determined in participants experiencing
confirmed virologic rebound using stored blood samples collected throughout the study, if deemed
necessary by the sponsor.
Urine samples will be collected for measurement of various parameters as mentioned in Schedule of
NCT04442737


45
Approved, Date: 24 March 2023
Activities (SoA).
9.1.2.
Pharmacokinetic Parameters and Evaluations
Not applicable.
9.2.
Pharmacodynamics
Not applicable.
NCT04442737


46
Approved, Date: 24 March 2023
REFERENCES
1.
Pepkowitz SH. PhenoSense GT PlusIntegrase.  Monogram Biosciences. 2019. 
https://www.monogrambio.com/sites/default/files/2019-10/PhenoSenseGT-Plus-
INtegrase_watermark.pdf
2.
Eron J, Orkin C, Gallant J. et al. A week-48 randomized phase-3 trial of
darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.
AIDS.2018,32:1431–1442.
3.
Orkin C, DeJesus E, Khanlou H. et al. Final 192-week efficacy and safety of once-daily
darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients
in the ARTEMIS trial. HIV Medicine. 2013;14: 49-59.
4.
Bretz, F., König, F., Brannath, W., Glimm, E., Posch, M. (2009)., Adaptive designs for 
conﬁrmatory clinical trials, Statist. Med. 2009; 28:1181–1217
5.
Justice A, Holmes W, Giford A. et al. Development and validation of a self-completed HIV
symptom index. J Clin Epidemiol. 2001;(54): S77-90.
6.
Edelman EJ, Gordon K, Rodriguez-Barradas MC, Justice AC, Vacs Project T. Patient-reported
symptoms on the antiretroviral regimen efavirenz/emtricitabine/tenofovir. AIDS Patient Care
STDS. 2012; 26:312-319.
7.
Cooper PJ, Taylor MJ, Cooper Z, and Fairburn CG. The development and validation of the Body
Shape Questionnaire. International Journal of Eating Disorders 1986,6:485-494.
8.
Evans C, Dolan B. Body Shape Questionnaire: derivation of shortened "alternate forms. 
International Journal of Eating Disorders, 1993;13 (3),315-321.
NCT04442737


NCT04442737


NCT04442737


NCT04442737


NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA  (darunavir 800mg/cobicistat 150 
mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX4004
51
Approved, Date: 24 March 2023
Routine Urinalysis
Dipstick
Specific gravity
pH
Glucose
Protein
Blood
Ketones
Bilirubin
Urobilinogen
Nitrite
Leukocyte esterase
Urine chemistry panel (only in the
setting of a suspected renal adverse
event):
Urine Creatinine
Urine Sodium
Urine Phosphate
Urine Glucose
Urine Albumin
Urine Protein
Serum creatinine
If dipstick results are abnormal, flow cytometry will be used to measure sediment.
In case of discordance between the dipstick results and the flow cytometry results,
the sediment will be examined microscopically.
In the microscopic examination, observations other than the presence of WBC,
RBC, and casts may also be reported by the laboratory.
Other Screening Tests
!Hepatitis C virus (HCV) testing (HCV antibodies [Ab] and HCV RNA level
[only if HCV Ab+]) and hepatitis B virus (HBV) testing (anti- hepatitis B
core [HBc], anti-hepatitis B 
surface
[HBs],
hepatitis B surface antigen
[HBsAg]) (at screening only). Whenever clinically relevant, the investigator
can request additional tests at other visits.
!Urine Pregnancy Testing for women of childbearing potential only. A serum
human chorionic gonadotropin pregnancy test will be assessed at Screening at
a central laboratory. A urine pregnancy test will be performed at subsequent
study visits as outlined in the Schedule of Activities.
Fasting Metabolic Profile
Total, high density lipoprotein [HDL] and low-density lipoprotein [LDL],
cholesterol, triglycerides, glucose. If a participant has not fasted prior to the visit,
the visit may proceed, but participant must return within 72 hours in a fasted state
to have a blood draw for the metabolic assessments.
!
Calculations
Body Mass Index (BMI)
(kg/m2)
Weight (kg) / [Height (m)]2
Child Pugh Class
eGFRcr(Cockcroft-Gault
Formula)
CrCl (male) = ([140-age] × weight in kg)/(serum creatinine × 72)
CrCl (female) = ([140-age] × weight in kg)/(serum creatinine × 72) × 0.85
Note:
If a participant’s actual body weight is greater than 20% over their Ideal
Body Weight (IBW), the participant’s Adjusted Body Weight (ABW) will be used 
for eGFRcr (Cockcroft-Gault Formula):
IBW:   
Male: 50kg + 0.9kg x (height(cm) – 152)
             Female: 45.5kg + 0.9kg x (height(cm) – 152)
ABW:   IBW(kg) + 0.4 x (Weight(kg) – IBW(kg))
NCT04442737


TMC114+JNJ-48763364-AAA+JNJ-35807551-AAA+JNJ-63625328-ZCA  (darunavir 800mg/cobicistat 150 
mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX4004
52
Approved, Date: 24 March 2023
HOMA-IR (mg/dL)
Fasting insulin x Fasting glucose / 405
Non-Alcoholic Fatty Liver
Disease (NAFLD) Fibrosis
Score10
-1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG/diabetes (yes =
1, no = 0) + 0.99 × AST/ALT ratio – 0.013 × platelet (×109/l) – 0.66 × albumin
(g/dl)
NAFLD Score <-1.455 = F0-F2
NAFLD Score -1.455 – 0.675 = indeterminate score
NAFLD Score >0.675 = F3 – F4
NAFLD Score >0.675 = F3-F4
NASH: HAIR Scores11
HAIR score (0–3) is calculated by adding Hypertension = 1, ALT >40 IU
=1, and IR index >5.0 = 1
A score of ≥2 is high risk for NASH.
NCT04442737