A Phase 3, Randomized, Active-controlled, Open-label Study to Evaluate the Efficacy, Safety and Tolerability of Switching to a Darunavir/ Cobicistat/ Emtricitabine/ Tenofovir Alafenamide (D/C/F/TAF) Once-daily Single-tablet Regimen Versus Continuing the Current Regimen Consisting of a Boosted Protease Inhibitor (bPI) Combined With Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) in Virologically-suppressed, Human Immunodeficiency Virus Type 1 (HIV-1) Infected Subjects
Phase: PHASE3
Conditions: Human Immunodeficiency Virus Type 1
Sponsor: Janssen R&D Ireland

1
Status: Approved, Date: 29 May 2015
Janssen Research & Development *
Clinical Protocol
A Phase 3, randomized, active-controlled, open-label study to evaluate the efficacy, safety 
and tolerability of switching to a darunavir/cobicistat/emtricitabine/tenofovir alafenamide 
(D/C/F/TAF) once-daily single-tablet regimen versus continuing the current regimen 
consisting of a boosted protease inhibitor (bPI) combined with emtricitabine/tenofovir 
disoproxil fumarate (FTC/TDF) in virologically-suppressed, human immunodeficiency 
virus type 1 (HIV-1) infected subjects.
Protocol TMC114IFD3013 Amendment 4; Phase 3
D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)  
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen 
R&D Ireland; or Janssen Research & Development, LLC. The term ‘sponsor’ is used throughout the 
protocol to represent these various legal entities; the sponsor is identified in the Contact Information page 
that accompanies the protocol.
This compound is being investigated in Phase 2 and 3 clinical studies.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER:         2014-003052-31
Status:
Approved  
Date:
29 May 2015
Prepared by:
Janssen Infectious Diseases - Diagnostics BVBA
EDMS no:
EDMS-ERI-104187761, 5.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
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.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
2
Approved, Date: 29 May 2015
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENT ......................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 14
TIME AND EVENTS SCHEDULE .............................................................................................................. 23
ABBREVIATIONS ...................................................................................................................................... 27
DEFINITIONS OF TERMS.......................................................................................................................... 29
1.
INTRODUCTION................................................................................................................................ 30
1.1.
Background .................................................................................................................................... 30
1.2.
Darunavir (PREZISTA®)................................................................................................................ 31
1.3.
Cobicistat (Tybost®)....................................................................................................................... 32
1.4.
Emtricitabine (Emtriva®) ................................................................................................................ 33
1.5.
Tenofovir Alafenamide ................................................................................................................... 33
1.5.1.
General Information.................................................................................................................... 33
1.5.2.
Preclinical Pharmacology and Toxicology.................................................................................. 34
1.5.3.
Preclinical Pharmacokinetics...................................................................................................... 35
1.5.4.
Nonclinical Toxicology ................................................................................................................ 35
1.5.5.
Clinical Studies ........................................................................................................................... 37
1.6.
Overall Rationale and Risks Assessment for the Study ................................................................ 40
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 42
2.1.
Objectives ...................................................................................................................................... 42
2.2.
Hypothesis ..................................................................................................................................... 43
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 44
3.1.
Overview of Study Design.............................................................................................................. 44
3.2.
Study Design Rationale.................................................................................................................. 47
3.2.1.
Rationale for Design ................................................................................................................... 47
3.2.2.
Rationale for Dose Selection ...................................................................................................... 48
4.
SUBJECT POPULATION.................................................................................................................. 49
4.1.
Inclusion Criteria ............................................................................................................................ 50
4.2.
Exclusion Criteria ........................................................................................................................... 52
4.3.
Prohibitions and Restrictions ......................................................................................................... 54
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 54
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 55
7.
TREATMENT COMPLIANCE............................................................................................................ 56
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 56
8.1.
Disallowed and Cautioned Concomitant Therapy.......................................................................... 57
9.
STUDY EVALUATIONS .................................................................................................................... 61
9.1.
Study Procedures by Visit.............................................................................................................. 61
9.1.1.
Overview..................................................................................................................................... 61
9.1.1.1.
Sample Collection and Handling ............................................................................................. 62
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D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
9.1.2.
Pretreatment Assessments......................................................................................................... 63
9.1.2.1.
Screening Visit......................................................................................................................... 63
9.1.2.2.
Baseline Visit (Day 1) .............................................................................................................. 64
9.1.3.
Treatment Period........................................................................................................................ 66
9.1.4.
Extension Phase......................................................................................................................... 67
9.1.5.
Posttreatment Assessments....................................................................................................... 69
9.1.5.1.
Early Study Treatment Discontinuation Visit ........................................................................... 69
9.1.5.2.
30-Day Follow-Up Visit............................................................................................................ 70
9.2.
Efficacy Evaluations....................................................................................................................... 71
9.2.1.
Antiviral Efficacy and Immunologic Change ............................................................................... 71
9.2.2.
Resistance Determinations......................................................................................................... 71
9.3.
Management of Virologic Rebound................................................................................................ 72
9.4.
Safety Evaluations ......................................................................................................................... 72
9.4.1.
Adverse Events/HIV-related Events ........................................................................................... 73
9.4.2.
Clinical Laboratory Tests ............................................................................................................ 73
9.4.3.
Electrocardiogram....................................................................................................................... 75
9.4.4.
Vital Signs................................................................................................................................... 76
9.4.5.
Physical Examination.................................................................................................................. 76
9.4.6.
Bone investigation substudy....................................................................................................... 76
9.5.
Toxicity Management..................................................................................................................... 77
9.5.1.
General Guidance for the Management of Clinical Events and Laboratory 
Abnormalities .............................................................................................................................. 77
9.5.2.
Cutaneous Events/Rash............................................................................................................. 78
9.5.3.
Acute Systemic Allergic Reaction............................................................................................... 80
9.5.4.
Potential Renal Toxicity .............................................................................................................. 82
9.5.5.
Potential Bone Toxicity ............................................................................................................... 83
9.5.6.
Potential Posterior Uveitis Cases ............................................................................................... 83
9.5.7.
Hyperglycemia............................................................................................................................ 83
9.5.8.
Hypertriglyceridemia and Hypercholesterolemia........................................................................ 84
9.5.9.
Lipodystrophy/Fat Redistribution/Body Changes ....................................................................... 84
9.6.
Pharmacokinetic Evaluations......................................................................................................... 85
9.6.1.
Evaluations ................................................................................................................................. 85
9.6.2.
Analytical Procedures................................................................................................................. 85
9.6.3.
Pharmacokinetic Parameters ..................................................................................................... 85
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 86
10.1.
Completion ..................................................................................................................................... 86
10.2.
Withdrawal From the Study............................................................................................................ 86
11.
STATISTICAL METHODS................................................................................................................. 87
11.1.
Analysis Objectives and Endpoints................................................................................................ 88
11.1.1.
Primary Endpoint ........................................................................................................................ 88
11.1.2.
Secondary Endpoints.................................................................................................................. 88
11.2.
Sample Size Determination ........................................................................................................... 89
11.3.
Analysis Sets.................................................................................................................................. 90
11.4.
Subject Information ........................................................................................................................ 91
11.5.
Efficacy Analyses ........................................................................................................................... 91
11.6.
Safety Analyses ............................................................................................................................. 93
11.7.
Pharmacokinetic Analyses............................................................................................................. 94
11.8.
Treatment Adherence .................................................................................................................... 95
11.9.
Data Monitoring Committee ........................................................................................................... 95
12.
ADVERSE EVENT REPORTING ...................................................................................................... 95
12.1.
Definitions ...................................................................................................................................... 96
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 96
12.1.2.
Attribution Definitions.................................................................................................................. 98
12.1.3.
Severity Criteria .......................................................................................................................... 98
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
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Approved, Date: 29 May 2015
12.2.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events 
or Serious Adverse Events ............................................................................................................ 99
12.3.
Special Reporting Situations.......................................................................................................... 99
12.4.
Procedures..................................................................................................................................... 99
12.4.1.
All Adverse Events...................................................................................................................... 99
12.4.2.
Serious Adverse Events ........................................................................................................... 100
12.4.3.
Pregnancy................................................................................................................................. 101
12.5.
Contacting Sponsor Regarding Safety......................................................................................... 102
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 102
13.1.
Procedures................................................................................................................................... 102
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 102
14.
STUDY DRUG INFORMATION....................................................................................................... 103
14.1.
Physical Description of Study Drugs............................................................................................ 103
14.2.
Packaging .................................................................................................................................... 103
14.3.
Labeling........................................................................................................................................ 103
14.4.
Preparation, Handling, and Storage............................................................................................. 103
14.5.
Drug Accountability ...................................................................................................................... 104
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 104
16.
ETHICAL ASPECTS ....................................................................................................................... 105
16.1.
Study-Specific Design Considerations......................................................................................... 105
16.2.
Regulatory Ethics Compliance..................................................................................................... 105
16.2.1.
Investigator Responsibilities ..................................................................................................... 105
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 105
16.2.3.
Informed Consent ..................................................................................................................... 107
16.2.4.
Privacy of Personal Data .......................................................................................................... 108
16.2.5.
Long-term Retention of Samples for Additional Future Research............................................ 108
16.2.6.
Country Selection ..................................................................................................................... 108
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 108
17.1.
Protocol Amendments.................................................................................................................. 108
17.2.
Regulatory Documentation .......................................................................................................... 109
17.2.1.
Regulatory Approval/Notification .............................................................................................. 109
17.2.2.
Required Prestudy Documentation........................................................................................... 109
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 110
17.4.
Source Documentation................................................................................................................. 110
17.5.
Case Report Form Completion .................................................................................................... 111
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 111
17.7.
Record Retention ......................................................................................................................... 112
17.8.
Monitoring .................................................................................................................................... 112
17.9.
Study Completion/Termination..................................................................................................... 113
17.9.1.
Study Completion ..................................................................................................................... 113
17.9.2.
Study Termination..................................................................................................................... 113
17.10.
On-Site Audits .............................................................................................................................. 113
17.11.
Use of Information and Publication.............................................................................................. 114
REFERENCES.......................................................................................................................................... 116
ATTACHMENTS....................................................................................................................................... 119
INVESTIGATOR AGREEMENT ............................................................................................................... 152
LAST PAGE.............................................................................................................................................. 152
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
LIST OF ATTACHMENTS
Attachment 1:
Management of Virologic Rebound................................................................................. 119
Attachment 2: Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events.............................................................................................................................. 120
Attachment 3: WHO Clinical Staging of HIV/AIDS ................................................................................. 142
Attachment 4: Management of Clinically Significant Laboratory Toxicities ............................................ 144
Attachment 5:
Management of Dyslipidemia.......................................................................................... 145
Attachment 6:
Cardiovascular Safety: Definitions of Abnormalities ....................................................... 149
Attachment 7:
Anticipated Events........................................................................................................... 150
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Exclusionary Concomitant Medications With the D/C/F/TAF Tablet................................. 53
Table 2:
Concomitant Therapy: Disallowed and Cautioned Use With the D/C/F/TAF Tablet......... 57
Table 3:
Summary of Cutaneous Reaction/Rash Follow-up ........................................................... 80
Table 4:
Summary of Allergic Reaction Follow-up .......................................................................... 81
Table 5:
Rebound Rates (Snapshota or Confirmed ≥50 Copies/mL) From Historical 
Studies of Virologically Suppressed Patients.................................................................... 90
Table 6:
BMD at the Lumbar Spine, Power Calculations ................................................................ 90
Table 7:
LDL and non-HDL Cholesterol Goals and Thresholds for Therapeutic Lifestyle 
Changes and Drug Therapy in Different Risk Categories............................................... 147
Table 8:
Choice of Drug Therapy for Dyslipidemia in HIV-infected Individuals Receiving 
HAART ............................................................................................................................ 148
FIGURES
Figure 1:
Schematic Overview of the Study ..................................................................................... 45
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
PROTOCOL AMENDMENT
Protocol History
TMC114IFD3013_Protocol
Document Type and
File Name
Issued Date
Amendment
Type
Comments
Initial Clinical Protocol
TMC114IFD3013_Protocol
22-Aug-2014
-
-
Protocol Amendment 1
TMC114IFD3013_Protocol_Amend_1
25-Sep-2014
Non-substantial
For details, please refer to 
Section Amendment_1
Protocol Amendment 2
TMC114IFD3013_Protocol_Amend_2
12-Dec-2014
Substantial
For details, please refer to 
Section Amendment_2
Protocol Amendment 3
TMC114IFD3013_Protocol_Amend_3
06-Mar-2015
Substantial
For details, please refer to 
Section Amendment_3
Protocol Amendment 4
TMC114IFD3013_Protocol_Amend_4
This document
Substantial
For details, please refer to 
Section Amendment_4
Amendment_1  
The overall reason for the amendment: This amendment was written to remove the name PLATO from the 
protocol. Further, it was corrected that urine instead of blood should be collected for determination of the urine 
renal biomarkers. Finally, it was clarified that no re-packaging of study medication will be done.
The changes made to the clinical protocol TMC114IFD3013, dd. 22-Aug-2014, are listed below, including 
rationale of each change and a list of all applicable sections.
Rationale: As the name PLATO was used for a competitor study, this name was removed from the protocol.
Title Page
SYNOPSIS
1.6 Overall Rationale and Risks Assessment for the Study
3.1 Overview of Study Design
Rationale: In the protocol, it was wrongly stated that blood (instead of urine) should be collected for determination 
of the urine renal biomarkers.
9.1.2.2 Baseline Visit (Day 1)
9.1.3 Treatment Period
9.1.5.1 Early Study Treatment Discontinuation Visit
Rationale: No re-packaging of study medication will be done. The wording was slightly adapted as the previous 
wording, ie, "study-specific packaging", implied re-packaging.
14.2 Packaging
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
Amendment_2 
The 
overall 
reason 
for 
the 
amendment:
Following 
regulatory 
feedback 
on 
the 
darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) development plan, the sponsor designed a 
separate efficacy study in treatment-naïve human immunodeficiency virus type 1 (HIV-1) infected subjects and 
re-oriented the present study into a 48-week safety study. The timing of virologic HIV-1 RNA retesting is also 
amended upon regulatory request. Bone investigations (including bone biomarkers and dual energy x-ray 
absorptiometry [DXA] scans) will be performed in a substudy. Further changes have been made to the protocol for 
clarification or optimization of assessments.
The changes made to the clinical protocol TMC114IFD3013 Amendment 1, dd. 25-Sep-2014, are listed below, 
including the rationale of each change and a list of all applicable sections.
Rationale: The study objectives have been revised in order to focus on the evaluation of the safety and tolerability 
of the D/C/F/TAF once-daily singe-tablet regimen, instead of the efficacy comparison of D/C/F/TAF versus a 
continued boosted protease inhibitor (bPI)-based regimen in virologically suppressed subjects. In that respect, the 
sample size has been decreased to approximately 420 subjects, with a 2:1 randomization ratio to 1 of the 2
treatment arms.
SYNOPSIS
2 OBJECTIVES AND HYPOTHESIS
3 STUDY DESIGN AND RATIONALE
4 SUBJECT POPULATION
5 TREATMENT ALLOCATION AND BLINDING
11 STATISTICAL METHODS
Rationale: In order to minimize the chance of resistance development, HIV-1 RNA retesting in subjects with 
HIV-1 RNA ≥50 copies/mL will occur 2-4 weeks after the date of confirmation of viral load ≥50 copies/mL rather 
than after 3-6 weeks.
TIME AND EVENTS SCHEDULE
9.2.2 Resistance Determinations
9.3 Management of Virologic Rebound
Attachment 1
Rationale: After Week 48, all subjects will be given the opportunity to receive the D/C/F/TAF once-daily single-
tablet regimen in an extension phase of the study until D/C/F/TAF is commercially available and is reimbursed, or 
can be accessed through another source in the country where he/she is living, or until the sponsor terminates 
clinical development. Subjects will come for visits every 12 weeks between Week 48 and 96 and every 6 months
thereafter. Subjects who prematurely discontinue or change study treatment during the treatment phase (from Day 
1 to Week 48) or during the extension phase (only between Week 48 and 96), will be required to complete early 
study treatment discontinuation (ESTD) visit assessments within 72 hours of stopping/changing study treatment. A 
30-day follow-up visit is required for subjects who prematurely discontinue study treatment before Week 48 or 96, 
or subjects who complete the study through Week 48 and have an ongoing adverse event (AE) or serious adverse 
event (SAE) at that time.
SYNOPSIS
TIME AND EVENTS SCHEDULE
3 STUDY DESIGN AND RATIONALE
6 DOSAGE AND ADMINISTRATION
9 STUDY EVALUATIONS
10SUBJECT COMPLETION/WITHDRAWAL
Rationale: Bone investigations (including bone biomarkers and DXA scans) will be performed in a subset of 
subjects who provide informed consent for the substudy (approximately 100-150 subjects irrespective of treatment 
arm). 
SYNOPSIS
TIME AND EVENTS SCHEDULE
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
ABBREVIATIONS
2.1 Objectives
3.1 Overview of Study Design
9.1 Study Procedures by Visit
9.4 Safety Evaluations
9.5 Toxicity Management
10 SUBJECT COMPLETION/WITHDRAWAL
11.1 Analysis Objectives and Endpoints
11.6 Safety Analyses
12.2 Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or Serious Adverse 
Events
15 STUDY-SPECIFIC MATERIALS
Rationale: The pharmacokinetic sampling procedure and timing have been revised in order to optimize the 
pharmacokinetic assessment of TAF plasma concentrations. For subjects in the D/C/F/TAF arm, a single 
pharmacokinetic blood sample will be collected at Weeks 2, 4, 12, 24, 48 and ESTD (if applicable), at least 
15 minutes postdose. At Weeks 8 and 36, 2 pharmacokinetic samples will be collected with at least 2.5 hours in 
between sampling. The first pharmacokinetic sample for the Weeks 8 and 36 visits should be taken between 1 and 
4 hours postdose (dosing may occur prior to the visit).
SYNOPSIS
TIME AND EVENTS SCHEDULE
3 STUDY DESIGN AND RATIONALE
DOSAGE AND ADMINISTRATION
Treatment Period
9.1.5.1 Early Study Treatment Discontinuation Visit
9.6 Pharmacokinetic Evaluations
Rationale: Minor modifications and clarifications to the text.
INTRODUCTION
SYNOPSIS
TIME AND EVENTS SCHEDULE
ABBREVIATIONS
DEFINITIONS OF TERMS
1 INTRODUCTION
8.1 Disallowed and Cautioned Concomitant Therapy
9 STUDY EVALUATIONS
SUBJECT COMPLETION/WITHDRAWAL
11 STATISTICAL METHODS
Adverse Event Definitions and Classifications
12.2 Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or Serious Adverse 
Events
STUDY DRUG INFORMATION
15 STUDY-SPECIFIC MATERIALS
16.2.3 Informed Consent
16.2.5 Long-term Retention of Samples for Additional Future Research
REFERENCES
Attachment 5
Attachment 6
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
Amendment_3
The 
overall 
reason 
for 
the 
amendment:
Following 
regulatory 
feedback 
on 
the 
darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) development plan, the sponsor changed the
primary endpoint into an efficacy endpoint. Further changes have been made to the protocol for clarification or 
optimization of assessments.
The changes made to the clinical protocol TMC114IFD3013 Amendment 2, dd. 12-Dec-2014, are listed below, 
including the rationale of each change and a list of all applicable sections.
Rationale: The study objectives have been revised in order to focus on the efficacy comparison (with endpoint of 
virologic rebound) of D/C/F/TAF versus a continued boosted protease inhibitor (bPI)-based regimen in 
virologically suppressed subjects. To that end, the sample size has been increased to approximately 600 subjects
for the main study, and to approximately 150 subjects for the bone investigation substudy.
SYNOPSIS
TIME AND EVENTS SCHEDULE
1.6 Overall Rationale and Risks Assessment for the Study
2 OBJECTIVES AND HYPOTHESIS
3 STUDY DESIGN AND RATIONALE
4 SUBJECT POPULATION
6 DOSAGE AND ADMINISTRATION
9 STUDY EVALUATIONS
11 STATISTICAL METHODS
Rationale: Provided results from the Data Monitoring Committee (DMC) analyses or Week 24 interim analysis 
does not preclude (further) exposing subjects to D/C/F/TAF, subjects from the D/C/F/TAF arm will enter in the 
extension phase once they have completed their Week 48 visit. In addition, subjects in the control arm will receive 
the D/C/F/TAF tablet in the extension phase if, according to the investigator they will benefit from it and if all
conditions are fulfilled (which includes adequate viral load results). Subjects from the control arm will be required 
to attend a switch visit at Week 52 to receive D/C/F/TAF. All subjects in the extension phase will have to attend 
visits every 12 weeks up to Week 96. As from Week 96, all subjects are offered the possibility to continue 
D/C/F/TAF treatment, if they wish and if they continue to benefit from it, until D/C/F/TAF becomes commercially 
available and is reimbursed, or can be accessed through another source in the country where he/she is living, or 
until the sponsor terminates clinical development. After Week 96, subjects should attend visits every 6 months.
Subjects who prematurely discontinue or change study treatment during the treatment phase (from Day 1 to 
Week 48) or during the extension phase (only between Week 48 and 96), will be required to complete early study 
treatment discontinuation (ESTD) visit assessments within 72 hours of stopping/changing study treatment. A 30-
day follow-up visit is required for subjects who prematurely discontinue study treatment before Week 48 or 96, or 
subjects who complete the study through Week 48 and have an ongoing adverse event (AE) or serious adverse 
event (SAE) at that time.
SYNOPSIS
TIME AND EVENTS SCHEDULE
3 STUDY DESIGN AND RATIONALE
6 DOSAGE AND ADMINISTRATION
9 STUDY EVALUATIONS
10SUBJECT COMPLETION/WITHDRAWAL
Rationale: For clarity, signs or symptoms of posterior uveitis have been added, and specific instructions for the
investigators have been reworded.
1.6 Overall Rationale and Risks Assessment for the Study
9.5.6 Potential Posterior Uveitis Cases
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
Rationale: To be consistent with the most stringent local Prescribing Information of the countries where the study 
will be conducted, certain additional concomitant medications as listed below were added to the list of disallowed 
medication, and Tables 1 and 2 have been updated accordingly. Furthermore, it was clarified that the local 
Prescribing Information should always be consulted for the most up-to-date information.
-
Apixaban, Dabigatran etexilate (Drug class: Anticoagulants)
-
Fixed dose combination tablet containing Ombitasvir, Paritaprevir, and Ritonavir copackaged with Dasabuvir
(Drug class: Anti-HCV drugs)
-
Everolimus (Drug class: Antineoplastics and Immunosuppressants)
-
Any antiretroviral drug that is not part of the study regimen (Drug class: Antiretrovirals)
-
Ticagrelor (Drug class: Platelet aggregation inhibitor)
-
Quetiapine, Sertindole (Drug class: Antipsychotics/Neuroleptics)
-
Salmeterol (Drug class: inhaled beta agonists)
-
Lidocaine (systemic) (Drug class: Antiarrhythmics)
4.2 Exclusion Criteria
8.1 Disallowed and Cautioned Concomitant Therapy
Rationale: The pharmacokinetic objective was revised to DRV only and the recommendation for intake of study 
drug in the morning (related to pharmacokinetic sampling) was revised. Furthermore, the sampling schedule has 
been simplified, with a reduction in the number of samples taken. 
SYNOPSIS
2 OBJECTIVES AND HYPOTHESIS
3 STUDY DESIGN AND RATIONALE
6 DOSAGE AND ADMINISTRATION
9 STUDY EVALUATIONS
11 STATISTICAL METHODS
Rationale: For completeness, it has been specified that parathyroid hormone and 25-hydroxy vitamin D are also 
secondary endpoints to be assessed in subjects participating in the bone investigation substudy, and that renal, 
metabolic and optional bone investigations have been added at Week 96. 
SYNOPSIS
TIME AND EVENTS SCHEDULE
9 STUDY EVALUATIONS
11 STATISTICAL METHODS
Rationale: For clarity, it has been specified that subjects in the control arm must have a Week 52 visit before 
switching to D/C/F/TAF in the extension phase.
SYNOPSIS
TIME AND EVENTS SCHEDULE
3 STUDY DESIGN AND RATIONALE
6 DOSAGE AND ADMINISTRATION
9 STUDY EVALUATIONS
Rationale: For clarity, wording on withdrawal from the study has been changed and reference to the local 
Prescribing Information of Truvada® has been added to the section on management of potential renal toxicity.
9.5.4 Potential Renal Toxicity
10.2 Withdrawal From the Study 
Rationale: The wording on the physical description and the storage conditions of the study drugs has been 
corrected.
14.1 Physical Description of Study Drugs
14.4 Preparation, Handling, and Storage
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
11
Approved, Date: 29 May 2015
Rationale: The Division of AIDS table for grading the severity of adult and pediatric adverse events of December 
2004 has been replaced with the updated version of November 2014.
9.5 Toxicity Management
Attachment 2: 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events
Rationale: The list of anticipated events has been added as attachment, per new company policy.
12.4.1 All Adverse Events
REFERENCES
Attachment 7:
Anticipated Events
Rationale: The wording on the composition and role of the external Data Monitoring Committee (DMC) has been 
changed for clarity.
SYNOPSIS
3.1 Overview of Study Design
11 STATISTICAL METHODS
11.9 Data Monitoring Committee
Rationale: Minor modifications and clarifications to the text.
TIME AND EVENTS SCHEDULE
ABBREVIATIONS
1 INTRODUCTION
4.1 Inclusion Criteria
4.2 Exclusion Criteria
5 TREATMENT ALLOCATION AND BLINDING
6 DOSAGE AND ADMINISTRATION
9 STUDY EVALUATIONS
Attachment 1:
Management of Virologic Rebound
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
12
Approved, Date: 29 May 2015
Amendment_4 (this document) 
The overall reason for the amendment: Based on literature research, it was found that in studies conducted in 
HIV-1 infected virologically suppressed subjects who received a boosted protease inhibitor regimen, virologic 
rebound rates varied from 1.4% to 5%. Furthermore, subjects who have virologically failed a previous regimen are 
allowed to participate in this study. Therefore, the assumed virologic rebound rate for the sample size 
determination was changed from 2% to 4%. In order to yield enough power with an expected rebound rate of 4%, 
the sample size has been increased to approximately 1,100 subjects. Further changes have been made to the 
protocol for clarification or error correction.
The changes made to the clinical protocol TMC114IFD3013 Amendment 3, dd. 06-Mar-2015, are listed below, 
including the rationale of each change and a list of all applicable sections.
Rationale: Data from studies in a virologically suppressed, HIV-1 infected population showed that rebound rates 
varied from 1.4% to 5% in subjects who received a boosted protease inhibitor regimen. Furthermore, subjects who 
have virologically failed a previous regimen are allowed to participate in this study. Therefore, the assumed 
virologic rebound rate for the sample size determination was changed from 2% to 4%. A sample size of 1,100
subjects is needed to achieve 89% power. In addition, the sample size for the bone investigation substudy was 
increased to approximately 300 subjects in order to obtain more precise information on bone parameters.
SYNOPSIS
3.1 Overview of Study Design
4 SUBJECT POPULATION
9.4.6 Bone investigation substudy
11.2 Sample Size Determination
REFERENCES
Rationale: The Per Protocol population for the efficacy analysis will also exclude subjects with a baseline HIV-1 
RNA value ≥50 copies/mL, in addition to the subjects with major protocol deviation(s) considered to potentially 
affect efficacy outcomes. The study aims to assess the ability of D/C/F/TAF to maintain suppression in 
virologically suppressed subjects when initiating D/C/F/TAF treatment. The protocol requires the subject to be 
virologically suppressed, with at least 1 plasma HIV-1 RNA measurement <50 copies/mL (or HIV-1 RNA 
undetectable by a local HIV-1 RNA test) occurring between 12 and 2 months prior to the screening visit while on 
the stable ARV regimen and HIV-1 RNA <50 copies/mL at the screening visit. A subject with HIV-RNA 
value ≥50 copies/mL at the baseline visit cannot be excluded from participation to the study, as the baseline HIV-1 
RNA value will not be available to the investigator in due time, ie, prior to randomization and initiation of the 
study medication. Since such subjects do not represent the population of interest, they will be excluded from the 
Per Protocol analysis.
SYNOPSIS
11.3 Analysis Sets
Rationale: For clarification, it has been specified that the opportunity to receive D/C/F/TAF treatment after 
Week 96 will be performed to collect long-term safety and efficacy data on D/C/F/TAF.
SYNOPSIS
3.2.1 Rationale for Design
6 DOSAGE AND ADMINISTRATION
Rationale: For clarification, a note has been added to inclusion criterion 2 to specify that a change in 
pharmacokinetic booster is allowed up to 1 month prior to screening. 
4.1 Inclusion Criteria
Rationale: For completeness, it has been added in inclusion criterion 11 that the use of birth control methods does 
not apply for women who are surgically sterile (have had a total hysterectomy or bilateral oophorectomy, tubal 
ligation/bilateral tubal clips without reversal operation, or otherwise are incapable of becoming pregnant).
4.1 Inclusion Criteria
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
13
Approved, Date: 29 May 2015
Rationale: For completeness, penile intra-epithelial neoplasia has been added to the exceptions in exclusion 
criterion 9.
4.2 Exclusion Criteria
Rationale: Plasma storage samples and peripheral blood mononuclear cell samples at Week 96 were erroneously 
missing and have been added.
TIME AND EVENTS SCHEDULE
9.1.4 Extension Phase
Rationale: For clarity, the timing of the sampling for the assessment of parathyroid hormone and 25-hydroxy 
vitamin D has been added to the footnotes in the Time and Events Schedule. Furthermore, the assessment of 
parathyroid hormone and 25-hydroxy vitamin D at the early study treatment discontinuation visit (if applicable) 
has been added for completeness.
TIME AND EVENTS SCHEDULE
9.1.5.1 Early Study Treatment Discontinuation Visit
Rationale: For clarity, the conditions when the use of lidocaine is disallowed have been specified.
4.2 Exclusion Criteria
8.1 Disallowed and Cautioned Concomitant Therapy
Rationale: Minor modifications and clarifications to the text.
SYNOPSIS
TIME AND EVENTS SCHEDULE
DEFINITIONS OF TERMS
1.3 Cobicistat (Tybost®)
3.1 Overview of Study Design
8.1 Disallowed and Cautioned Concomitant Therapy
9.1.4 Extension Phase
9.1.5 Posttreatment Assessments
9.4.6 Bone investigation substudy
11.2 Sample Size Determination
11.9 Data Monitoring Committee
12.4.3 Pregnancy
Attachment 1 Management of Virologic Rebound
Attachment 5 Management of Dyslipidemia
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
14
Approved, Date: 29 May 2015
SYNOPSIS
A Phase 3, randomized, active-controlled, open-label study to evaluate the efficacy, safety and 
tolerability of switching to a darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) once-
daily single-tablet regimen versus continuing the current regimen consisting of a boosted protease 
inhibitor (bPI) combined with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in virologically-
suppressed, human immunodeficiency virus type 1 (HIV-1) infected subjects.
OBJECTIVES AND HYPOTHESIS
Primary Objectives
To demonstrate noninferiority in efficacy of a D/C/F/TAF once-daily single-tablet regimen relative to 
continuing the current bPI combined with FTC/TDF in virologically-suppressed (HIV-1 RNA 
<50 copies/mL) HIV-1 infected subjects, in regard to the proportion of virologic rebounders (defined as 
either having confirmed HIV-1 RNA ≥50 copies/mL through Week 48, or in case of early discontinuation 
a last single viral load of HIV-1 RNA ≥50 copies/mL), with a maximum allowable difference of 4%.
Secondary Objectives
-
To evaluate superiority of switching to a D/C/F/TAF once-daily single-tablet regimen versus 
continuing the current bPI combined with FTC/TDF in regard to the proportion of virologic 
rebounders, in case noninferiority is established;
-
To evaluate the proportion of rebounders through Week 24 in the 2 treatment arms;
-
To evaluate efficacy as determined by continued suppression of HIV-1 RNA (<20, <50, and 
<200 HIV-1 RNA copies/mL as defined by the FDA snapshot analysis and time to loss of virologic 
response [TLOVR] algorithm) at Weeks 24 and 48 in the 2 treatment arms;
-
To evaluate the safety and tolerability of the D/C/F/TAF regimen through 24 and 48 weeks of 
treatment;
-
To evaluate the change from baseline in serum creatinine, estimated glomerular filtration rate 
(eGFR) for creatinine clearance (eGFRcr) by Cockcroft-Gault and by Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI), and eGFR for cystatin C clearance (eGFRcyst) by CKD-
EPI in the 2 treatment arms at Weeks 24 and 48;
-
To evaluate the change from baseline in renal biomarkers at Weeks 24 and 48;
-
To evaluate immunologic changes (CD4+ cell count) through 24 and 48 weeks of treatment in the 
2 treatment arms;
-
To evaluate adherence to drug intake (as derived by drug accountability data), and explore 
correlation with primary efficacy outcome;
-
To evaluate resistance in subjects who show confirmed virologic rebound through Weeks 24 and 48
in the 2 treatment arms;
-
To evaluate long-term efficacy, resistance, and safety of the D/C/F/TAF regimen (until Week 96 and 
beyond);
-
To evaluate the steady-state pharmacokinetics of DRV in the D/C/F/TAF arm.
Secondary objectives to be assessed in a bone investigation substudy performed at selected study sites:
-
To evaluate the changes from baseline in bone biomarker levels at Weeks 24 and 48.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
15
Approved, Date: 29 May 2015
-
To evaluate the safety of the 2 treatment arms as determined by the percent change from baseline in 
spine and hip bone mineral density (BMD) and changes in associated T-score at Weeks 24 and 48.
Hypothesis
The null hypothesis in this study is that the proportion of subjects with virologic rebound through
Week 48 in the investigational treatment arm (D/C/F/TAF once-daily single-tablet regimen) is more than 
4% higher than that in the control treatment arm (ongoing regimen consisting of a bPI combined with 
FTC/TDF); the alternative hypothesis is that the rebounder rate in the D/C/F/TAF arm is at most 4% 
higher than that in the control arm.
OVERVIEW OF STUDY DESIGN
Study TMC114IFD3013 is a randomized, active-controlled, open-label, multicenter, Phase 3 study to 
evaluate the efficacy, safety and tolerability of switching to a D/C/F/TAF once-daily single-tablet 
regimen compared to continuing the current regimen consisting of a bPI combined with FTC and TDF
(single agents or fixed dose combination [FDC]; both hereafter referred to as FTC/TDF) in virologically-
suppressed (HIV-1 RNA <50 copies/mL), HIV-1 infected adult subjects over a 48-week treatment period.
Approximately 1,100 subjects will be included in this study. Eligible subjects are to be currently treated 
with a stable antiretroviral (ARV) regimen consisting of a bPI (limited to darunavir [DRV] once daily 
with low-dose ritonavir [rtv] or cobicistat [COBI], atazanavir [ATV] with rtv or COBI, or lopinavir 
[LPV] with rtv) combined with FTC/TDF only, for at least 6 consecutive months preceding the screening 
visit, and with a suppressed viral load prior to and at screening. Subjects treated with the combination 
DRV + COBI + FTC/TDF and having completed the required visits in the Gilead Sciences Inc. 
(GSI)-sponsored study GS-US-216-0130, and who are fulfilling the present protocol criteria, will also be 
given the option to participate in this study. Prior to or at the baseline visit (Day 1), subjects who meet all 
eligibility criteria will be randomized in a 2:1 ratio to 1 of the following 2 treatment arms:
-
D/C/F/TAF Arm:
Switch to regimen of an FDC tablet containing DRV 800 mg/ COBI 
150 mg/ FTC 200 mg/ TAF 10 mg (further referred to as D/C/F/TAF tablet) 
once daily, (n = 734);
-
Control Arm: 
Continue current regimen consisting of a bPI (limited to DRV once daily with 
rtv or COBI, ATV with rtv or COBI, or LPV/rtv) combined with FTC/TDF
only, (n = 367).
Randomization will be stratified by bPI used at screening.
Subjects will be treated for 48 weeks, and will return for study visits at Weeks 2, 4, 8, 12, 24, 36, and 48.
Provided results from the Data Monitoring Committee (DMC) analyses or Week 24 interim analysis does 
not preclude (further) exposing subjects to D/C/F/TAF, subjects from the D/C/F/TAF arm will enter in 
the extension phase once they have completed their Week 48 visit. In addition, subjects in the control arm 
will receive the D/C/F/TAF tablet in the extension phase if, according to the investigator they will benefit 
from it and if all conditions are fulfilled (which includes adequate viral load results). Subjects from the 
control arm will be required to attend a switch visit at Week 52 to receive D/C/F/TAF. All subjects in the 
extension phase will have to attend visits every 12 weeks up to Week 96. As from Week 96, all subjects 
are offered the possibility to continue D/C/F/TAF treatment, if they wish and if they continue to benefit 
from it, until D/C/F/TAF becomes commercially available and is reimbursed, or can be accessed through 
another source in the country where he/she is living, or until the sponsor terminates clinical development.
After Week 96, subjects should attend visits every 6 months.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
16
Approved, Date: 29 May 2015
Subjects who prematurely discontinue or change study treatment during the treatment phase (from Day 1 
to Week 48) or during the extension phase (only between Week 48 and 96) will be required to complete 
the early study treatment discontinuation (ESTD) visit assessments within 72 hours of stopping/changing 
study treatment.
In addition, a 30-day follow-up (FU) visit will be required for any subject who has an ongoing AE or 
serious adverse event (SAE) at the time of his/her last study visit (unless consent is withdrawn).
Thus, the study will include a screening period of approximately 30 days (up to maximum 6 weeks) 
starting from the signature of the informed consent form (ICF), a controlled treatment period of 48 weeks
and an extension phase. A 30-day FU visit may take place as described above.
Assessment of drug accountability, monitoring of treatment adherence using a study medication 
log booklet, concomitant medications, AEs, laboratory evaluations for efficacy and safety (viral load, 
CD4+ count, biochemistry, hematology, urinalysis, urine chemistry), vital signs and (complete or 
symptom-directed) physical examinations will be performed at each visit (except at the Week 52 switch 
visit). A 12-lead electrocardiogram (ECG) will be performed at screening. Urine for selected renal 
biomarkers will be collected at baseline and at several visits during the study.
A bone investigation substudy will be performed at selected study sites, to assess bone biomarkers and 
dual energy x-ray absorptiometry [DXA] scans, in approximately 300 subjects (200 in the D/C/F/TAF 
treatment arm versus 100 in the control arm) who provide informed consent for the substudy.
Pharmacokinetic assessments (sparse sampling) will be performed for subjects randomized to the 
D/C/F/TAF arm (single sample from Weeks 2 to 48 or the ESTD visit if applicable). 
For subjects with confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥50 copies/mL at 
a scheduled or unscheduled visit) and a HIV-1 RNA value ≥400 copies/mL, HIV-1 genotypic resistance
testing will be performed and phenotypic resistance testing may be done upon request of the study
virologist. If genotypic/phenotypic resistance to study drugs is determined, study drugs may be 
discontinued and the ARV regimen can be changed at the discretion of the investigator. 
The efficacy, as well as safety and tolerability, of the enrolled subjects and treatment regimens will be 
monitored by an external DMC. In addition to the planned primary (Week 48), the Week 24, 96, and final 
analyses, a formal DMC analysis will be performed for monitoring purposes, including a futility analysis 
for lack of (non-inferior) efficacy and a blinded sample size re-estimation.
SUBJECT POPULATION
Approximately 1,100 subjects will be randomized in a 2:1 ratio to 1 of the 2 treatment arms. Assuming a 
screening failure rate of 20%, approximately 1,375 subjects need to be screened to achieve the total 
1,100 subjects randomized. All screened eligible subjects may be randomized and participate in the study.
Eligible subjects are to be: 1) currently treated with a stable ARV regimen consisting of a bPI (DRV once 
daily with rtv or COBI, ATV with rtv or COBI, or LPV with rtv) combined with FTC/TDF only, for at 
least 6 consecutive months preceding the screening visit, 2) virologically suppressed, with at least 1 
plasma HIV-1 RNA measurement <50 copies/mL (or HIV-1 RNA undetectable by a local HIV-1 RNA 
test) occurring between 12 and 2 months prior to the screening visit while on the stable ARV regimen and 
have HIV-1 RNA <50 copies/mL at the screening visit.
Subjects treated with the combination DRV + COBI + FTC/TDF and having completed the required
visits in the GSI-sponsored study GS-US-216-0130, and who are fulfilling the present protocol criteria, 
will also be given the option to participate in this study.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
17
Approved, Date: 29 May 2015
DOSAGE AND ADMINISTRATION
Prior to or at the baseline visit (Day 1), eligible subjects will be randomized in a 2:1 ratio to the 
investigational treatment arm (switch to D/C/F/TAF tablet) or the control arm (maintain current regimen 
consisting of a bPI with FTC/TDF only). Randomization will be stratified by bPI used at screening.
Blinding is not applicable in this open-label study.
The investigational medication, D/C/F/TAF tablets, will be manufactured, packaged and provided by the 
sponsor. The bPIs and FTC/TDF for the regimens in the control arm will also be provided by the sponsor.
If deemed necessary by the sponsor, and in case local regulations allow, local sourcing of any compounds 
in the comparator arm can be considered.
The investigational medication, the D/C/F/TAF tablets, will be administered orally, once daily with food, 
at approximately the same time each day. If the regular dosing time coincides with the study visit, study 
drugs can be taken on site with food during all visits up to Week 48 after all laboratory assessments
which require fasting are performed. If subjects notice that they missed a medication intake and it is still 
within 12 hours of their regular dosing time, they should take the medication immediately with food. 
Subjects can then continue their usual dosing schedule. If subjects notice that they missed their 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. Subjects should not take a double dose to make up for a missed dose.
Prolonged temporary study treatment interruptions are only deemed acceptable if motivated by safety 
reasons and do not last longer than 4 consecutive weeks. The sponsor should be notified if such 
temporary interruption occurs.
The bPI and FTC/TDF in the control arm should be used in the dosing schedule specified in the ARV 
agent's local Prescribing Information. Applicable procedures and treatment guidance based on the
Prescribing Information should be respected. The following boosted PIs are allowed: DRV once daily
with rtv or COBI, ATV with rtv or COBI, LPV with rtv. Only FTC/TDF can be used in combination with 
the bPI; no other HIV-1 ARVs are allowed. If a subject accidentally misses a scheduled dose of any of 
the selected ARVs, the investigator should advise according to the local Prescribing Information in the 
individual package inserts. 
If the conditions are fulfilled to enter the extension phase, subjects from the D/C/F/TAF arm will 
continue their D/C/F/TAF regimen as from completion of the Week 48 visit until Week 96, and subjects 
in the control arm will receive D/C/F/TAF as from completion of the Week 52 switch visit until Week 96. 
In order to collect long-term safety and efficacy data on D/C/F/TAF, all subjects will be given the 
opportunity to receive D/C/F/TAF after Week 96 until it becomes commercially available and is 
reimbursed, or can be accessed through another source in the country where he/she is living, or until the 
sponsor terminates clinical development.
EVALUATIONS
Efficacy
Samples for determination of plasma HIV-1 RNA viral load and immunologic parameters, and for HIV-1 
genotypic/phenotypic resistance testing will be taken at the time points specified in the Time and Events 
Schedule. 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
18
Approved, Date: 29 May 2015
Safety 
Safety and tolerability will be evaluated throughout the study from the time a signed and dated ICF is 
obtained until completion of the subject’s last study-related activity.
The study will include the following evaluations of safety and tolerability as indicated in the Time and 
Events Schedule:

AEs;

Clinical laboratory tests (including biochemistry, hematology, urinalysis, urine chemistry, renal 
biomarkers);

Vital signs;

Physical examination (complete or symptom-directed);

Bone investigations (bone biomarkers and DXA scans of spine and hip) in subjects participating 
in the bone investigation substudy, who provided separate informed consent;

Follow-up on specific toxicities.
Pharmacokinetics
Pharmacokinetic assessments (sparse sampling) will be performed for subjects randomized to 
the D/C/F/TAF arm to evaluate the pharmacokinetics of DRV at the time points specified in the Time and 
Events Schedule. The pharmacokinetic samples may also be used for evaluation of the pharmacokinetics 
of COBI, FTC, TAF and/or tenofovir (TFV), if deemed necessary, upon request of the study 
pharmacologist. Pharmacokinetics of the ARVs in the control arm may also be evaluated (using stored
plasma samples), if deemed necessary, upon request of the study pharmacologist.
Treatment Adherence
Treatment adherence will be assessed by pill count at the time points specified in the Time and Events 
Schedule.
STATISTICAL METHODS
Endpoints 
The primary endpoint is the proportion of subjects having confirmed virologic rebound (confirmed HIV-1 
RNA ≥50 copies/mL through 48 weeks of treatment, or in case of early discontinuation a last single viral 
load of HIV-1 RNA ≥50 copies/mL).
Secondary endpoints are:
-
The proportion of subjects having confirmed virologic rebound through 24 and 96 weeks of 
treatment;
-
The time to virologic rebound in weeks;
-
The proportion of subjects experiencing grade 3 and 4 AEs through 24, 48, and 96 weeks of 
treatment;
-
The proportion of subjects experiencing SAEs and premature discontinuations due to AEs through 
24, 48, and 96 weeks of treatment;
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
19
Approved, Date: 29 May 2015
-
The change from baseline in serum creatinine, eGFRcr (by Cockcroft-Gault and by CKD-EPI) and 
eGFRcyst (by CKD-EPI) at Weeks 24, 48, and 96;
-
The change from baseline in renal biomarkers at Weeks 24, 48, and 96;
-
The proportion of subjects with HIV-1 RNA <20, <50, and <200 copies/mL at Weeks 24, 48, and 96
as defined by the FDA snapshot analysis and TLOVR algorithm;
-
The change from baseline in CD4+ cell count at Weeks 24, 48, and 96;
-
Adherence to drug intake based on drug accountability through 24, 48, and 96 weeks;
-
Genotypic, and phenotypic if applicable, resistance to ARVs in subjects with confirmed HIV-1 RNA 
rebound through Weeks 24, 48, and 96;
-
Pharmacokinetic parameters for DRV in the D/C/F/TAF arm.
Secondary endpoints to be assessed in subjects participating in the bone investigation substudy at selected 
study sites:
-
The percent change from baseline in bone biomarkers C-type collagen sequence (CTX), procollagen 
type 1 N-terminal propeptide (P1NP), parathyroid hormone (PTH), and 25-hydroxy vitamin D at 
Weeks 24, 48, and 96.
-
The percent change from baseline in spine and hip BMD and change from baseline in BMD T-score 
at Weeks 24, 48, and 96.
Sample Size Determination
A sample size of 1,100 subjects will yield 89% power when it is assumed that both treatment arms will 
have an equal rebound rate of 4% (confirmed HIV-1 RNA ≥50 copies/mL up to, and including the upper 
bound of the Week 48 window or have discontinued prematurely, irrespective of reason, with the last 
available HIV-1 RNA ≥50 copies/mL ), that the noninferiority margin is 4%, and that the significance 
level of the test is at a 1-sided, 0.025 level.
For the bone investigation substudy, with 300 subjects (200 in the D/C/F/TAF treatment arm versus 100
in the control arm) and assuming an inter-subject variability of 4%, there is approximately 98% power to 
detect a 2% difference between the D/C/F/TAF treatment arm and the control arm in percent change from 
baseline in BMD at the spine.
Analysis Schedule 
A formal DMC analysis will be performed for monitoring purposes including a futility analysis for lack 
of (non-inferior) efficacy and a blinded sample size re-estimation. 
A planned Week 24 interim analysis will be performed after the last subject completes 24 weeks on 
study, or prematurely discontinues from the study. This analysis will be done mainly to evaluate the 
safety and tolerability of D/C/F/TAF. However, efficacy of the 2 treatment arms will also be looked at.
Results of which will also be shared with the DMC.
The primary Week 48 analysis will be performed after the last subject enrolled in the D/C/F/TAF arm 
reaches Week 48 or the last subject enrolled in the control arm completes the Week 52 visit (whichever 
comes last), or prematurely discontinues from the study.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
20
Approved, Date: 29 May 2015
The Week 96 analysis will be performed after the last subject completes 96 weeks on study, or 
prematurely discontinues from the study.
The final analysis will be performed after the last subject completes the extension phase (and the 30-day 
FU visit, if applicable). Additional statistical analyses may be done as needed to prepare for interactions 
with regulatory authorities.
Analysis Sets
-
The intent-to-treat (ITT) population 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 or control) to which they were randomized. The ITT 
analysis set is the primary analysis set for efficacy analysis. Efficacy data up to the last dose date of 
the randomized study treatment will be included. The safety analysis (including all data collected at 
the 30-day FU visit) is also performed on this analysis set.
-
Since an analysis on the ITT population may not be conservative in a noninferiority setting, 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 
analysis results. The PP population will include all subjects who (1) are randomized into the study, 
(2) have received ≥1 dose of treatment in the study, (3) without any major protocol deviation that is 
considered to potentially affect efficacy outcomes (eg, previous DRV failure, use of concomitant 
medication interfering with antiviral efficacy, inadequate adherence to drug intake), and (4) have a 
baseline HIV-1 RNA value <50 copies/mL. Specific details will be provided in the Statistical 
Analysis Plan. The PP analysis set is the secondary analysis set for efficacy analysis.
The pharmacokinetic analysis set will include all subjects who are randomized to the D/C/F/TAF arm 
(and the control arm, if applicable) and have received at least 1 dose of investigational treatment (or 
control treatment, if applicable) in the study, and for whom plasma concentration data are available.
Statistical Analyses
Efficacy
-
The primary analysis will consist of a noninferiority evaluation of switching to the D/C/F/TAF 
single-tablet regimen (investigational treatment arm) versus maintaining the current regimen 
consisting of a bPI combined with FTC/TDF (control arm), with respect to the proportion of 
virologic rebounders through Week 48 after the start of treatment in this study. The rebounders are 
defined as

subjects who show confirmed HIV-1 RNA ≥50 copies/mL up to, and including the upper 
bound of the Week 48 window (ie, 54 weeks),
OR

subjects who discontinued prematurely (irrespective of reason) for which the last available 
(single) HIV-1 RNA ≥50 copies/mL.
It will be concluded that the D/C/F/TAF single-tablet regimen is noninferior to the control regimen if 
the upper bound of the 2-sided 95% confidence interval (CI) of the difference between treatment 
arms (D/C/F/TAF arm - control arm) in rebounder rate is less than 4% (ie, a margin of 4% is applied 
to noninferiority assessment). The 2-sided 95% CI will be constructed using the stratum-adjusted 
Mantel-Haenszel difference in proportions, where the stratification factor (bPI used at screening) 
determines the strata. 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
21
Approved, Date: 29 May 2015
If noninferiority of the D/C/F/TAF arm to control arm is established, the upper bound of the 95% CI 
will be compared to 0; if the upper bound of the 95% CI is less than 0, then superiority of 
D/C/F/TAF over the control arm will be established.
-
The proportion of subjects having confirmed virologic rebound through 24 and 96 weeks of 
treatment. Treatment difference (with 95% CI) through 24 and 96 weeks will be derived similary as 
for the primary efficacy parameter.
-
The proportion of subjects with HIV-1 RNA <20, <50 and <200 copies/mL at Weeks 24, 48, and 96, 
as defined by the FDA snapshot analysis will be analyzed, as well as confirmed virologic response 
defined as HIV-1 RNA <20, <50, and <200 copies/mL at Weeks 24, 48, and 96 determined by the 
TLOVR algorithm will be derived and tabulated. Treatment difference (with associated 95% 
confidence interval [CI]) of these response rates at Weeks 24 and 48 will be derived using the 
stratum adjusted Mantel-Haenszel difference in proportions, where the stratification factor (bPI at 
screening) determines the strata.
-
Time to virologic rebound will be graphically presented by means of Kaplan-Meier curves and the 
treatment groups will be compared by means of the Cox proportional hazards model including terms 
for treatments and bPI at screening.
-
The changes from baseline in CD4+ cell count at Weeks 24, 48, and 96 will be summarized using 
descriptive statistics. The difference in changes from baseline in CD4+ cell count between the 
2 treatment arms and the associated 95% CIs at Weeks 24 and 48 will be constructed using 
ANCOVA, including term for bPI used at screening in the model and baseline CD4+ value as a 
covariate.
-
HIV-1 genotypes, and phenotypes if applicable, will be analyzed from samples of subjects 
with confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥50 copies/mL or last available 
HIV-1 RNA ≥50 copies/mL) and with HIV-1 RNA ≥400 copies/mL. The number of protease (PR) 
mutations (including International AIDS Society [IAS]-USA PI resistance-associated mutations 
[RAMs] and IAS-USA primary PI mutations), and reverse transcriptase (RT) mutations (including 
IAS-USA nucleoside/nucleotide RT inhibitor [NRTI] RAMs and IAS-USA non-nucleoside RT 
inhibitor [NNRTI] RAMs), as well as specific mutations associated with resistance to DRV, FTC, 
TFV, and the PIs in the control treatment regimen (DRV, ATV, LPV) will be tabulated. Fold change 
(FC) in 50% effective concentration (EC50) of ARVs may be analyzed and tabulated.
Safety
-
The original terms used by investigators to identify AEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). All reported AEs with onset during the study will be included 
in the analysis. For each AE, the percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized.
Summaries (number and percentage of subjects) of treatment-emergent AEs (by system organ class 
and preferred term) will be provided by treatment arm. Additional summaries will include 
summaries for AEs by severity grade (with special attention to grade 3 or 4 AEs), investigator’s 
assessment of relationship to treatment, SAEs, and AEs leading to discontinuation of study 
treatment.
-
The changes from baseline in serum creatinine, eGFRcr (by Cockcroft-Gault and by CKD-EPI) and 
eGFRcyst (by CKD-EPI) at Weeks 24, 48, and 96 will be summarized by treatment arm and using 
descriptive statistics. The difference between the 2 treatment arms in change from baseline in serum 
creatinine and eGFR at Weeks 24 and 48 will be tested using analysis of covariance (ANCOVA), 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
including corresponding baseline value and other clinically relevant factors (if deemed necessary) in 
the model. 
Only in subjects participating in the bone investigation substudy at selected study sites:
-
The percent change from baseline at Weeks 24, 48, and 96 for selected bone biomarkers will be 
summarized by treatment arm and visit using descriptive statistics. The within-treatment comparison 
will be done using Wilcoxon signed-rank test. The comparison between the 2 treatment arms will be 
performed using the Van Elteren test stratified for bPI used at screening.
-
The percent change from baseline at Weeks 24, 48, and 96 in spine and hip BMD as well as the 
change from baseline in BMD T-score will be summarized by treatment arm and visit using 
descriptive statistics. The between-treatment differences at Weeks 24 and 48 will be estimated using 
ANCOVA model, including baseline BMD value and other clinically relevant factors (if deemed 
necessary) in the model. The within-treatment comparison will be done using paired t-test.
Pharmacokinetics
Individual pharmacokinetic parameters will be derived with population pharmacokinetic analysis (if 
appropriate population pharmacokinetic models are available) using the sparse samples (or stored
samples) collected at Weeks 2, 4, 8, 12, 24, 36, and 48, or ESTD (if applicable) for DRV, and other 
ARVs as requested by the sponsor. Model specifications will be described in separate report(s), as 
applicable.
Descriptive statistics will be calculated for the plasma concentrations of DRV by visit and for the derived 
pharmacokinetic parameters as available, and also for any of the ARVs analyzed upon sponsor’s request 
(COBI, FTC, TAF, TFV, ARVs in the control arm), if applicable. Summary statistics include sample 
size, mean, standard deviation, coefficient of variation, geometric mean, median, minimum and 
maximum.
Treatment Adherence
Treatment adherence based on pill count will be summarized by means of descriptive statistics and 
frequency tabulations.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
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Approved, Date: 29 May 2015
TIME AND EVENTS SCHEDULE
Period
Screeninga Baseline
Day 1b
48-Weeks Treatment Periodc
Extension Phased
ESTDf
30-Day 
FUg
Visit 
Week 
2
Week 
4
Week 
8
Week 
12
Week 
24
Week 
36
Week 
48
Week 
52e
Every 
12 Weeks
Week 
96
Every 
6 months
Study Procedures
Screening/Administrative
Informed consenth
X
Medical history
X
12-Lead ECG
X
Height
X
HBV and HCV testing
X
Serum pregnancy testi
X
FSH testj
X
Inclusion/exclusion criteria
X
Check clinical status
Xk
Study Drug Administration
Randomizationl
X
Adherence (log booklet)m
X
X
X
X
X
X
X
X
X
X
X
Drug dispensation & 
accountability
X
Xn
X
X
X
X
X
X
X
X
X
X
Xn
Safety Evaluations
Vital signs and weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Xo
Complete physical 
examination
X
X
X
X
X
Symptom-directed physical 
examination
X
X
X
X
X
Xp
Xp
Xp
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events (AEs)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory Testsq
Chemistry profiler
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic profiles
X
X
X
X
Hematology profilet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cystatin C and eGFRcyst
X
X
X
X
X
X
X
X
X
X
eGFRcru
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis and urine 
chemistryv
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test i
X
X
X
X
X
X
X
X
X
X
X
X
X
Renal biomarkersw
X
X
X
X
X
X
X
X
NCT02269917

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Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
Period
Screeninga Baseline
Day 1b
48-Weeks Treatment Periodc
Extension Phased
ESTDf
30-Day 
FUg
Visit 
Week 
2
Week 
4
Week 
8
Week 
12
Week 
24
Week 
36
Week 
48
Week 
52e
Every 
12 Weeks
Week 
96
Every 
6 months
Study Procedures
Efficacy Evaluations
Plasma HIV-1 RNAx
X
X
X
X
X
X
X
X
Xy
X
X
X
X
X
CD4+ cell count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 genotype/phenotypez
X
X
X
X
X
X
X
X
X
X
X
PBMC sampleaa
X
X
X
X
X
Bone investigation 
substudy
Bone biomarkersbb
X
X
X
X
X
X
X
X
DXA scanscc
X
X
X
X
X
Pharmacokinetic 
Evaluations
Pharmacokinetic sampledd
X
X
X
X
X
X
X
X
Other
Plasma sample storageee
X
X
X
X
X
X
X
X
X
X
DXA: dual energy x-ray absorptiometry; ECG: electrocardiogram; ESTD: Early Study Treatment Discontinuation visit; FSH: follicle-stimulating hormone; FU: 
Follow-up; HBV: hepatitis B; HCV: hepatitis C; PBMC: peripheral blood mononuclear cells.
a
Evaluations to be completed within 30 days prior to baseline (Day 1). The screening period may be extended on a case-by-case basis after discussion with the 
sponsor; however, no extensions beyond 6 weeks will be allowed.
b
The baseline visit (Day 1) cannot proceed until the investigator has received all results of the screening visit and subject eligibility has been confirmed. Subjects 
will be dispensed investigational drug on the baseline visit; initiation of treatment with the investigational drug must take place within 24 hours after the baseline 
visit.
c
All study visits are to be scheduled relative to the baseline visit date and are to occur at the end of Weeks 2, 4, 8, 12, 24, 36, 48. The visit window is ±2 days of the 
protocol-specified date at Week 2, ±7 days of the protocol-specified date through Week 48.
d
Study visits during the extension phase are to be completed within ±7 days of the protocol-specified visit date. Visits in the extension phase will occur every 
12 weeks up to Week 96 and every 6 months thereafter, until D/C/F/TAF becomes commercially available and is reimbursed, or can be accessed through another 
source in the country where he/she is living, or until the sponsor terminates clinical development.
e
Visit only applicable for subjects from the control arm to allow them to switch to D/C/F/TAF. At this visit, the D/C/F/TAF tablets will be dispensed to those 
subjects. Subjects in the control arm will receive the D/C/F/TAF tablets in the extension phase if, according to the investigator they will benefit from it and if all 
conditions are fulfilled (which includes adequate viral load results).
f
Subjects who prematurely discontinue or change study treatment during the treatment phase (from Day 1 to Week 48) or during the extension phase (only between 
Week 48 and 96), will be required to complete the early study treatment discontinuation (ESTD) visit assessments within 72 hours of stopping/changing study 
treatment.
g
Required for any subject who has an ongoing AE or serious adverse event (SAE) at the time of his/her last study visit (unless consent is withdrawn); ±7 days 
window may be used.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
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h
Signing of the informed consent form (ICF) needs to be done before the first study-related activity.
i
Females of childbearing potential only. 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 throughout the study. Findings during these unscheduled visits or assessments need to be reported in the 
eCRF.
j
Follicle-stimulating hormone (FSH) test for female subjects who have stopped menstruating for at least 2 years but do not have documentation of ovarian failure.
k
If a subject's clinical status changes (including available laboratory results or receipt of additional medical records) after screening but before the first dose of study 
drug is given such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the study.
l
Randomization should be performed on the same day as the baseline visit, provided that all screening procedures have been completed and subject eligibility has 
been confirmed.
m
Dispensation of the study medication log booklet at the baseline visit, in which missed study medication intakes need to be recorded; checking of the log booklet 
and discussion with the subject by the investigator or designated study personnel at all subsequent visits up to Week 96.
n
Drug accountability only; study drug will not be dispensed at this visit.
o
Weight only.
p
A symptom-directed physical examination (physical examination of body parts for which symptoms have been reported by the subject) will be performed as 
needed at Weeks 60, 72, 84, 96 and every 6 months after Week 96.
q
If the regular dosing time coincides with the study visit, study drugs can be taken on site during all visits up to Week 48 after all laboratory assessments which
require fasting are performed.
r
Chemistry profile: AAG, ALP, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, CPK, bicarbonate, BUN, chloride, creatinine, 
glucose, phosphorus, potassium, sodium, uric acid, amylase (reflex lipase testing is performed in subjects with total amylase >1.5xULN). At baseline, Weeks 24,
48, and 96, analyses of glucose will be done as part of the fasting metabolic assessments and not as part of the chemistry profile.
s
Fasting metabolic profile (total, HDL and LDL cholesterol, triglycerides, glucose). If a subject has not fasted prior to the visit, the visit may proceed, but subject 
must return within 72 hours in a fasted state to have a blood draw for the metabolic assessments.
t
Hematology profile: hemoglobin, hematocrit, RBC count and parameters (mean corpuscular hemoglobin [MCH], MCH concentration and mean corpuscular 
volume), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count.
u
At screening only eGFRcr by Cockcroft-Gault, at other visits during the treatment and extension phase also eGFRcr by CKD-EPI. 
v
Urine chemistry (quantitative measurement): creatinine, sodium, phosphate, glucose, protein, albumin. 
Urinalysis by dipstick: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase, and microscopic analysis if needed.
w
Urine sample for selected renal biomarkers (including retinol binding protein [RBP] and beta-2-microglobulin) should be collected fasted. If the subject has not 
fasted prior to the visit, the visit may proceed, but the subject must return within 72 hours in a fasted state to provide a urine sample for renal biomarkers. Required 
on the ESTD visit if the last test was more than 12 weeks before the ESTD visit. Selected renal biomarkers are only performed up to Week 48.
x
If the HIV-1 RNA value is ≥50 copies/mL a retest should be collected at a scheduled or unscheduled visit, 2 to 4 weeks after availability of the results (except for 
screening and baseline results).
y
For subjects from the control arm only: if the HIV-1 RNA value is ≥50 copies/mL at Week 48, a retest should be performed within 3 weeks to determine if their
viral load has returned toacceptable levels before they can switch to D/C/F/TAF at Week 52.
z
For subjects with confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥50 copies/mL or last available HIV-1 RNA ≥50 copies/mL) and with a HIV-1 
RNA value ≥400 copies/mL: HIV-1 genotypic resistance test will be performed; phenotypic resistance test may be done upon request of the study virologist. 
aa
A peripheral blood mononuclear cell (PBMC) sample will be taken for storage and will only be analyzed if deemed necessary by the study virologist to 
characterize archived viral resistance.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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bb The blood sample for selected bone biomarkers (including C-type collagen sequence [CTX], procollagen type N-terminal propeptide [P1NP], parathyroid hormone 
[PTH], and 25-hydroxy vitamin D) is to be collected fasted. If the subject has not fasted prior to the visit, the visit may proceed but the subject must return within 
72 hours in a fasted state to draw blood for bone biomarkers. Samples for PTH and 25-hydroxy vitamin D should be drawn at Day 1, Weeks 24, 48, 96, and ESTD 
(if applicable) only.
cc
DXA scan of spine and hip (provided the necessary approvals have been obtained and informed consent is provided for the substudy): to be performed between 
screening and baseline (+2 weeks), at Weeks 24, 48, 96, and the ESTD visit (±10 days) (only to be performed at ESTD if the last scan is more than 12 weeks from 
the date of the ESTD visit and the ESTD visit takes place before Week 48). A rescan for technical reasons at all scheduled time points is allowed within 2 weeks.
dd For the D/C/F/TAF arm only: at Weeks 2, 4, 8, 12, 24, 36, 48, and ESTD (if applicable) subjects will have a single pharmacokinetic blood sample collected. If the 
regular dosing time coincides with the study visit, the sample should be taken at least 15 minutes postdose. If the dosing time does not coincide with the scheduled 
study visit the sample can be taken at any time during the visit.
ee
A portion of the plasma samples drawn will be frozen and stored. Plasma storage samples will be banked for possible additional protocol-related testing (virology, 
safety, pharmacokinetic analysis). 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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ABBREVIATIONS
3TC
lamivudine
ABC
abacavir
ADR
adverse drug reaction
AE
adverse event
AGEP
acute generalized exanthematous pustulosis
AIDS
acquired immunodeficiency syndrome
AK
adenylate kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance 
ARV
antiretroviral
AST
aspartate aminotransferase
ATV
atazanavir
AUC
area under the concentration-time curve
AUCinf
AUC extrapolated to infinity
AUClast
AUC from time of administration up to the last time point with a measurable concentration 
after dosing
AUCtau
AUC from time of administration up to the end of the dosing interval
BMD
bone mineral density
bPI
boosted protease inhibitor
BUN
blood urea nitrogen
CXh
plasma concentration X hours after dosing
CAD
coronary artery disease
CI
confidence interval
CHD
coronary heart disease
CHMP
Committee for Medicinal Products for Human Use
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
maximum plasma concentration
COBI
cobicistat
CPK
creatine phosphokinase
CTX
C-type collagen sequence
CV
coefficient of variation
CYP
cytochrome P450
DAIDS
Division of AIDS
D/C/F/TAF
darunavir/cobicistat/emtricitabine/tenofovir alafenamide 
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DP
diphosphate
DRESS
drug rash with eosinophilia and systemic symptoms
DRV
darunavir
DTG
dolutegravir
DXA
dual energy x-ray absorptiometry
EC50
50% effective concentration
E/C/F/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 
E/C/F/TDF
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate
ECG
electrocardiogram
eCRF 
electronic case report form 
eDC
electronic data capture
EFV
efavirenz
(e)GFR
(estimated) glomerular filtration rate 
NCT02269917

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Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
eGFRcr
eGFR for creatinine clearance 
eGFRcyst
eGFR for cystatin C clearance 
EOT
end of treatment
ESTD
early study treatment discontinuation
EVG
elvitegravir
FC
fold change
FDA
Food and Drug Administration
FDC
fixed-dose combination
FEV1
forced expiratory volume in 1 second
FSH
follicle-stimulating hormone
FTC
emtricitabine
FU
follow-up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GS-7430 (free base)
TAF (see also below)
GS-7430-02
TAF monofumarate
GS-7430-03
TAF fumarate
GSI
Gilead Sciences Inc.
HAART
highly-active antiretroviral therapy
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human Ether-à-go-go-related gene
HDL
high-density lipoprotein
HIV-1
human immunodeficiency virus type 1
HPF
high-pass filter
IAS
International AIDS Society
IB
Investigator's Brochure
IC50
50% inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
international normalized ratio
InSTI
integrase strand transfer inhibitor
IRB
Institutional Review Board
ITT
intent to treat
IUD
intrauterine device
IWRS
Interactive Web Response System
LC-MS/MS
liquid chromatography-tandem mass spectroscopy 
LDL
low-density lipoprotein
LLN
lower limit of normal range
LPV
lopinavir
MCH
mean corpuscular hemoglobin
MedDRA
Medical Dictionary for Regulatory Activities
MCV
mean corpuscular volume
n
sample size
NA
not applicable
NNRTI
non-nucleoside reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
P1NP
procollagen type 1 N-terminal propeptide
PBMC
peripheral blood mononuclear cell
PDE
phosphodiesterase
NCT02269917

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Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
PI
protease inhibitor
PK
pharmacokinetics
PP
per protocol
PQC
product quality complaint
PR
protease
PT
prothrombin time
PTH
parathyroid hormone
PTT
partial thromboplastin time
QTcB
QT interval corrected for heart rate according to Bazett
QTcF
QT interval corrected for heart rate according to Fridericia
RAL
raltegravir
RAM
resistance-associated mutation
RBC
red blood cell
RBP
retinol binding protein
RNA
ribonucleic acid
RPV
rilpivirine
RT
reverse transcriptase
rtv
low-dose ritonavir
SAE
serious adverse event
SD
standard deviation
SJS
Stevens-Johnson syndrome
SmPC
Summary of Product Characteristics
TAF
tenofovir alafenamide
TDF
tenofovir disoproxil fumarate
TEN
toxic epidermal necrolysis
TFV
tenofovir
TLOVR
time to loss of virologic response
tmax
time to reach the maximum plasma concentration
UGT1A1
uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1
ULN
upper limit of normal range
USPI
US Prescribing Information 
WBC
white blood cell
WHO
World Health Organization
DEFINITIONS OF TERMS
Investigational treatment (medication)
D/C/F/TAF FDC tablet
Control/Comparator treatment (regimen, 
medications)
bPI (limited to DRV once daily+ rtvor COBI; ATV + rtv or 
COBI; LPV+ rtv) combined with FTC/TDF only
Study treatment (medication)
Any ARV regimen received in the investigational treatment arm 
or control arm in the current study
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1.
INTRODUCTION
1.1.
Background
Human immunodeficiency virus (HIV) infection is a life-threatening and serious disease that is 
of major public health interest around the world. In 2012, approximately 35.3 million people
were living with HIV-1 worldwide, an estimated 2.3 million people became newly infected with 
HIV-1 and 1.6 million died from acquired immunodeficiency syndrome (AIDS)-related causes.36
The infection, if left untreated or suboptimally treated, is characterized by deterioration in 
immune function, the subsequent occurrence of opportunistic infections and malignancies, 
ultimately resulting in death. 
Therapeutic strategies for the treatment of HIV-1 disease have been significantly advanced 
by the availability of highly-active antiretroviral therapy (HAART); the introduction of 
HAART was associated with a dramatic decrease in AIDS-related morbidity and mortality.22,23,30
The primary goals of antiretroviral (ARV) therapy for HIV-1 infection are to reduce 
HIV-associated morbidity and prolong the duration and quality of life, restore and preserve 
immunologic function, maximally and durably suppress plasma HIV viral load, and prevent HIV
transmission. The treatment guidelines suggest that initial therapy for ARV treatment-naïve
HIV-1 infected patients consists of 2 nucleoside/nucleotide reverse transcriptase inhibitors
(NRTIs) and either a non-nucleoside reverse transcriptase inhibitor (NNRTI) (usually efavirenz 
[EFV]), a boosted protease inhibitor (bPI), or the integrase strand transfer inhibitor (InSTI)
raltegravir (RAL).25,41
Despite the successful reduction in the morbidity and mortality associated with human HIV
disease since the advent of HAART, a significant proportion of subjects eventually experience 
loss of virologic, immunologic, or clinical benefit from their current regimens.23 Incomplete 
adherence to ARV regimens is a critical factor contributing to treatment failure and the
development of viral resistance, and thus a primary barrier to successful long-term treatment. In 
the HIV-1 infected population receiving ARV therapy, total pill burden, dosing frequency, and 
safety concerns are among the greatest obstacles to achieving adherence.10,31,32 This is supported 
by studies in which simple, once-daily HAART regimens demonstrate high levels of adherence 
and treatment satisfaction resulting in persistent suppression of HIV viral load.4,13,20
Currently, 4 highly effective, once-daily tablets are approved for the treatment of HIV-1
infection: Atripla® (EFV/emtricitabine [FTC]/ tenofovir disoproxil fumarate [TDF]), Complera®
(rilpivirine [RPV]/FTC/TDF), Stribild® (elvitegravir [EVG]/ cobicistat [COBI]/ FTC/TDF or 
E/C/F/TDF) and Triumeq® (abacavir [(ABC]/lamivudine [3TC]/dolutegravir (DTG]). There 
remains a need for simplified PI-based ARV regimens that combine potent and sustained 
efficacy, favorable tolerability, and minimal long-term toxicity, with practical, convenient 
dosing.
To address this need, the sponsor is developing an investigational, 4-agent, once-daily fixed-dose 
combination (FDC) tablet containing the PI darunavir (DRV; developed by the sponsor), the 
pharmacokinetic enhancer (booster) COBI (developed by Gilead Sciences, Inc. [GSI[), the NRTI 
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FTC (developed by GSI), and the next-generation tenofovir (TFV) prodrug tenofovir 
alafenamide (TAF; developed by GSI)). This FDC tablet, hereafter referred to as the D/C/F/TAF 
tablet, is indicated for the treatment of HIV-1 infection.
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.
1.2.
Darunavir (PREZISTA®)
DRV is an inhibitor of the catalytic activity of HIV-1 protease (PR) with potent in vitro antiviral 
activity against wild-type and PI-resistant strains of HIV-1. DRV has a high genetic barrier to the 
development of resistance, resulting in continued antiviral activity against a large panel of 
viruses resistant to currently licensed PIs. 
DRV has been developed by the sponsor as tablets at different strengths and as an oral 
suspension (100 mg/mL). In combination with low-dose ritonavir (rtv) as a pharmacokinetic 
booster and other ARVs, it has shown significant efficacy in treatment-naïve to highly treatment-
experienced patients. It is currently indicated for the treatment of HIV-1 infection in adults and 
pediatric patients aged 3 years and older, in either a twice daily regimen with rtv or a once daily 
dosing regimen, with either rtv or COBI. The once daily regimens are approved only in
treatment-naïve patients and treatment-experienced patients who have no DRV resistance-
associated mutations (RAMs), and COBI-boosted DRV is only approved in adults.
DRV was first registered in the United States (June 2006) and has obtained marketing 
authorization in the European Union in February 2007. As of 23 December 2014, DRV was 
registered in more than 99 countries around the world. Adverse drug reactions (ADRs) identified 
during postmarking experience were: drug hypersensitivity, angioedema, urticaria, osteonecrosis, 
toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug 
rash with eosinophilia and systemic symptoms (DRESS).
In treatment-naïve and treatment-experienced patients with no DRV RAMs, the recommended 
dose of DRV is 800 mg (2 x 400-mg tablets) taken with rtv or COBI once daily and with food. 
This dose recommendation is generally safe and well tolerated. The majority of the DRV ADRs
reported in the Phase 3 studies during treatment with DRV/rtv and NRTIs were mild in severity. 
In ARV-treatment-naïve HIV-1 infected adult subjects (343 subjects, total exposure of 
1,072 patient years), the most frequent (≥5%) ADRs of moderate to severe (grade 2 to 4) 
intensity with DRV/rtv 800/100 mg once daily were diarrhea, headache and abdominal pain. 
Only 2.3% of the subjects discontinued DRV treatment due to ADRs. Frequency, type and 
severity of ADRs in pediatric patients were comparable to those observed in adults.
For the most comprehensive nonclinical and clinical information regarding DRV, available at the 
time of protocol finalization, refer to the Investigator’s Brochure (IB) for D/C/F/TAF and its 
addendum.16,17
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1.3.
Cobicistat (Tybost®)
COBI (formerly known as GS-9350) is a structural analog of rtv that has been shown to be a 
potent inhibitor of cytochrome P450 (CYP) 3A enzymes. COBI has been shown to be a more 
specific, mechanism-based CYP3A inhibitor than rtv. COBI displays weak to minimal inhibition 
of other CYP enzymes; it is a less potent inducer of other metabolizing enzymes in vitro, and has 
been shown to have less potential for clinically significant drug interactions via non-CYP3A 
pathways. In addition, COBI is devoid of anti-HIV activity and may have fewer adverse 
biochemical effects (eg, effect on adipocyte functions such as lipid accumulation) than rtv.
COBI, as a single 150-mg tablet, has been developed by GSI and is approved for once daily use 
in adults as a pharmacokinetic enhancer to increase systemic exposure levels of coadministered 
drugs metabolized by CYP3A, including PIs such as DRV and atazanavir (ATV) for the 
treatment of HIV-1 infection. COBI has also been coformulated with other HIV-1 ARV drugs in 
several FDCs such as DRV/COBI (codeveloped with the sponsor), ATV/COBI (by GSI), a 
combination tablet containing EVG boosted with COBI, and FTC + TDF (or E/C/F/TDF, by 
GSI) for use in HIV-1-infected, ARV treatment-naïve patients. As part of these FDCs, COBI has 
shown to inhibit CYP3A-mediated metabolism of EVG, ATV, and DRV similar to rtv.
The efficacy and safety of COBI have been established in the pivotal Phase 3 Study GS-US-
216-0114 and the supportive Phase 2 Study GS-US-216-0105. Both of these studies were 
double-blind and active-controlled studies with combination ARV regimens in ARV-treatment-
naive subjects with HIV-1 infection, and both studies were designed to compare COBI-boosted 
ATV with rtv-boosted ATV in combination with FTC and TDF. In addition, study GS-US-216-
0130 demonstrated the safety and efficacy of COBI with DRV dosed in a once daily regimen 
combined with a backbone therapy of 2 NRTIs in HIV-1 infected, ARV treatment-naïve and 
treatment-experienced adults with no DRV RAMs.
In the clinical studies to date, COBI 150-mg tablets, dosed daily for up to 60 weeks, were 
generally well tolerated, did not cause clinically significant toxicities in humans that were 
identified in nonclinical testing (heart, liver, thyroid abnormalities, and decreased 
immunoglobulin G levels), and did not potentiate the side effects of the coadministered ARV 
medications. In Phase 2 clinical studies (GS-US-216-0105 and GS-US-236-0104), small 
(approximately 12%-15%) decreases in estimated glomerular filtration rate (eGFR) calculated 
using the Cockcroft-Gault calculation occurred within the first few weeks of COBI initiation (in 
GS-US-216-0105, the decreases were comparable to those associated with rtv in the comparator 
group). 
A Phase 1 study of the effect of COBI on eGFR was performed by measuring iohexol clearance 
in healthy subjects. Results indicated that COBI produces small increases in serum creatinine 
translating into decreases in eGFR, but not affecting actual GFR, as measured by iohexol 
clearance. The data suggest that COBI blocks secretion of serum creatinine, resulting in a 
difference between eGRF and actual GFR, as seen with several other drugs that are currently 
approved, including trimethoprim and cimetidine. The increase in serum creatinine with COBI 
occurs within days of drug initiation and is reversible with values returning to baseline within 
days of cessation of COBI. 
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For the most comprehensive nonclinical and clinical information regarding COBI and COBI/
DRV FDC, available at the time of protocol finalization, refer to the IB for D/C/F/TAF and its 
addendum.16,17
1.4.
Emtricitabine (Emtriva®)
FTC is an NRTI for the treatment of HIV-1 infection, in combination with other ARVs, in adults 
and pediatrics patients aged 3 months and older. FTC has been developed by GSI and is 
marketed as a once-daily capsule (200 mg) and as an oral solution (10 mg/mL). It is a synthetic 
analogue of the naturally occurring nucleoside, 2′-deoxycytidine, a pyrimidine nucleoside that is 
structurally similar to 3TC (Epivir®). Intracellularly, FTC is phosphorylated by cellular enzymes 
to form the active metabolite, emtricitabine triphosphate.
Since first marketing authorization in the United States (July 2003), FTC obtained marketing
authorization in the 27 countries in the European Union, and also Argentina, Israel, Switzerland, 
Mexico, Australia, Japan, New Zealand, and Canada. The registration of FTC for the treatment 
of HIV-1 infection in adults and pediatric patients under 18 years of age was supported by an 
extensive program of clinical studies in healthy subjects and HIV-infected subjects, which 
provided detailed assessments of its pharmacokinetics, pharmacodynamics, potential drug-drug 
interactions, and clinical efficacy and safety. FTC has also been coformulated with other HIV-1 
ARV drugs in several FDCs such as EVG/FTC/TDF, E/C/F/TDF, and FTC/TDF. 
For further nonclinical and clinical information regarding FTC, refer to the Prescribing 
Information for FTC.33,37
1.5.
Tenofovir Alafenamide
1.5.1.
General Information
TAF (also known as GS-7340) is a second generation oral prodrug of TFV, a nucleotide analog 
that inhibits HIV-1 reverse transcription. TAF has been developed by GSI as part of FDCs (such 
as E/C/F/TAF and D/C/F/TAF), for the treatment of HIV-1 infection because of its potential for 
enhanced distribution of TFV into peripheral blood mononucleated cells (PBMCs) and to 
lymphatic organs following oral administration. This provides the possibility for using a low 
dose and to reduce systemic TFV concentrations, resulting in lower potential for adverse effects 
(including renal and bone toxicity, see also Section 1.6) without compromising antiviral activity. 
Based on nonclinical data, the clinical safety profile for TAF is expected to be similar to that 
characterized for TDF.
Following its release from the TAF prodrug, TFV is metabolized intracellularly to the active 
metabolite, TFV-diphosphate (DP), a competitive inhibitor of HIV-1 reverse transcriptase (RT), 
thereby effectively blocking the replication and spread of infectious HIV-1. The in vitro activity 
of TAF against HIV-1 in various human immune cell types is 100- to 600-fold greater than that 
of TFV and 4- to 6-fold greater than that of TDF.
TDF is a first generation oral prodrug of TFV that has been studied extensively in clinical studies
for the treatment of HIV-1 infection and has demonstrated antiviral activity against both wild-
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type and nucleoside resistant strains of HIV-1. The majority of clinical and laboratory adverse 
events (AEs) in clinical studies of TDF were of mild intensity and the frequencies of these events 
in patients who received TDF have been similar to those in patients in the comparator arm. 
Under the trade name Viread®, TDF is marketed by GSI as a once-daily tablet (300 mg) and as a 
powder (1 g contains 40 mg TDF). In combination with other HIV-1 ARVs, it is indicated for the 
treatment of HIV-1 infection in adults and in pediatric patients at least 2 years of age. 
In addition, it is indicated for the treatment of hepatitis B virus (HBV) infection in adults and in 
pediatric patients at least 12 years of age. TDF has received marketing approval for the treatment 
of HIV-1 infection in 149 countries. TDF has also been coformulated and marketed in several 
coformulations with other HIV-1 ARV drugs, such as FTC/TDF FDC (Truvada®).
The following sections summarize the TAF findings at the time of protocol writing. For the most 
comprehensive nonclinical and clinical information regarding TAF and the D/C/F/TAF tablet, at 
the time of protocol finalization, refer to the latest version of the IB for D/C/F/TAF and its 
addendum.16,17 For further information regarding TDF and FTC/TDF FDC, refer to the 
Prescribing Information for TDF and FTC/TDF FDC.34,35,38,39
1.5.2.
Preclinical Pharmacology and Toxicology
Primary Pharmacodynamics
TAF is metabolized to TFV, a nucleotide analog, which is not dependent on an intracellular 
nucleoside kinase activity for the first step in the conversion to the active metabolite, TFV-DP. 
The cellular enzymes responsible for TFV metabolism to the active diphosphorylated form are 
adenylate kinase (AK) and nucleotide diphosphate kinase, which are highly active and 
ubiquitous. AK exists as multiple isozymes (AK1 to AK4), with the phosphorylation of TFV 
mediated most efficiently by AK2.
The intracellular metabolism of TAF and TFV are consistent with the 600-fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Metabolism of TAF was also studied in 
different human blood lymphocyte subpopulations, CD4+ and CD8+ T-cells, NK cells, B-cells 
and macrophages/monocytes. TAF is metabolized inside host cells to the active metabolite 
TFV-DP. Concentration of the active metabolite TFV-DP was substantial in all cell populations.
Safety Pharmacology
TAF monofumarate (GS-7430-02) has been evaluated to determine potential effects on the 
central nervous system, renal system, cardiovascular and gastrointestinal systems. Single doses 
did not induce pharmacologic effects on the central nervous system of the rat (1000 mg/kg), the 
renal system of the rat (1000 mg/kg), or the cardiovascular system of the dog (100 mg/kg). TAF 
monofumarate (at 1000 mg/kg reduced distal transit and increased stomach weights starting 
2 hours after dosing with reversibility beginning by 6 hours after dosing. The no observed 
adverse effect level (NOAEL) for gastrointestinal motility was 100 mg/kg. The 50% inhibitory 
concentration (IC50) of TAF fumarate (GS-7340-03) on hERG potassium current was estimated 
to be greater than 10 μM.
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1.5.3.
Preclinical Pharmacokinetics
All preclinical pharmacokinetic experiments in this section were performed using TAF 
monofumarate, and all study data described in this section reflect the dosage of the 
monofumarate. For reference, 100 mg of TAF monofumarate is equivalent to 80 mg of the 
GS-7340 free base (TAF).
Plasma pharmacokinetics of the intact prodrug, TAF, following oral administration of TAF 
monofumarate in dogs and monkeys demonstrated rapid absorption with peak plasma 
concentrations between 0.25 and 0.5 hours. 
Peak TFV plasma concentrations occurred following TAF absorption, with TFV time to 
maximum plasma concentration (tmax) between 0.25 to 1.7 hours in rats, dogs, and monkeys. 
TFV plasma concentrations declined with a terminal half-life of 11.2 to 16.4 hours in rats 
(fasted), >24 hours in dogs (fasted), and 8.1 to 12.5 hours in rhesus monkeys. 
The tissue distribution and recovery of [14C] radiolabeled TAF monofumarate was examined in 
beagle dogs. Radioactivity was detected in all tissues except brain, with the majority present in 
the contents of the gastrointestinal tract, liver, kidney, and large intestine. Tissue concentrations 
were the highest in kidney, PBMCs, liver, large intestine, and bile. Significant concentrations of 
TFV-related radioactive material were observed in lymph nodes from all 4 sites, suggesting that 
TAF may be selectively cleaved to TFV in the cells of the lymphoreticular system.
The primary route of elimination of TFV is renal excretion of unchanged drug. Following oral 
administration of TAF monofumarate, approximately 15% of a radiolabeled dose is recovered in 
dog urine in 24 hours. TFV was the major species present in the urine (90%), with about 3.4% of 
TAF also present. Biliary excretion of TFV in dogs and fecal elimination of TFV in rats and dogs 
are negligible.
TFV was the only species found in the intestinal contents and feces. In human systems, TAF is 
metabolized by hydrolytic cleavage and, to a lesser extent, by CYP3A4 catalyzed oxidation. As a 
result of the limited metabolism of TAF by CYP3A4 inhibition or induction of this enzyme 
should have little consequence on TAF exposure in vivo. TAF has limited potential to alter CYP 
enzyme activity through inhibition and does not inhibit UGT1A1 function. In addition, TAF is 
not an activator of either the aryl hydrocarbon receptor or human pregnane-X-receptor. These 
features combined with the relatively low plasma exposures of TAF in humans suggest that the 
potential of TAF to cause or be affected by clinically relevant drug-drug interactions is very low.
1.5.4.
Nonclinical Toxicology
TAF monofumarate was evaluated in mice, rats, dogs, and monkeys for treatment periods up to 
9-months and was negative in genetic toxicology studies. There was no effect on fetal viability or 
fetal development in pregnant rats administered doses of TAF monofumarate up to 
200 mg/kg/day or in pregnant rabbits administered TAF monofumarate up to 100 mg/kg/day (the 
highest doses tested).
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In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) and kidneys 
(karyomegaly) were the primary target organs after 26 weeks of treatment. TAF monofumarate 
also appeared to increase biochemical markers of bone turnover and decrease serum 
1,25-dihydroxy- and 25-hydroxyvitamin D3 at doses of 25 mg/kg/day and above. In chronic 
studies in dogs after 9 months of treatment with TAF monofumarate, the primary target organs 
were kidney and bone.
TAF monofumarate had no discernible electrocardiograph effect at the low dose of 2 mg/kg/day 
and slightly prolong PR intervals at 6 and 18/12 mg/kg/day. Additionally, at Week 39, TAF 
monofumarate appeared to reversibly reduce heart rate with an associated mild QT prolongation. 
At Week 39, decreases in serum T3 were noted for animals receiving 18/12 mg/kg/day but 
was reversible at the 3-month recovery period. Minor hematologic and biochemistry 
parameters changes were observed but remained within normal historical ranges with the 
following exceptions: aspartate aminotransferase (AST) (~100% increase) and total bilirubin 
(~40% increase). There were no clear treatment-related effects observed in monkeys following 
28 days of treatment including no changes in mitochondrial function.
The data from the 6-month rat study determined a NOAEL of 25 mg/kg/day (TFV exposure: 
AUC=3758 ng·h/mL); the 9-month dog study defined a NOAEL of 2 mg/kg/day (TFV 
AUC=1180 ng·h/mL), and the 28-day nonhuman primate study defined a NOAEL of 
30 mg/kg/day (TFV AUC=5870 ng·h/mL). In conjunction with the nonclinical data with TDF 
and the clinical experience with TDF and TAF, these toxicology studies support studies in 
humans of doses up to 150 mg/day (120 mg free base, the highest anticipated human dose) for 
chronic treatment.
At the time of the rodent toxicity studies, the bioassay could not detect plasma TAF, possibly due 
to instability in the matrix.
Because of the lack of exposure to the prodrug in mice and rats and achievable TFV exposures 
less than previously tested in chronic and carcinogenicity studies with TDF, carcinogenicity 
studies in mice and rats with TAF are currently not planned. 
TAF has not been evaluated in perinatal-postnatal reproductive toxicology studies. Reproductive 
tissues were examined in repeat-dose toxicology studies in the rat, dog, and monkey. There were 
no clearly treatment-related histologic alterations or changes in organ weights in the rat and the 
dog following chronic daily dosing, or in the monkey.
The TAF fumarate oral rat fertility study (TX-120-2012) data indicate dose related decreases in 
body weight gain in males and females occurred but no drug related changes occurred in male or 
female fertility endpoints at doses up to 160 mg free base equivalents/kg/day.
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1.5.5.
Clinical Studies
Clinical trials entailing the use of TAF for HIV include:
-
GS-120-1101, a Phase 1-2 study of the pharmacokinetics and antiviral activity of GS-7340 
(50 mg and 150 mg) in HIV-infected subjects (completed);
-
GS-US-120-0104, a Phase 1b study of the pharmacokinetics and antiviral activity of 
GS-7340 (8 mg, 25 mg, 40 mg) in HIV infected subjects (completed);
-
GS-US-311-0101, a Phase 1 healthy volunteer study evaluating the drug interaction potential 
between once-daily FTC/GS-7340 FDC and EFV or COBI-boosted DRV (completed);
-
GS-US-120-0107, a Phase 1, partially-blinded, randomized, placebo- and positive-controlled 
study to evaluate the effect of GS-7340 on the QT/QTc interval in healthy subjects 
(completed);
-
GS-US-120-0108, a Phase 1, open-label, parallel-design study to evaluate the 
pharmacokinetics of GS-7340 in subjects with severe renal impairment (completed);
-
GS-US-120-0109, a Phase 1 study to evaluate the pharmacokinetics, metabolism and 
excretion of GS-7340 (completed);
-
GS-US-120-0114, a Phase 1 study to evaluate the pharmacokinetics of TAF in subjects with 
normal and impaired hepatic function (completed);
-
GS-US-120-0117, a Phase 1 study to evaluate the pharmacokinetic drug interaction potential 
between rilpivirine and TAF in healthy subjects (completed);
-
GS-US-120-0118, a Phase 1 pharmacokinetic study to evaluate the drug interaction potential 
of TAF with a boosted PI or unboosted integrase inhibitor in healthy subjects (completed).
Clinical trials entailing the use of TAF for the treatment of chronic HBV infection:
-
GS-US-320-0101, a Phase 1b randomized, open-label, active-controlled study to assess the 
safety, viral kinetics and anti-HBV activity of GS-7340 in treatment-naïve adults with 
chronic hepatitis HBV infection (completed);
-
GS-US-320-1228, a Phase 1 single dose study to investigate the pharmacokinetics, safety 
and tolerability of TAF in healthy Japanese and non-Japanese subjects (completed).
The first proof-of concept study, GS-120-1101, as well as GS-US-120-0104 and 
GS-US-292-0101 were performed using TAF monofumarate. All subsequent studies were 
performed using TAF fumarate, with the exception of GS-US-311-0101 Cohort 4, which used 
TAF monofumarate for the GS-7340 single-agent 8-mg tablet.
GS-120-1101 was a Phase 1-2 randomized double-blind, active-controlled, dose escalation study 
of the safety, tolerance, pharmacokinetics, and antiviral activity of TAF in ARV-naïve subjects
who were chronically infected with HIV-1. The subjects were randomized to receive 14 days of 
monotherapy, fasting, with TAF monofumarate 50 mg once daily, 150 mg once daily, or TDF 
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300 mg once daily (n=10 per group). TAF was rapidly absorbed into the systemic circulation, 
and following attainment of Cmax (maximum plasma concentration), was eliminated rapidly with 
a short plasma half-life (20-40 minutes). Compared with TDF, TAF monofumarate 50 mg 
provided a ~16-fold lower TFV Cmax (207 ng/mL versus 13 ng/mL), approximately 2-fold longer 
elimination half-life (26 versus 48 hours) and lower overall systemic TFV exposure (AUCinf
1814 versus 383 ng.h/mL). TAF monofumarate 150 mg provided lower Cmax (42 ng/mL), but 
comparable AUCinf (1740 ng.h/mL) as TDF. In PBMCs, TFV was detectable earlier, more 
frequently, and in higher concentrations following dosing of TAF monofumarate. The 
intracellular delivery of TFV is approximately 30-fold greater for TAF monofumarate versus
TDF. The decrease from baseline to Day 14 in plasma HIV-RNA levels was greater for groups 
treated with TAF monofumarate 50 mg (p=0.02757) or 150 mg (p=0.0010) than the group 
treated with TDF 300 mg. The median changes from baseline in plasma HIV-1 RNA after 14 
days of monotherapy were -0.96, -1.65, and -1.68 log10 copies/mL, respectively, for TDF 
300 mg, TAF monofumarate 50 and 150 mg. 
A second proof-of-concept study, GS-US-120-0104, evaluated monotherapy, fasting, with 
3 lower doses of TAF or TDF 300 mg, or placebo, administered for 10 days. Potent antiviral 
activity was achieved in treatment-naïve HIV-1 infected subjects, with mean (± standard 
deviation [SD]) change from baseline in HIV-1 RNA of -0.95±0.45, -1.53±0.40, -1.7±0.22, 
and -0.81±0.66 log10 copies/mL at TAF 8 mg, 25 mg, 40 mg, and TDF 300 mg, respectively 
(data unblinded only at dose level). Mean viral load declines for both the 25- and 40-mg doses 
were statistically better than the 8-mg dose. TAF AUC was best associated with antiviral activity 
despite its short plasma half-life (~30 minutes). TFV AUC were 97%, 87%, and 80% lower at 
TAF 8 mg, 25 mg, and 40 mg, respectively, compared to TDF administration. When compared to 
40 mg and historical 120-mg data, TAF 25 mg provided near maximum activity (predicted to be 
~-1.7 to 1.8 log10 copies/mL). From this pharmacokinetic/pharmacodynamic analysis, a target 
dose of TAF 20-25 mg monotherapy was expected to provide near maximum activity and ~90% 
reduction in circulating TFV.
GS-US-311-0101 was a multi-dose Phase 1 study evaluating the drug interaction potential 
between once-daily FTC/TAF (200/40 mg) FDC and EFV (Cohort 1), between FTC/TAF 
(200/25 mg) FDC and COBI (150 mg)-boosted DRV (800 mg) (Cohorts 2 and 3), and between 
TAF 8 mg and COBI 150 mg (Cohort 4). Following multiple dosing of FTC/TAF plus EFV, no 
clinically relevant changes in TAF and TFV exposures were observed, indicating the lack of 
significant influence of the CYP pathway. Following multiple dosing of FTC/TAF plus 
DRV/COBI, the TAF exposure was unchanged but TFV Cmax and AUCtau were 3.2-fold higher, 
as compared with FTC/TAF only. Pharmacokinetic results indicated that when dosed with COBI, 
TAF Cmax and AUClast were 2.8- and 2.6-fold higher, respectively, while TFV Cmax and AUCtau
were 3.3-fold higher.
Study GS-US-120-0107 was a Phase 1, partially-blinded, randomized, placebo-
and 
positive-controlled study to evaluate the effect of TAF on the QT/QTc interval in healthy 
subjects. This was a negative thorough QTc study. No effect of TAF was observed on the QTcF 
interval (ie, no QTc interval prolongation >10 ms at any time point postdose and assay
sensitivity was confirmed via the positive control [moxifloxacin]). As such, these findings satisfy 
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the guidelines set forth in the International Conference on Harmonization (ICH) E14 guidance 
and support the conclusion that there is no significant effect of TAF on the QT/QTc interval.9
Study GS-US-120-0108 was a Phase 1, open-label, parallel-design study to evaluate the 
pharmacokinetics of TAF in subjects with severe renal impairment. TAF was well tolerated in 
the study. Subjects with severe renal impairment had approximately <2-fold higher TAF and 
5 to 6-fold higher TFV systemic exposures as assessed by AUC relative to subjects with normal 
renal function. TFV exposures in subjects with severe renal impairment are comparable to those 
with normal renal function receiving 300 mg TDF once daily as well as severely renally 
impaired subjects (clearance <50 mL/min) receiving TDF 300 mg twice weekly. Given the 
extensive safety data available for TDF at a dose of 300 mg, TFV exposures in severely renally 
impaired subjects similar to those associated with TDF 300 mg are deemed appropriate for 
further study of TAF in HIV-infected subjects without TAF dose modification.
Results from Study GS-US-120-0109, a Phase 1 pharmacokinetics, metabolism and excretion 
study (in 8 healthy male subjects) demonstrated that TAF is eliminated in both feces and urine, 
with total mean (±SD) recovery of 84.4%±2.45%. TAF and its metabolites are eliminated in both 
feces and urine. The predominant species detected in feces and urine is TFV, accounting for 
31.4%±10.4% and 22.2% ±4.47% of the total radioactive dose. These human data are consistent 
with the established preclinical profile of TAF. Following administration of TAF, plasma [14C]
radioactivity showed a time dependent profile with TAF as the most abundant species in the 
initial few hours and uric acid in the remaining period. The whole blood-to-plasma concentration 
ratio of [14C] radioactivity increased from 0.511 at 0.25 hours postdose to 2.32 at 216 hours 
postdose, suggesting a relatively slower clearance of [14C]radioactivity from blood cells relative 
to the plasma [14C] radioactivity time-course. In addition to TFV and uric acid, additional low 
quantities of metabolites were formed, including xanthine, hypoxanthine, and adenine. They are 
identical to the endogenous products of purine metabolism and therefore should not cause any 
safety risk. TAF 25-mg tablets administered together with tracer dose of [14C] radiolabeled TAF 
as a single oral tablet, were well tolerated.
GS-US-120-0114 was a Phase 1 study to evaluate the pharmacokinetics of TAF in subjects with 
normal and impaired hepatic function. No clinical relevant changes in TAF or TFV 
pharmacokinetics were observed in subjects with mild to moderate hepatic impairment compared 
to the normal matched control subjects following administration of a single dose of TAF 25 mg. 
The results of this study indicate that no dose adjustment of TAF is necessary in subjects with 
mild to moderate hepatic impairment. Single doses of TAF 25 mg were generally well tolerated 
in subjects with mild or moderate hepatic impairment and in subjects with normal hepatic 
function.
GS-US-120-0117 was a Phase 1 study to evaluate the pharmacokinetic drug interaction potential 
between single doses of rilpivirine and TAF in healthy subjects. The study concluded that TAF 
and RPV coadministration does not result in clinically relevant changes in RPV, TAF, or TFV 
exposure, and no dose adjustments are necessary. Single doses of TAF 25 mg, TAF 25 mg plus 
RPV 25 mg, and RPV 25 mg were generally well tolerated in these healthy subjects.
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GS-US-120-118 was a Phase 1 study to evaluate the drug interaction potential of TAF with the 
ritonavir-boosted PIs ATV, DRV, and lopinavir (LPV), or with the unboosted InSTI dolutegravir 
(DTG). Results of the study showed that coadministration of FTC+TAF with DTG did not result 
in clinically relevant changes in TAF or TFV exposure. Coadministration of FTC+TAF with 
ATV/rtv or LPV/rtv resulted in increased TAF and TFV exposures. Coadministration of 
FTC+TAF with DRV/rtv did not result in clinically relevant changes in TAF, but resulted in 
increased TFV exposure.
GS-US-320-0101 was a Phase 1b study of TAF in otherwise healthy HBV-infected subjects, 
exploring the differences in short-term antiviral activity between doses of TAF (8 , 25, 40, and 
120 mg) with respect to the time weighted average change from baseline through Week 4 in 
serum HBV DNA (log10 IU/mL). Results in all treatment cohorts demonstrated viral suppression 
over a treatment duration of 4 weeks, with no perceivable differences in the potency of TAF at 
lower doses compared to higher doses. Viral suppression with TAF was also comparable to that 
with TDF. TAF was safe and well tolerated. The safety profile for TAF did not differ among 
dose groups and was similar to that of TDF.
GS-US-320-1228 was a Phase 1 single dose study to investigate the pharmacokinetics, safety and 
tolerability of TAF in healthy Japanese and non-Japanese subjects. The study found that the 
pharmacokinetics of TAF and TFV following administration of TAF 25 mg are comparable 
between Japanese and non-Japanese subjects and support dosing of 25 mg in Japanese subjects, 
TAF 25 mg was safe and well tolerated in this study.
1.6.
Overall Rationale and Risks Assessment for the Study
The success of HAART and the apparent benefits of maximally suppressed viremia has shifted 
clinical attention towards ARV agents that optimize long-term safety and tolerability. 
This medical need becomes clearer as the HIV-positive population ages; morbidity and mortality 
are increasingly driven by non-AIDS associated comorbidities, and these age-associated 
comorbidities are observed earlier than in the non-HIV-1 infected population despite the 
best current chronic therapy.7,8 In addition, young, newly infected patients are diagnosed earlier, 
initiate therapy earlier, and look ahead towards lifelong therapy, often more than 50 years.26
Incomplete adherence to ARV regimens, which is a critical factor contributing to the 
development of viral resistance and treatment failure, is an important barrier to successful long-
term treatment (see also Section 1.1). Studies have shown that once-daily single-tablet regimens 
improve adherence, treatment satisfaction, and virologic outcomes for patients infected with 
HIV-1.1,12,15,43 Due to longer duration of high adherence, patients taking single-tablet regimens 
also have better clinical outcomes, such as fewer hospitalizations, when compared with multiple-
tablet regimens.29
To improve care for HIV-infected patients and maximize tolerability, safety, clinical efficacy, 
and adherence, the sponsor and GSI are codeveloping DRV with COBI, FTC and TAF into a
single tablet (D/C/F/TAF). This new antiviral formulation would provide an additional single-
tablet option, in particular for subjects requiring PI-based regimens, and would be an attractive 
new once-daily simplified regimen. The D/C/F/TAF tablet also represents a new alternative for 
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individuals intolerant to currently available combination tablet regimens, and may promote better 
adherence to bPI-based regimens. Additionally, compared with TDF, the use of TAF in the 
D/C/F/TAF tablet is postulated to provide greater lymphatic delivery of TFV resulting in higher 
intracellular levels of the active phosphorylated moiety TFV-DP, more effective suppression of 
residual viral replication in a wider range of reservoir and anatomic sanctuaries of HIV, greater 
and faster viral load reduction during initial therapy, and lower systemic circulating levels of 
TFV.6,18
The principal anticipated drug-drug interaction upon administration of the 4-drug combination is 
the intended inhibition of CYP3A activity by COBI and the consequent increase in DRV 
exposure to levels similar to those observed using rtv as a boosting agent. The DRV/COBI 
800/150 mg once dialy dose regimen with other ARV agents has already been established for use 
in HIV-1 infected patients. DRV and COBI concentrations are not anticipated to be affected by 
FTC or TAF. For TAF regimens including a pharmacoenhancer (rtv or COBI), a TAF dose of 10 
mg is used as opposed to a dose of 25 mg currently in development for use with other (non-bPI) 
ARV agents (see also the rationale for dose selection in Section 3.2.2).
Administration of DRV, FTC, and TAF in a single tablet, with COBI as a pharmacokinetic 
enhancer, is expected to have similar antiviral activity and resistance profile as DRV, FTC, and 
TAF administered as single tablets. 
The combination of D/C/F/TAF is not anticipated to exacerbate known toxicities or lead to new
toxicities. DRV and FTC have established clinical safety profiles with no significant toxicities 
observed. Liver toxicity related to COBI, which was observed preclinically, has not been 
observed clinically to date. Standard liver enzyme assays will be used to monitor for these 
potential adverse effects. Minimal mononuclear cell infiltration in the posterior uvea has been 
observed at the highest dose of TAF (12-18 mg/kg) in dogs, but has not been observed in humans 
and clinical studies. More than 3,000 HIV-positive subjects have been exposed to TAF as part of 
the Phase 2 and 3 E/C/F/TAF clinical development program by GSI and no AEs consistent with 
posterior uveitis in humans have been reported. Nonetheless, if subjects 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 prompt referral of the subject for 
specialized ophthalmologic evaluation including dilated fundoscopy, and if required, optical 
coherence tomography. 
The primary nonclinical toxicities for TAF are renal and bone toxicity.
Based on available data from the ongoing COBI and E/C/F/TDF tablet clinical development 
programs, decreases in eGFR are anticipated due to the known effects of COBI on the renal 
tubular excretion of creatinine, without an impact on the renal glomerular function. Studies 
GS-US-292-0102 and GS-US-236-0118 showed that the E/C/F/TDF tablet, as well as 
ATV/COBI or DRV/COBI + background regimens were safe and well tolerated in subjects 
with mild renal impairment (eGFR 50-89 mL/min).16 The eligibility criteria for study 
TMC114IFD3013 with the D/C/F/TAF tablet allow the inclusion of subjects with a screening 
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eGFR of ≥50 mL/min. In addition, a renal management algorithm to optimally evaluate and 
determine the benefit/risk profile for continued participation of subjects whose eGFR decreases 
to <50 mL/min is included in the study protocol. As recent data suggested that the combined use 
of COBI and TDF (expected to be less with TAF) might increase proteinuria, this study protocol 
will also assess the effects of the D/C/F/TAF tablet on proteinuria, albuminuria, beta-2-
microglobulinuria, and urine retinol-binding protein (RBP). 
Two clinical studies to date have been performed with the D/C/F/TAF tablet (GS-US-299-0101 
in healthy volunteers [N=102, Phase 1], and GS-US-299-0102 in ARV-naïve HIV-1 infected 
subjects [N=153, Phase 2]).16 No new or unexpected ADRs as compared to the ADRs with the 
individual components were identified in these studies. The Phase 2 results showed significantly 
smaller increase in serum creatinine and significantly smaller decrease in bone mineral density of 
hip and spine in the D/C/F/TAF arm compared to the D+C+F/TDF arm.
While the combination of D/C/F/TAF is not anticipated to have an effect on actual GFR, 
monitoring of creatinine along with other standard clinical tests is planned in all clinical studies 
with the D/C/F/TAF tablet.
Based on the available data and proposed safety measures, the overall risk/benefit assessment for 
the TMC114IFD3013 clinical study is acceptable.
The aim of study TMC114IFD3013, is to evaluate the efficacy, safety and tolerability of 
switching to a single tablet containing a fixed dose of D/C/F/TAF in HIV-1 infected individuals 
who are virologically suppressed on their current stable regimen. The active comparator (control) 
in this open-label, randomized, comparative study is continuing the current regimen consisting of 
a bPI (limited to DRV once daily with rtv or COBI, ATV with rtv or COBI, or LPV] with rtv) 
combined with FTC/TDF. Subjects in the control arm will switch to the D/C/F/TAF tablet at 
Week 48 if all conditions are fulfilled (for details, see Section 3.1). 
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective of this study is to demonstrate noninferiority in efficacy of a D/C/F/TAF
once-daily single-tablet regimen relative to continuing the current bPI combined with FTC/TDF
in virologically-suppressed (HIV-1 RNA <50 copies/mL) HIV-1 infected subjects, in regard to 
the proportion of virologic rebounders (defined as having confirmed HIV-1 RNA ≥50 copies/mL 
through Week 48, or in case of early discontinuation a last single viral load of HIV-1 RNA 
≥50 copies/mL), with a maximum allowable difference of 4%. See Section 11.5 for more details
on the definition of virologic rebounder.
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Secondary Objectives
The secondary objectives of this study are:
-
To evaluate superiority of switching to a D/C/F/TAF once-daily single-tablet regimen versus 
continuing the current bPI combined with FTC/TDF in regard to the proportion of virologic 
rebounders, in case noninferiority is established;
-
To evaluate the proportion of rebounders through Week 24 in the 2 treatment arms;
-
To evaluate efficacy as determined by continued suppression of HIV-1 RNA (<20, <50, and 
<200 HIV-1 RNA copies/mL as defined by the FDA snapshot analysis and time to loss of 
virologic response [TLOVR] algorithm) at Weeks 24 and 48 in the 2 treatment arms;
-
To evaluate the safety and tolerability of the D/C/F/TAF regimen through 24 and 48 weeks 
of treatment;
-
To evaluate the change from baseline in serum creatinine, eGFR for creatinine clearance 
(eGFRcr, by Cockcroft-Gault and by Chronic Kidney Disease Epidemiology Collaboration
[CKD-EPI]) and eGFR for cystatin C clearance (eGFRcyst, by CKD-EPI) in the 2 treatment 
arms at Weeks 24 and 48;11,19
-
To evaluate the change from baseline in renal biomarkers at Weeks 24 and 48;
-
To evaluate immunologic changes (CD4+ cell count) through 24 and 48 weeks of treatment
in the 2 treatment arms;
-
To evaluate adherence to drug intake (as derived by drug accountability data), and explore 
correlation with primary efficacy outcome;
-
To evaluate resistance in subjects who show confirmed virologic rebound through Weeks 24 
and 48 in the 2 treatment arms;
-
To evaluate long-term efficacy, resistance, and safety of the D/C/F/TAF regimen (until 
Week 96 and beyond);
-
To evaluate the steady-state pharmacokinetics of DRV in the D/C/F/TAF arm.
Secondary objectives to be assessed in a bone investigation substudy performed at selected study 
sites:
-
To evaluate the changes from baseline in bone biomarker levels at Weeks 24 and 48;
-
To evaluate the safety of the 2 treatment arms as determined by the percent change from 
baseline in spine and hip bone mineral density (BMD) and changes in associated T-score at 
Weeks 24 and 48.
2.2.
Hypothesis
The null hypothesis in this study is that the proportion of subjects with virologic rebound through
Week 48 in the investigational treatment arm (D/C/F/TAF once-daily single-tablet regimen) is 
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more than 4% higher than that in the control treatment arm (ongoing regimen consisting of a bPI 
combined with FTC/TDF); the alternative hypothesis is that the rebounder rate in the D/C/F/TAF 
arm is at most 4% higher than that in the control arm.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
Study TMC114IFD3013 is a randomized, active-controlled, open-label, multicenter, Phase 3
study to evaluate the efficacy, safety and tolerability of switching to a D/C/F/TAF once-daily 
single-tablet regimen compared to continuing the current regimen consisting of a bPI (limited to 
DRV once daily with rtv or COBI, ATV with rtv or COBI, or LPV with rtv) combined with FTC
and TDF (single agents or FDC; both hereafter referred to as FTC/TDF) in virologically-
suppressed (HIV-1 RNA <50 copies/mL), HIV-1 infected adult subjects over a 48-week 
treatment period. 
Approximately 1,100 subjects will be included in this study. Eligible subjects are to be currently 
treated with a stable ARV regimen consisting of a bPI (limited to DRV once daily with rtv or 
COBI, ATV with rtv or COBI, or LPV with rtv) combined with FTC/TDF only, for at least 
6 consecutive months preceding the screening visit, and virologically suppressed, with at least 
1 plasma HIV-1 RNA measurement <50 copies/mL (or HIV-1 RNA undetectable by a local 
HIV-1 RNA test) occurring between 12 and 2 months prior to screening while being on the 
stable ARV regimen and have HIV-1 RNA <50 copies/mL at the screening visit.
Subjects treated with the combination DRV + COBI + FTC/TDF and having completed the 
required visits in the GSI-sponsored study GS-US-216-0130, and who are fulfilling the present 
protocol criteria, will also be given the option to participate in this study.16
Prior to or at the baseline visit (Day 1), subjects who meet all eligibility criteria will be 
randomized in a 2:1 ratio to 1 of the following 2 treatment arms:
-
D/C/F/TAF Arm: Switch to regimen of a single FDC tablet containing DRV 800 mg/ COBI 
150 mg/ FTC 200 mg/ TAF 10 mg (D/C/F/TAF tablet) once daily, 
(n = 734);
-
Control Arm: 
Continue current regimen consisting of a bPI (limited to DRV once daily
with rtv or COBI, ATV with rtv or COBI, or LPV with rtv) combined
with FTC/TDF only, (n = 367).
Randomization will be stratified by bPI used at screening (see also Sections 3.2.1 and 5).
Subjects will be treated for 48 weeks, and will return for study visits at Weeks 2, 4, 8, 12, 24, 36, 
and 48.
Provided results from the Data Monitoring Committee (DMC) analyses or Week 24 interim 
analysis does not preclude (further) exposing subjects to D/C/F/TAF, subjects from the 
D/C/F/TAF arm will enter in the extension phase once they have completed their Week 48 visit. 
In addition, subjects in the control arm will receive the D/C/F/TAF tablet in the extension phase 
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if, according to the investigator they will benefit from it and if all conditions are fulfilled (which 
includes adequate viral load results). Subjects from the control arm will be required to attend a 
switch visit at Week 52 to receive D/C/F/TAF. All subjects in the extension phase will have to
attend visits every 12 weeks up to Week 96. As from Week 96, all subjects are offered the 
possibility to continue D/C/F/TAF treatment, if they wish and if they continue to benefit from it,
until D/C/F/TAF becomes commercially available and is reimbursed, or can be accessed through 
another source in the country where he/she is living, or until the sponsor terminates clinical 
development. After Week 96, subjects should attend visits every 6 months.
Subjects who prematurely discontinue or change study treatment during the treatment phase 
(from Day 1 to Week 48) or during the extension phase (only between Week 48 and 96) will be 
required to complete the early study treatment discontinuation (ESTD) visit assessments within 
72 hours of stopping/changing study treatment.
In addition, a 30-day follow-up (FU) visit will be required for any subject who has an ongoing 
AE or serious adverse event (SAE) at the time of his/her last study visit (unless consent is 
withdrawn).
Thus, the study will include a screening period of approximately 30 days (up to maximum 
6 weeks, see also Section 9.1.2.1) starting from the signature of the informed consent form (ICF), 
a controlled treatment period of 48 weeks and an extension phase. A 30-day FU visit may take 
place as described above. A diagram of the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study
Baseline
(Day 1)a
Week 24
Week 48b
Primary analysis
Week 96 or 
beyondb
Screening
Treatment phasec
Extension 
phaseb,c
Follow-
up
≤30 days prior to 
baseline
Treatment arm 1 (Test): D/C/F/TAF once dailyd
(n=734)
D/C/F/TAFd
ESTDc
and/or
30-day 
FU visitf
Treatment arm 2 (Control): Continue current bPI combined 
with FTC/TDF onlye (n=367)
a
Following the baseline visit, subjects will return for study visits at Weeks 2, 4, 8, 12, 24, 36, and 48.
b
Provided results from the DMC analyses or Week 24 interim analysis does not preclude (further) exposing 
subjects to D/C/F/TAF, subjects from the D/C/F/TAF arm will enter in the extension phase once they have 
completed their Week 48 visit. In addition, subjects in the control arm will receive the D/C/F/TAF tablet in 
the extension phase if, according to the investigator they will benefit from it and if all conditions are fulfilled 
(which includes adequate viral load results). Subjects from the control arm will be required to attend a switch 
visit at Week 52 to receive D/C/F/TAF. All subjects in the extension phase will have to attend visits every 12 
weeks until Week 96. As from Week 96, all subjects are offered the possibility to continue D/C/F/TAF 
treatment, if they wish and if they continue to benefit from it, until D/C/F/TAF becomes commercially 
available and is reimbursed, or can be accessed through another source in the country where he/she is living, 
or until the sponsor terminates clinical development. After Week 96, subjects should attend visits every 6 
months.
c
Subjects who prematurely discontinue or change study treatment during the treatment phase (from Day 1 to 
Week 48) or during the extension phase (only between Week 48 and 96) will be required to complete the 
ESTD visit assessments within 72 hours of stopping/changing study treatment.
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d
D/C/F/TAF tablet will be administered orally, once daily with food, at approximately the same time each 
day.
e
The bPI (DRV once daily with rtv or COBI, ATV with rtv or COBI, or LPV with rtv) and FTC/TDF should 
be used in the dosing schedule specified in the ARV agent's local Prescribing Information. Applicable 
procedures and treatment guidance based on the Prescribing Information should be respected. 
f
Subjects who have an ongoing AE or SAE at the time of their last visit will be required to have a 30-day FU 
visit (unless consent is withdrawn).
Assessment of drug accountability, monitoring of treatment adherence using a study medication 
log booklet, concomitant medications, AEs, laboratory evaluations for efficacy and safety (viral 
load, CD4+ count, biochemistry, hematology, urinalysis, urine chemistry), vital signs and 
(complete or symptom-directed) physical examinations will be performed at each visit (except at 
the Week 52 switch visit). A 12-lead electrocardiogram (ECG) will be performed at screening.
Urine for selected renal biomarkers will be collected at baseline and at several visits during the 
study. 
A bone investigation substudy will be performed at selected study sites, to assess bone 
biomarkers and dual energy x-ray absorptiometry (DXA) scans, in approximately 300 subjects 
(200 in the D/C/F/TAF treatment arm versus 100 in the control arm) who provide informed 
consent for the substudy.
Pharmacokinetic assessments (sparse sampling) will be performed for subjects randomized to the 
D/C/F/TAF arm (single sample from Weeks 2 to 48 or the ESTD visit if applicable). For subjects 
with confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥50 copies/mL at 
a scheduled or unscheduled visit) and a HIV-1 RNA value ≥400 copies/mL, HIV-1 genotypic 
resistance testing will be performed and phenotypic resistance testing may be done upon request 
of the study virologist. If genotypic/phenotypic resistance to study drugs is determined, study 
drugs may be discontinued and the ARV regimen can be changed at the discretion of the 
investigator. 
A planned Week 24 interim analysis will be performed after the last subject completes 24 weeks 
on study, or prematurely discontinues from the study. This analysis will be done mainly to 
evaluate the safety and tolerability of D/C/F/TAF. However, efficacy of the 2 treatment arms will 
also be looked at. Results of which will also be shared with the DMC. The primary Week 48 
analysis will be performed after the last subject enrolled in the D/C/F/TAF arm reaches Week 48 
or the last subject enrolled in the control arm completes the Week 52 visit (whichever comes 
last), or prematurely discontinues from the study. The Week 96 analysis will be performed after 
the last subject completes 96 weeks on study, or prematurely discontinues from the study. The 
final analysis will be performed after all subjects have completed the extension phase (and the 
30-day FU visit, if applicable). 
The efficacy, as well as safety and tolerability, of the enrolled subjects and treatment regimens 
will be monitored by an external DMC. Refer to Section 11.9 for details. In addition to the 
planned primary (Week 48), the Week 24, 96, and final analyses, a formal DMC analysis will be 
performed for monitoring purposes, including a futility analysis for lack of (non-inferior) 
efficacy and a blinded sample size re-estimation. 
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3.2.
Study Design Rationale
3.2.1.
Rationale for Design
Control, Blinding, Randomization, and Stratification
An active control will be used to determine treatment effects in this study. Continuation of the 
current regimen consisting of a bPI (limited to DRV once daily with rtv or COBI, ATV with rtv 
or COBI, or LPV with rtv) combined with FTC/TDF only was chosen as comparator because this 
study evaluates the effects of switching from a multi-tablet bPI-based ARV regimen to a 
simplified once-daily FDC tablet bPI-based regimen. The use of FTC/TDF as a fixed backbone
in the comparator arm allows for the most accurate assessment of potential renal toxicity related 
to TAF or TDF.
This study will not be blinded due to the uneven pill burden in the 2 treatment arms (1 tablet 
once daily in the investigational treatment arm versus 2 or more tablets in 1 or more intakes daily
in the control arm). Double-blinding is not considered appropriate because this would result in an 
increased pill burden, and the loss of convenience and ease of adherence for patients who will 
use the investigational simplified regimen.
Randomization will be used to minimize bias in the assignment of subjects to treatment arms, to 
increase the likelihood that known and unknown subject attributes (eg, demographic or baseline 
characteristics) are evenly balanced across treatment arms, and to enhance the validity of 
statistical comparisons across treatment arms. A 2:1 randomization was chosen to allow a more 
robust quantification (increased precision) of the safety of D/C/F/TAF.
One stratification factor (bPI used at screening) will be applied in the randomization process and 
will subsequently be used in the statistical analysis as covariates in the models: 1) DRV once 
daily with rtv or COBI, 2) ATV with rtv or COBI, and 3) LPV with rtv. This ensures a balanced 
distribution of subjects previously on regimens with boosted DRV, ATV, or LPV across 
treatment arms, given that DRV is the PI in the investigational regimen, and the potential effects 
on safety outcomes and repercussion on the efficacy parameter (ie, missing viral load values 
because of discontinuation due to AE) for subjects exposed to a new PI.
Primary Analysis Time Point and Study Period 
Week 48 is the primary analysis time point, as the present study evaluates the efficacy, safety
and tolerability of switching ARV regimens to a D/C/F/TAF once-daily regimen in treatment-
experienced subjects who have been virologically suppressed prior to the study and at screening, 
and a 48-week period of treatment is deemed sufficient to detect any relevant differences in 
treatment effects in such a switch setting. In addition, preliminary results from the clinical Phase 
2b study GS-US-299-0102, which evaluated the safety and efficacy of the D/C/F/TAF tablet 
versus COBI-boosted DRV plus FTC/TDF in HIV-1 infected, ARV treatment-naïve adults,
showed that Week 24 data are consistent with data at later time points for both efficacy and 
safety.
A treatment duration up to 48 weeks was chosen to evaluate the sustained efficacy, tolerability 
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and safety of the D/C/F/TAF single-tablet regimen in the selected population. To assure 
continued follow-up of the study participants and gain further safety information, subjects who 
prematurely discontinue or change study treatment during the controlled treatment period will be 
asked to remain in the study and attend the ESTD (and 30-day FU visit, if applicable.
In addition, to further assure continued treatment of the study participants and collect further 
extended safety data, and provided the conditions are fulfilled to enter the extension phase,
subjects from the D/C/F/TAF arm will continue their D/C/F/TAF regimen as from completion of 
the Week 48 visit until Week 96, and subjects from the control arm will receive D/C/F/TAF as 
from completion of the Week 52 switch visit until Week 96. In order to collect long-term safety and 
efficacy data on D/C/F/TAF, all subjects are offered the possibility to continue D/C/F/TAF 
treatment after Week 96, until D/C/F/TAF becomes commercially available and is reimbursed, or 
can be accessed through another source in the country where they are living, or until the sponsor 
terminates clinical development.
Toxicity Management
The combination of D/C/F/TAF is not anticipated to exacerbate known toxicities or lead to new 
toxicities (see also Section 1.6). 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 9.5). The presented toxicity management guidelines are applicable 
throughout the entire study, including the screening period and the 48-week treatment period. 
Further, it is recommended that investigators also follow these guidelines and apply the same 
safety measures for subjects in the extension phase.
Safety and Efficacy Monitoring
Eligible subjects for this study are virologically suppressed and all individual components of the 
investigational regimen are well-established or authorized. Yet, the combination as such and the 
single-tablet formulation used in this study are new. Therefore, an external DMC will be 
established and monitor the safety and efficacy information, to ensure the safety of the subjects 
enrolled in this study, and to allow regular assessment of the risk/benefit profile of the applied 
therapy schemes (see also Section 11.9).
3.2.2.
Rationale for Dose Selection
DRV 800 mg boosted by COBI 150 mg, and FTC 200 mg in the D/C/F/TAF tablet represent the 
marketed doses. The dose of TAF 10 mg in the D/C/F/TAF tablet is the study-selected dose
expected to attain TAF plasma concentrations in range of those demonstrated to show potent 
antiviral activity with TAF as a stand-alone agent, and TFV plasma concentrations that are 
considerably lower than those obtained with TDF.
The proof-of-concept study GS-US-120-0104 evaluated 3 doses of TAF monotherapy (8, 25 and 
40 mg once daily) and demonstrated potent antiviral activity in HIV-1 patients, with mean (SD) 
change from baseline in HIV-1 RNA of -0.95 (0.45), -1.53 (0.40), and -1.7 (0.22) log10
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copies/mL at TAF 8, 25, 40 mg once daily, respectively (data unblinded only at dose level; TAF 
dosed for 10 days).16
Administration of TAF 25 mg in the presence of DRV/COBI resulted in approximately 3-fold 
higher than historical TFV exposures following administration of TAF 25 mg alone
(GS-US-120-0104, GS-US-292-0101, and GS-US-292-0103).16 GS-US-299-0101 was a Phase 1, 
healthy-volunteer, adaptive-design, multiple-dose study that evaluated the bioavailability of 
3 formulations of a D/C/F/TAF FDC tablet. The results indicated that the D/C/F/TAF 25 mg 
tablet formulations provided TAF exposures in a range associated with antiviral activity 
(GS-US-120-0104) and consistent with the findings from study GS-US-311-0101 (Cohorts 2 and 
3), where DRV/COBI was coadministered with FTC/TAF (25 mg). The pharmacokinetic data 
also demonstrated achievement of TAF exposures that were associated with potent antiviral 
activity with the D/C/F/TAF 10 mg (monolayer formulation) tablet, and moreover TFV 
exposures with this formulation were in the range of historical data with TAF 25 mg dosed alone 
or with the E/C/F/TAF 10 mg tablet. In addition, administration of the D/C/F/TAF 10 mg tablet
resulted in ~90% lower steady-state TFV exposure versus COBI-boosted DRV plus FTC/TDF. 
Exposures of COBI-boosted DRV and FTC were comparable when administered as a single
tablet (D/C/F/TAF) or as individual components. Study GS-US-299-0101 also evaluated the 
relative bioavailability of DRV, COBI, FTC, and TFV when administered as COBI-boosted 
DRV plus FTC/TDF relative to the administration of the individual components. Results showed 
that the exposures of all analytes were similar between both treatments.
Thus, cumulative results from GS-US-120-0104, GS-US-311-0101 and GS-US-299-0101 were 
used in selecting a 10 mg TAF dose for subsequent clinical development of the D/C/F/TAF 
tablet.
4.
SUBJECT POPULATION
Approximately 1,100 subjects will be randomized in a 2:1 ratio to 1 of the 2 treatment arms. 
Assuming a screening failure rate of 20%, approximately 1,375 subjects need to be screened to 
achieve 1,100 subjects randomized. All screened eligible subjects may be randomized and 
participate in the study.
Screening for eligible subjects will be performed within 30 days before administration of the 
study drug. Signing of the ICF needs to be done before the first study-related activity. 
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study. No exemptions or waivers related to inclusion or exclusion criteria will be granted.
For a discussion of the statistical considerations of subject selection, see Section 11.2.
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4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
The ability to understand and sign a written ICF, which must be obtained prior to initiation 
of study procedures. 
2.
Currently being treated with a stable ARV regimen consisting of a bPI (limited to DRV 
once daily with rtv or COBI, ATV with rtv or COBI, or LPV with rtv) combined with 
FTC/TDF only, for at least 6 consecutive months preceding the screening visit.
Subjects treated with the combination DRV + COBI + FTC/TDF and having completed the 
required visits in the GS-US-216-0130 study, and who are fulfilling the present protocol 
criteria, will be given the option to participate in this study.
Note: A change in pharmacokinetic booster (ie, rtv or COBI) will be allowed provided 
such a switch occurred no less than 1 month prior to the screening visit.
3.
Documented evidence of being virologically suppressed while on a stable ARV regimen
prior to screening: at least 1 plasma HIV-1 RNA measurement <50 copies/mL (or HIV-1 
RNA undetectable by a local HIV-1 RNA test) occurring between 12 and 2 months prior to 
the screening visit while on the stable 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 (‘blip’) within 12 months prior to screening is 
allowed, provided a subsequent viral load measurement is <50 HIV-1 RNA copies/mL
(or HIV-1 RNA undetectable by a local HIV-1 RNA test) prior to screening.
4.
Screening eGFRcr ≥50 mL/min according to the Cockcroft-Gault formula for creatinine 
clearance.11
5.
Absence of history of failure on DRV treatment and absence of DRV RAMs (including 
V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V), if documented 
historical genotypes are available.
-
If no historical genotype is available, the subject can be included, provided no previous 
failure on DRV treatment has been documented. 
6.
Normal ECG at screening (or if abnormal, determined by the investigator to be not 
clinically significant).
7.
Screening hepatic transaminases (alanine aminotransferase [ALT] and AST) ≤5 x upper
limit of the normal range (ULN). 
8.
Screening direct bilirubin ≤1.5 x ULN. 
-
Subjects with documented Gilbert's Syndrome or hyperbilirubinemia due to ATV 
therapy may have total bilirubin up to 5 x ULN.
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9.
Adequate hematologic parameters at screening: platelets ≥50,000/µL, hemoglobin 
≥8.5 g/dL, absolute neutrophil count ≥1,000/µL. 
10.
Screening serum amylase ≤2 x ULN (subjects with serum amylase >2 x ULN will remain
eligible if serum lipase is ≤2 x ULN). 
11.
Women of childbearing potential must agree to practice sexual abstinence or use adequate 
reliable contraceptive methods as per local regulations and as per applicable Prescribing 
Information guidance, from screening until 90 days after end of treatment (EOT) (or 
longer, if dictated by local regulations). The investigator will counsel subjects on the use of 
contraceptive methods to avoid pregnancy.
-
Women receiving oral contraceptives or patch contraceptives should consider other 
methods of contraception (see also Section 8.1).
-
Women who are not heterosexually active must have periodic confirmation of 
continued abstinence from heterosexual intercourse and have regular pregnancy testing 
while taking study drugs; the investigator should counsel subjects on adequate reliable 
contraceptive methods for avoiding pregnancy if they choose not to continue 
abstinence. 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 throughout the study.
-
The use of birth control methods does not apply if the male partner has been 
vasectomized minimally 2 months prior to screening. 
-
The use of birth control methods does not apply for women of nonchildbearing 
potential, ie:
o
who have been postmenopausal for at least 2 years; medical documentation 
of cessation of menses for at least 2 years and of hormonal ovarian failure 
(follicle-stimulating hormone [FSH] level ≥40 mIU/mL) is required.
o
who are surgically sterile (have had a total hysterectomy or bilateral 
oophorectomy, tubal ligation/bilateral tubal clips without reversal operation, 
or otherwise are incapable of becoming pregnant).
12.
Men with a female partner of childbearing potential must agree to use adequate reliable 
contraceptive methods (see also Inclusion Criterion 11) during the study until 90 days after 
EOT (or longer, if dictated by local regulations). 
-
Men who have had a vasectomy without reversal operation minimally 2 months prior 
to screening are not required to use birth control methods.
-
For all male subjects, it is the responsibility of the subject to ensure that his partner(s) 
do(es) not become pregnant during treatment with the tested study treatment and for up 
to 90 days after EOT.
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13.
Men must agree not to donate sperm during the study until 90 days after EOT (or longer, if 
dictated by local regulations).
14.
Able to swallow tablets.
15.
Age at least 18 years.
16.
Having documented HIV-1 infection.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
A new AIDS-defining condition diagnosed within the 30 days prior to screening.
2.
Proven or suspected acute hepatitis within 30 days prior to screening.
3.
Hepatitis C antibody positive; however, subjects spontaneously cured of hepatitis C virus 
(HCV) infection and subjects cured of HCV infection after treatment (with documented 
sustained virologic response, ie, undetectable HCV RNA 24 weeks after the last dose of 
HCV treatment), are allowed to participate.
4.
Hepatitis B surface antigen (HBsAg) positive.
5.
Subjects with history of cirrhosis as diagnosed based on local practices. 
6.
Women who are breastfeeding. 
7.
Positive serum pregnancy test. 
8.
Current alcohol or substance use judged by the investigator to potentially interfere with 
subject study adherence. 
9.
History of malignancy within the past 5 years or ongoing malignancy other than cutaneous 
Kaposi’s sarcoma, basal cell carcinoma, resected, noninvasive cutaneous squamous 
carcinoma, or anal, cervical, or penile intra-epithelial neoplasia. 
10.
Active, severe infections (other than HIV-1 infection) requiring parenteral antibiotic or 
antifungal therapy within 30 days prior to baseline. 
11.
Any other clinical condition or prior therapy that, in the opinion of the investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements.
12.
Subject unlikely to comply with the protocol requirements, based on clinical judgment.
13.
Participation in any other clinical study without prior approval from the sponsor.
14.
Subjects receiving therapy with any of the drugs in Table 1, or with drugs not to be used 
with DRV, COBI, FTC, TAF, and TDF (see also Table 2 or the individual agents local 
NCT02269917

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Approved, Date: 29 May 2015
Prescribing Information), and for whom it is impossible to have these discontinued at least 
30 days prior to baseline.
15.
Subjects with any known allergies to the excipients of the D/C/F/TAF tablet.
16.
Subjects whom's clinical status changed (including available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given 
such that he or she no longer meets all eligibility criteria.
Table 1:
Exclusionary Concomitant Medications With the D/C/F/TAF Tablet
Drug Class
Agents Disalloweda,b
Alpha adrenergic receptor antagonists
Alfuzosin
Analeptics
Modafenil
Anti-anginals
Ranolazine
Anti-arrhythmics
Amiodarone, Quinidine, Dronedarone, systemic Lidocaine (IV or 
IM) used as anti-arrhythmic
Anticoagulants
Rivaroxaban, Apixaban, Dabigatran etexilate
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Anti-HCV drugs
Telaprevir, Boceprevir, Simeprevir, fixed dose combination tablet 
containing Ombitasvir, Paritaprevir, and Ritonavir copackaged 
with Dasabuvir
Antigout
Colchicine (in patients with renal or hepatic impairment)
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Antineoplastics
Everolimus
Antipsychotics/Neuroleptics
Pimozide, Quetiapine, Sertindole
Antiretrovirals
Any antiretroviral drug that is not part of the study regimen
Calcium channel blockers
Bepridil
Corticosteroids: systemic
All agents, including dexamethasone with the exception of short-
term (less than 1 week) use of prednisone as a steroid burst
Endothelin receptor antagonists
Bosentan
Ergot derivatives
Ergotamine, Ergonovine, Dihydroergotamine, 
Methylergonovine, Ergometrine
Gastrointestinal motility agents
Cisapride
Herbal supplements
St. John’s Wort, Echinacea
HMG-CoA reductase inhibitors
Simvastatin, Lovastatin
Immunosuppressants
Everolimus
Inhaled beta agonists
Salmeterol
Phosphodiesterase (PDE)-5 inhibitors
Avanafil, Use of any other PDE-5 inhibitor in the 
treatment of pulmonary arterial hypertension
Platelet aggregation inhibitor
Ticagrelor
Sedatives/Hypnotics
Midazolam (oral), Triazolam; 
with the exception of one-time use for procedures
a
Administration of any of the above medications must have been discontinued at least 30 days prior to baseline 
(Day 1) and for the duration of the study. If such discontinuation of treatment is not clinically acceptable, the 
subject should not be allowed to participate in the study.
b
This list of disallowed medication may not be exhaustive. Refer to the local Prescribing Information for these 
medications, where available, for additional and up to date information.
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4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
All HIV-infected subjects should be advised to take the necessary precautions to reduce the 
risk of transmitting HIV.
2.
Since reproductive risks have been noted with some HIV-1 ARVs, non-vasectomized 
heterosexually active males and/or females of childbearing potential having heterosexual 
intercourse must agree to use a highly effective method of birth control (see Section 4.1 for 
details).
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation - Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomized in a 2:1 
ratio to the investigational treatment arm (switch to D/C/F/TAF tablet), or the control arm 
(maintain current regimen consisting of a bPI combined with FTC/TDF only) (for details on 
dosage and administration, see Section 6).
Randomization will be stratified by bPI used at screening (DRV once daily with rtv or COBI, 
ATV with rtv or COBI, LPV with rtv) (see also Section 3.2.1). Randomization will be based on a 
computer-generated schedule, constructed via random permuted blocks to ensure balance across 
treatment groups in each stratum of the stratification factors, and prepared before the start of the 
study by or under the supervision of the sponsor.
It is the responsibility of the investigator to ensure that the subject is eligible for the study prior 
to enrollment. Subjects will be assigned a unique subject number at the time of screening, using 
the Interactive Web Response System (IWRS). Once a subject number has been assigned to a 
subject, it will not be reassigned to any other subject. 
The randomization and baseline visit (Day 1) cannot proceed until the investigator has received
all results of the screening visit and subject eligibility has been confirmed in IWRS, which 
should occur within approximately 30 days after the screening visit (for further details, see 
Section 9.1.2.1). Randomization should be performed on the same day as the baseline visit
(Day 1), provided that all screening procedures have been completed and subject eligibility has 
been confirmed.
Both the investigator and the subject will know to which treatment arm the subject is 
randomized.
The IWRS will assign open-label kit numbers at each study visit (except Week 2, when no 
medication will be assigned). Study drug will be dispensed to the subject in an open-label 
fashion. All baseline (Day 1) tests and procedures must be completed prior to the administration 
of the first dose of investigational drug. Initiation of treatment with the investigational drug must 
take place within 24 hours after the baseline visit.
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Blinding
As this is an open-label study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
From screening up to the baseline visit (Day 1) (approximately 30 days), subjects will continue 
their current bPI-based ARV regimen with FTC/TDF.
Prior to or at the baseline visit (see Section 5), eligible subjects will be randomized in a 2:1 ratio
to the investigational treatment arm (D/C/F/TAF tablet) or the control arm (maintain current 
regimen consisting of a bPI with FTC/TDF) (see also Figure 1).
-
D/C/F/TAF Arm: Switch to regimen of a single FDC tablet containing DRV 800 mg/ COBI 
150 mg/ FTC 200 mg/ TAF 10 mg (D/C/F/TAF tablet) once daily;
-
Control Arm: 
Continue current regimen consisting of a bPI combined with FTC/TDF
only.
Initiation of treatment with the investigational drug can start after all baseline tests and 
procedures have been completed and must take place within 24 hours after the baseline visit. 
The investigational medication, D/C/F/TAF tablets, will be administered orally, once daily with 
food, at approximately the same time each day. If the regular dosing time coincides with the 
study visit, study drugs can be taken on site with food during all visits up to Week 48 after all 
laboratory assessments which require fasting are performed. If subjects notice that they missed a 
medication intake and it is still within 12 hours of their regular dosing time, they should take the 
medication immediately with food. Subjects can then continue their usual dosing schedule. If 
subjects notice that they missed their 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. Subjects 
should not take a double dose to make up for a missed dose. Prolonged temporary study 
treatment interruptions are only deemed acceptable if motivated by safety reasons and do not last 
longer than 4 consecutive weeks. The sponsor should be notified if such temporary interruption 
occurs.
Study-site personnel will instruct subjects on how to store investigational drug for at-home use as
indicated for this protocol.
In the control arm, the following boosted PIs are allowed: DRV once daily with rtv or COBI, 
ATV with rtv or COBI, LPV with rtv. Only FTC/TDF can be used in combination with the bPI; 
no other other HIV-1 ARVs are allowed.
The bPI and FTC/TDF in the control arm should be used in the dosing schedule specified in the 
ARV agent's local Prescribing Information. Applicable procedures and treatment guidance based 
on the Prescribing Information should be respected. If a subject accidentally misses a scheduled 
dose of any of the selected ARVs, the investigator should advise according to the Prescribing 
Information in the individual package inserts.
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If the conditions are fulfilled to enter the extension phase, subjects from the D/C/F/TAF arm will 
enter in the extension phase once they have completed their Week 48 visit until Week 96, and
subjects in the control arm will receive the D/C/F/TAF as from completion of the switch visit at 
Week 52 until Week 96. In order to collect long-term safety and efficacy data on D/C/F/TAF, all 
subjects will be given the opportunity to receive D/C/F/TAF after Week 96 until it becomes 
commercially available and is reimbursed, or can be accessed through another source in the 
country where he/she is living, or until the sponsor terminates clinical development.
7.
TREATMENT COMPLIANCE
Adherence to study medication intake (investigational medication and ARVs in the control arm) 
will be assessed by pill counts. For this purpose, subjects will be requested to bring unused 
medication and empty packaging to the study site at each visit, and the amount of study drug 
dispensed will be compared with the amount returned. 
The investigator or designated study personnel will maintain a log of all study drugs 
(investigational medication and ARVs in the control arm) dispensed and returned. Drug supplies 
for each subject will be inventoried and accounted for throughout the study (see also 
Section 14.5). 
In addition, adherence to study medication (investigational medication and ARVs in the control 
arm) intake will be monitored by the investigator using study medication log booklets. At the
baseline visit (Day 1), subjects will be given a study medication log booklet, in which they are to 
record their missed study medication intakes. Subjects should be instructed to bring their log
booklet at each visit, and these will be checked and discussed with the subject by the investigator 
or designated study personnel at each visit.
If a subject’s medication intake is not according to the protocol, it will be the investigator’s 
responsibility to take the necessary measures to ensure future compliance to the protocol.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapies administered up to 30 days before first dose of study drug must be recorded at
screening.
All therapies (prescriptions or over-the-counter medications, including vitamins and herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) continued at the start of the study or started during the study and 
different from the investigational medication (D/C/F/TAF tablet, or ARVs in the control arm) 
must be recorded in the concomitant therapy section of the electronic case report form (eCRF). 
Reported information will include a description of the type of the drug, treatment period, 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 subject into the study if such 
modification of treatment is not clinically acceptable. Any change in dosage of the medication 
must also be reported in the eCRF.
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For any concomitant therapy given as a treatment for a new condition or a worsening of an 
existing condition occurring after signing the ICF, the condition must be documented in the 
AE/HIV-related event section of the eCRF.
Data on concomitant medication will be collected up to the last study visit, even after withdrawal 
of a subject. Concomitant therapies should be recorded beyond the last study visit only in 
conjunction with SAEs that meet the criteria outlined in Section 12.4.2.
8.1.
Disallowed and Cautioned Concomitant Therapy
Females of childbearing potential must use effective birth control methods (as outlined in 
Section 4.1, see also Section 4.3) during the entire study and for at least 90 days after the last 
intake of study medication. Subjects receiving oral contraceptives or patch contraceptives should 
consider other methods of contraception, as concentrations of ethinyl estradiol, norgestimate or 
norethindrone may increase or decrease on coadministration with the investigational medication. 
The use of any oral, injectable and implantable hormonal contraceptives should be recorded in 
the concomitant therapy section of the eCRF. Applicable procedures and treatment guidance 
based on package inserts should be respected.
Because the concomitant use of some medications or herbal supplements may result in altered 
exposure to the investigational medication or the concomitant medication, due to 
pharmacokinetic interactions, certain medications or supplements are excluded or are to be used 
with caution while taking the D/C/F/TAF tablet. Guidance on dose adjustments for these 
concomitant medications, if applicable, is provided in Table 2. 
For the allowed ARVs in the control arm, see Section 6. Refer to the current individual agents
local Prescribing Information of the continued bPI and FTC/TDF 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.
Should a subject have a need to initiate treatment with any excluded concomitant medication, the 
sponsor’s medical monitor must be consulted beforehand. If an excluded medication is initiated 
prior to discussion with the medical monitor, the investigator must notify the sponsor as soon as 
becoming aware.
Table 2:
Concomitant Therapy: Disallowed and Cautioned Use With the D/C/F/TAF Tablet
Drug Class
Agents Disalloweda
Use Discouraged or 
to be Used With Cautiona
Alpha adrenergic receptor
antagonist
Alfuzosin
Analeptic
Modafinil
Analgesics
Tramadol, Propoxyphene: Concentrations 
may increase with study drug(s); clinical 
monitoring is recommended.
Anti-anginals
Ranolazine
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Drug Class
Agents Disalloweda
Use Discouraged or 
to be Used With Cautiona
Anti-arrhythmics
Amiodarone, Quinidine, 
Dronedarone, systemic Lidocaine
(IV or IM) used as anti-
arrhythmic
Flecainide, Propafenone, Mexilitine, 
Digoxin Disopyramide: Concentrations may 
increase with study drug(s) resulting in a 
potential for cardiac arrhythmias; caution is 
warranted and therapeutic drug monitoring 
of antiarrhythmics is recommended 
when available.
The lowest dose of Digoxin should be 
administered and dose should be titrated. 
Serum digoxin concentrations should be 
monitored to assist in the titration.
Antibacterials
Concentrations of telithromycin may 
increase with study drug(s). Clinical 
monitoring is recommended.
Clarithromycin: Concentrations may 
increase with study drug(s); consider an 
alternative; if coadministration cannot be 
avoided, consult the local Prescribing 
Information for further dosing 
recommendations.
Anticoagulants
Rivaroxaban, Apixaban, 
Dabigatran etexilate
Warfarin: Concentrations may be affected 
by study drug(s); frequent international 
normalized ratio (INR) monitoring is 
recommended.
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Clonazepam, Ethosuximide, Concentrations 
may increase with study drug(s). 
Divalproex, Lamotrigine: Concentrations 
may be affected by study drug(s). Clinical 
monitoring is recommended.
Antidepressants
Bupropion: Concentrations may be affected 
by study drug(s). Subjects receiving 
bupropion should be monitored for adequate 
clinical response. 
Selective serotonin reuptake inhibitors, eg, 
Trazodone, Paroxetine, Sertraline: A dose 
reduction may be required. Dosing should 
be titrated in conjunction with clinical 
monitoring.
Tricyclics: Concentrations may increase 
with study drug(s). Concentration 
monitoring is recommended to ensure 
adequate clinical response. 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
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Drug Class
Agents Disalloweda
Use Discouraged or 
to be Used With Cautiona
Antigout
Colchicine (in patients with renal 
or hepatic impairment)
Colchicine: Concentrations may increase 
with study drug(s). Dose reductions of 
colchicine may be required. 
Treatment for gout-flare: 0.6 mg (1 tablet) 
x 1 dose, followed by 0.3 mg (half tablet) 
1 hour later. Treatment course to be 
repeated no earlier than 3 days. 
Prophylaxis of gout-flare: If the original 
regimen was 0.6 mg twice daily, the 
regimen should be adjusted to 0.3 mg once 
daily. If the original regimen was 0.6 mg 
once daily, the regimen should be adjusted 
to 0.3 mg once every other day. 
Treatment of familial Mediterranean fever: 
Maximum daily dose of 0.6 mg (may 
be given as 0.3 mg twice daily).
Antifungals
Ketoconazole, Fluconazole, Posaconazole, 
Itraconazole: Concomitant use with 
study drug(s) may result in an increase in 
concentrations. Daily dose of ketoconzazole 
and itraconazole should be restricted 
to 200mg. 
Voriconazole: Plasma concentrations 
may be increased or decreased in 
the presence of DRV/COBI, and should 
not be administered unless an assessment 
of the benefit/risk ratio justifies the use. 
Subjects receiving antifungals should be 
monitored for adequate clinical response.
Note: topical administration of antifungals 
is allowed.
Anti-HCV drugs
Telaprevir, Boceprevir, 
Simeprevir, fixed dose 
combination tablet containing 
Ombitasvir, Paritaprevir, and 
Ritonavir copackaged with 
Dasabuvir
Sofosbuvir, Ledipasvir, Daclatasvir
Antihistamines
Astemizole, Terfenadine
Antimalarials
Artemether/Lumefantrine: Use with caution.
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Antineoplastics
Everolimus
Dasatinib, Nilotinib, Vinblastine, 
Vincristine: Caution should be exercised. 
Antipsychotics/Neuroleptics
Pimozide, Quetiapine, Sertindole
Perphenazine, Risperidone, Thioridazine: A 
dose decrease may be needed.
Antiretrovirals
Any ARV drug that is not part of 
the study regimen
β-Blockers
Carvedilol, Metoprolol, Timolol: 
Clinical monitoring is recommended 
when coadministering β -blockers and 
a lower dose of the β -blocker should 
be considered.
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Clinical Protocol TMC114IFD3013 Amendment 4
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Drug Class
Agents Disalloweda
Use Discouraged or 
to be Used With Cautiona
Calcium channel blockers
Bepridil
Felodipine, Nifedipine, Nicardipine, 
Verapamil, Diltiazem, Amlodipine: 
Concentrations may increase with study 
drug(s). Caution is warranted and careful 
clinical monitoring is recommended.
Contraceptives
Ethinylestradiol, Norethindrone, 
Norgestimate: Concentrations of 
contraceptives may decrease or increase 
with study drug(s). Alternative methods 
of nonhormonal contraception 
are recommended.
Corticosteriods: inhaled/nasal
Concomitant use of inhaled fluticasone 
and study drug(s) may increase plasma 
concentrations of fluticasone and/or 
decrease concentrations of COBI and/or 
DRV. Alternatives should be considered, 
particularly for long term use.
Corticosteroids: systemic
All agents, including 
dexamethasone with the 
exception of short term (less than 
1 week) use of prednisone as a 
steroid burst
Use of Prednisone as a steroid burst 
(maximum 1 week of use) should be 
monitored appropriately.
Endothelin receptor antagonists
Bosentan
Ergot derivatives
Ergotamine, Ergonovine, 
Dihydroergotamine, 
Methylergonovine, Ergometrine
Gastrointestinal motility agents
Cisapride
Herbal/Natural supplements
St. John’s Wort, Echinacea
HMG-CoA reductase inhibitors
Simvastatin, Lovastatin
Atorvastatin, Rosuvastatin, Pravastatin: 
Concentrations may increase with study 
drug(s). Titrate atorvastatin, pravastatin 
or rosuvastatin dose carefully and use 
the lowest necessary dose while 
monitoring for safety. 
Pitavastatin: Caution should be exercised 
when coadministering pitavastatin.
Immunosuppressants
Everolimus
Cyclosporine, Sirolimus, Tacrolimus: 
Concentrations may increase with study 
drug(s). Therapeutic monitoring should be 
considered. 
Inhaled beta agonist
Salmeterol
Opiates
Methadone: Concentrations may increase 
with study drug(s). Concentration 
monitoring is recommended to ensure 
adequate clinical response; a methadone 
dose adjustment may be required.
Buprenorphine/Naloxone: Concentrations of 
buprenorphine or its active metabolite may 
be affected by study drug(s). Careful clinical 
monitoring is recommended.
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Drug Class
Agents Disalloweda
Use Discouraged or 
to be Used With Cautiona
PDE-5 inhibitors
Avanafil, Use of any other PDE-5 
inhibitor in the treatment of 
pulmonary arterial hypertension
Sildenafil, Vardenafil, Taladafil: It is 
recommended that a single dose of 
Sildenafil ≤25 mg in 48 hours, Vardenafil 
≤2.5 mg in 72 hours, or Taladafil ≤10 mg 
in 72 hours be coadministered.
Platelet aggregation inhibitor
Ticagrelor
Sedatives/Hypnotics
Midazolam (oral), Triazolam; 
with the exception of one-time 
use for procedures
Buspirone, Clorazepate, Diazepam, 
Estazolam, Flurazepam, Zolpidem: A dose 
decrease may be needed for these drugs.
Coadministration of parenteral midazolam 
should be done in a setting that ensures 
close clinical monitoring and appropriate 
medical management in case of respiratory 
depression and/or prolonged sedation. Dose 
reduction for parenteral midazolam should 
be considered, especially if more than a 
single dose of midazolam is administered.
a
This list of disallowed concomitant medication or concomitant medications with specific precautions may not be 
exhaustive. Refer to the current local Prescribing Information for these medications, where available for 
additional and up to date information.
9.
STUDY EVALUATIONS
The Time and Events Schedule summarizes the timing of efficacy, safety, and pharmacokinetic 
measurements applicable to this study. The protocol procedures are described in detail in 
Sections 9.1.2 through 9.6.
9.1.
Study Procedures by Visit
9.1.1.
Overview
It is the responsibility of the investigator to follow the screening procedures and ensure that each 
subject is eligible for the study before enrollment. Please see Sections 5 and 6 for details on
randomization and assigned treatment, and Section 9.1.2 for details on pretreatment procedures. 
Following the baseline visit (Day 1), subjects will return for study visits at the end of Weeks 2, 4, 
8, 12, 24, 36, and 48. All study visits are to be scheduled relative to the baseline visit date. Some 
flexibility in the planning of the visits is allowed, however, the total treatment duration at the end 
of the treatment period should be 48 weeks. The study visit at Week 2 is to be completed within 
±2 days of the protocol-specified visit date based on the baseline visit. The study visits through 
Week 48 are to be completed within ±7 days of the protocol-specified visit date. For further 
details, see Section 9.1.3.
Provided results from the DMC analyses or Week 24 interim analysis does not preclude (further) 
exposing subjects to D/C/F/TAF, subjects from the D/C/F/TAF arm will enter in the extension 
phase once they have completed their Week 48 visit. In addition, subjects in the control arm will 
receive the D/C/F/TAF tablet in the extension phase if, according to the investigator they will 
benefit from it and if all conditions are fulfilled (which includes adequate viral load results). 
Subjects from the control arm will be required to attend a switch visit at Week 52 to receive 
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D/C/F/TAF. All subjects in the extension phase will have to attend visits every 12 weeks up to 
Week 96. As from Week 96, all subjects are offered the possibility to continue D/C/F/TAF 
treatment, if they wish and if they continue to benefit from it, until D/C/F/TAF becomes 
commercially available and is reimbursed, or can be accessed through another source in the 
country where he/she is living, or until the sponsor terminates clinical development. After Week 
96, subjects should attend visits every 6 months. These study visits should be completed within 
±7 days of the protocol-specified visit date. For further details, see Section 9.1.4.
Subjects who prematurely discontinue or change study treatment during the treatment phase 
(from Day 1 to Week 48) or during the extension phase (only between Week 48 and 96) will be 
required to complete the ESTD visit assessments within 72 hours of stopping/changing study 
treatment. 
In addition, a 30-day FU visit will be required for any subject who has an ongoing AE or SAE at 
the time of his/her last study visit (unless consent is withdrawn) and must be scheduled within 
±7 days of the protocol-specified visit date (for further details, see Section 9.1.5.2).
For laboratory assessments that need to be performed fasted (no food or drinks, except water, for 
at least 8 hours prior to blood or urine collection) while the subject has not fasted prior to the 
visit, the visit may proceed, but the subject must return within 72 hours in a fasted state to 
provide the necessary sample(s) for the assessments.
9.1.1.1.
Sample Collection and Handling
Refer to the Time and Events Schedule for the planned timing and frequency of all sample 
collections. The actual dates and times of sample collection must be recorded in the eCRF or 
laboratory requisition form. 
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided.
The total blood volume to be collected from each subject in the treatment phase of this study 
(from screening through Week 48 visit in the controlled treatment period) is approximately 
310 mL. The blood volume per visit in the extension phase will be approximately 37 mL. 
Repeat or unscheduled blood samples may be taken for safety reasons or for technical issues 
with the samples. 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 throughout the study. Findings during these unscheduled visits or assessments need to 
be reported in the eCRF.
A portion of the plasma samples drawn from all visits (except the screening visit and 
unscheduled visits) will be frozen and stored. These stored samples may be used by the sponsor 
or its research partners for HIV-1 genotyping/phenotyping assays, for retesting the amount of 
HIV-1 in the blood, for measurement of antiviral drug levels in the blood, clinical laboratory 
testing to provide additional safety data, additional pharmacokinetic testing, or future testing to 
learn more about how the investigational drug has worked against HIV-1. No human genetic 
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testing will be performed. See also Section 16.2.5.
9.1.2.
Pretreatment Assessments
9.1.2.1.
Screening Visit
Subjects will be screened within 30 days before randomization to determine eligibility for 
participation in the study. The screening period may be extended on a case-by-case basis after 
discussion and approval by the sponsor. However, no extensions beyond 6 weeks will be 
allowed. The following evaluations will be performed and documented at screening.

Obtain written informed consent.

Obtain medical history including history of HIV-1 disease-related events and prior 
medications within 30 days of the screening visit.

Complete physical examination (urogenital/anorectal examinations will be performed at the 
discretion of the investigator).

Vital signs measurement (blood pressure and pulse) and weight.

12-lead ECG performed supine.

Height.

Midstream urine sample collection for the following laboratory procedures:
-
Urine chemistry (quantitative measurement): creatinine, sodium, phosphate, glucose, 
protein, albumin.
-
Urinalysis by dipstick: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, and leukocyte esterase.

Blood sample collection for the following laboratory analyses:
-
Serum pregnancy test (females of childbearing potential only). If the test is positive, the 
subject will not be enrolled. 
-
FSH test is required for female subjects who have stopped menstruating for at least 
2 years but do not have documentation of ovarian hormonal failure.
-
Chemistry profile: alpha 1-acid glycoprotein (AAG), alkaline phosphatase (ALP), AST, 
ALT, gamma-glutamyl transferase (GGT), total bilirubin, direct and indirect bilirubin, 
total protein, albumin, creatine phosphokinase (CPK), bicarbonate, blood urea nitrogen 
(BUN), chloride, creatinine, glucose, phosphorus, potassium, sodium, uric acid, and 
amylase (reflex lipase testing is performed in subjects with total amylase >1.5 x ULN).
-
Cystatin C and eGFRcyst according to the CKD-EPI formula.
-
eGFRcr ≥50 mL/min according to the Cockcroft-Gault formula for creatinine clearance; 
for details, see Section 9.5.4.
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-
Hematology profile: hemoglobin, hematocrit, red blood cell (RBC) count and 
parameters (mean corpuscular hemoglobin [MCH], MCH concentration and mean 
corpuscular volume [MCV]), white blood cell (WBC) count with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelet count.
-
CD4+ cell count.
-
Plasma HIV-1 RNA.
-
HBV and HCV testing (HBsAg, HCV antibody, and HCV RNA).

Review of AEs and concomitant medications.
Retesting of abnormal laboratory values that may lead to exclusion will be allowed once. 
Retesting will take place during an unscheduled visit in the screening period. The investigator 
may consider the subject eligible if the previously abnormal laboratory test result is within 
protocol acceptable range on a repeat testing in the central laboratory.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days after the screening visit for the baseline (Day 1) assessments. Subjects must 
continue to take their prior ARV treatment regimen up until their scheduled baseline visit.
9.1.2.2.
Baseline Visit (Day 1)
The investigator must have received all results from the screening visit before proceeding with 
the baseline visit. Once eligibility has been confirmed, the investigator will randomize the 
subject using IWRS prior to or during the baseline visit. The subject must complete all baseline 
procedures before being dispensed the study drug. The following procedures are to be completed 
and documented at the baseline visit.

Review of AEs and changes in concomitant medications.

Complete physical examination (urogenital/anorectal examinations will be performed at the 
discretion of the investigator).

Vital signs measurement (blood pressure and pulse) and weight.

Midstream urine sample collection for the following laboratory procedures:
-
Urinalysis and urine chemistry (see also Section 9.1.2.1).
-
Urine renal biomarkers (fasted, ie, no food or drinks, except water, at least 8 hours prior 
to urine collection): RBP and beta-2-microglobulin. If the subject has not fasted prior to 
the visit, the visit may proceed, but the subject must return within 72 hours in a fasted 
state to provide a urine sample for renal biomarkers.
-
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy 
test is positive at baseline, study drug will not be dispensed. The positive result will be 
confirmed with a serum pregnancy test. If the serum pregnancy test is positive, the 
subject will not be able to participate.
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
Blood sample collection for the following laboratory analyses:
-
Chemistry profile (see also Section 9.1.2.1). At baseline, glucose will be performed as 
part of the metabolic profile.
-
Metabolic profile (collected fasted): total, high-density lipoprotein (HDL) and low-
density lipoprotein (LDL) cholesterol, triglycerides, glucose. If the subject has not 
fasted prior to the visit, the visit may proceed, but the subject must return within 
72 hours in a fasted state to have a blood draw for the metabolic assessments. 
-
Cystatin C and eGFRcyst according to the CKD-EPI formula.
-
eGFRcr according to the Cockcroft-Gault formula and the CKD-EPI formula; for 
details, see Section 9.5.4.
-
Hematology profile.
-
Plasma HIV-1 RNA.
-
CD4+ cell count.
-
Plasma storage samples for possible additional testing.
-
PBMC storage sample that will only be analyzed if deemed necessary by the study
virologist to characterize archived viral resistance.

Study drug dispensation (D/C/F/TAF or bPI + FTC/TDF) in an open-label fashion:
-
Subjects in the investigational treatment arm must initiate dosing with D/C/F/TAF 
within 24 hours after the baseline visit.
-
Subjects in the control arm should be instructed to continue their current regimen 
consisting of a bPI + FTC/TDF.
-
Subjects should be counseled regarding the importance of adherence, and be instructed 
to bring unused medication and empty packaging to the unit at each visit. 

Dispensation of the study medication log booklet, in which subjects should record their 
missed study medication intakes. Subjects should also be instructed to bring their log booklet
at each study visit.
In subjects participating in the bone investigation substudy:

Bone biomarkers (collected fasted, ie, no food or drinks, except water, at least 8 hours prior 
to sample collection): C-type collagen sequence (CTX), procollagen type 1 N-terminal 
propeptide (P1NP), parathyroid hormone (PTH), and 25-hydroxy vitamin D. If the subject 
has not fasted prior to the visit, the visit may proceed but the subject must return within 
72 hours in a fasted state to provide a blood sample for bone biomarker assessment.

DXA scan of spine and hip: The scan is to be performed between the screening and the 
baseline visit (a window of +2 weeks is allowed) as long as eligibility has been confirmed. A 
rescan for technical reasons is allowed within 2 weeks.
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9.1.3.
Treatment Period
After the baseline visit, subjects will return for study visits at the end of Weeks 2, 4, 8, 12, 24, 
36, and 48 (scheduled relative to the baseline visit date). The time window for the Week 2 visit is 
±2 days, and for the visits through Week 48 is ±7 days of the protocol-specified visit date. The 
total treatment duration at the end of the treatment period should be 48 weeks. The following 
procedures are to be completed and documented at each visit.

Review of AEs and changes in concomitant medications.

Complete physical examination at Weeks 24 and 48 (urogenital/anorectal examinations will 
be performed at the discretion of the investigator).

Symptom-directed physical examination (physical examination of body parts for which 
symptoms have been reported by the subject) as needed at Weeks 2, 4, 8, 12, and 36.

Vital signs measurement (blood pressure and pulse) and weight.

Midstream urine sample collection for the following laboratory procedures:
-
Urinalysis and urine chemistry (see also Section 9.1.2.1).
-
Urine renal biomarkers (fasted, ie, no food or drinks, except water, at least 8 hours prior 
to urine collection; if the subject has not fasted prior to the visit, the visit may proceed, 
but the subject must return within 72 hours in a fasted state to provide a urine sample 
for renal biomarkers) at Weeks 2, 4, 12, 24, and 48 (see also Section 9.1.2.2).
-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confirmed with a serum test; if this test is positive, the subject will be 
withdrawn (see also Section 12.4.3).

Blood sample collection for the following laboratory analyses:
-
Chemistry profile (see also Section 9.1.2.1). At Weeks 24 and 48, analysis of glucose 
will be done as part of the fasting metabolic profile and not as part of the chemistry 
profile.
-
Metabolic profile (including glucose; collected fasted; if the subject has not fasted prior 
to the visit, the visit may proceed, but the subject must return within 72 hours in a fasted 
state to have a blood draw for the metabolic assessments) at Weeks 24 and 48 (see also 
Section 9.1.2.2).
-
Cystatin C and eGFRcyst according to the CKD-EPI formula.
-
eGFRcr according to the Cockcroft-Gault formula, and the CKD-EPI formula (for 
details, see Section 9.5.4).
-
Hematology profile (see also Section 9.1.2.1).
-
Plasma HIV-1 RNA.
-
CD4+ cell count.
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Clinical Protocol TMC114IFD3013 Amendment 4
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-
Blood sample for HIV-1 resistance testing. For subjects with confirmed HIV-1 RNA
≥50 copies/mL and a HIV-1 RNA value ≥400 copies/mL, HIV-1 genotypic resistance
test will be performed; phenotypic resistance test may be done upon request of the study 
virologist.
-
Plasma storage sample for possible additional clinical testing.
-
PBMC storage sample at Weeks 24 and 48, which will only be analyzed if deemed 
necessary by the study virologist to characterize archived viral resistance.

Pharmacokinetic sample collection for D/C/F/TAF arm only:
-
Blood samples will be collected at Weeks 2, 4, 8, 12, 24, 36, and 48. The sample will 
be taken at least 15 minutes postdose if the regular dosing time coincides with the study 
visit, or at any time during the visit if the dosing time does not coincide with the 
scheduled study visit.

Document study drug dispensation and accountability for all study drugs dispensed.

Checking of the study medication log booklet for review of treatment adherence. 
In subjects participating in the bone investigation substudy:
-
Bone biomarkers at Weeks 2, 4, 12, 24 and 48 (collected fasted, ie, no food or drinks, 
except water, at least 8 hours prior to sample collection): CTX and P1NP. Biomarkers 
PTH and 25-hydroxy vitamin D will be assessed at Weeks 24 and 48 only. If the 
subject has not fasted prior to the visit, the visit may proceed but the subject must return 
within 72 hours in a fasted state to provide a blood sample for bone biomarker 
assessment.
-
DXA scan of spine and hip at Weeks 24 and 48 (±10 days). A rescan for technical 
reasons is allowed within 2 weeks.
9.1.4.
Extension Phase 
Provided results from the DMC analyses or Week 24 interim analysis does not preclude (further) 
exposing subjects to D/C/F/TAF, subjects from the D/C/F/TAF arm will enter in the extension 
phase once they have completed their Week 48 visit. In addition, subjects in the control arm will 
receive the D/C/F/TAF tablet in the extension phase if, according to the investigator they will 
benefit from it and if all conditions are fulfilled (which includes adequate viral load results). 
Subjects from the control arm will be required to attend a switch visit at Week 52 to receive 
D/C/F/TAF. All subjects in the extension phase will have to attend visits every 12 weeks up to 
Week 96. As from Week 96, all subjects are offered the possibility to continue D/C/F/TAF 
treatment, if they wish and if they continue to benefit from it, until D/C/F/TAF becomes 
commercially available and is reimbursed, or can be accessed through another source in the 
country where he/she is living, or until the sponsor terminates clinical development. After Week 
96, subjects should attend visits every 6 months. The time window for these visits is ±7 days of 
the protocol-specified visit date.
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Subjects from the control arm must have a Week 52 visit (switch visit) to allow providing 
D/C/F/TAF to subjects likely to benefit from it, based on the investigator's medical judgment. No 
investigations are foreseen during this visit, except for a blood sample collection to determine 
plasma HIV-1 RNA for those subjects that had HIV-1 RNA ≥50 copies/mL at Week 48 and at 
the subsequent unscheduled visit. Information on concomitant medications, adherence and any 
AEs are to be collected during that visit.
In the extension phase, the following evaluations are to be completed and documented at each 
visit (except for the Week 52 switch visit).

Review of AEs and changes in concomitant medications.

Symptom-directed physical examination (physical examination for which symptoms have 
been reported by the subject) as needed at Weeks 60, 72, 84, 96 and every 6 months after 
Week 96.

Vital signs measurement (blood pressure and pulse) and weight.

Midstream urine sample collection for the following laboratory procedures:
-
Urinalysis and urine chemistry (see also Section 9.1.2.1).
-
Urine renal biomarkers (fasted, ie, no food or drinks, except water, at least 8 hours prior 
to urine collection; if the subject has not fasted prior to the visit, the visit may proceed, 
but the subject must return within 72 hours in a fasted state to provide a urine sample 
for renal biomarkers) at Week 96 only (see also Section 9.1.2.2).
-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confirmed with a serum test. If the test is positive, the subject will be 
withdrawn (see also Section 12.4.3).

Blood sample collection for the following laboratory analyses:
-
Chemistry profile (see also Section 9.1.2.1).
-
Metabolic profile (including glucose; collected fasted; if the subject has not fasted prior 
to the visit, the visit may proceed, but the subject must return within 72 hours in a fasted 
state to have a blood draw for the metabolic assessments) at Week 96 only (see also 
Section 9.1.2.2).
-
Cystatin C and eGFRcyst according to the CKD-EPI formula at Week 96 only.
-
eGFRcr according to the Cockcroft-Gault formula and the CKD-EPI formula (for 
details, see Section 9.5.4).
-
Hematology profile (see also Section 9.1.2.1).
-
Plasma HIV-1 RNA.
-
CD4+ cell count.
-
Blood sample for HIV-1 resistance testing. For subjects with confirmed HIV-1 RNA
≥50 copies/mL and with a HIV-1 RNA value ≥400 copies/mL, HIV-1 genotypic 
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resistance test will be performed; phenotypic resistance test may be done upon request 
of the study virologist.
-
Plasma storage sample for possible additional clinical testing at Week 96 only.
-
PBMC storage sample at Week 96 only, which will only be analyzed if deemed 
necessary by the study virologist to characterize archived viral resistance.

Document study drug dispensation and accountability for all study drugs dispensed.
In subjects participating in the bone investigation substudy:

Bone biomarkers at Week 96 (collected fasted, ie, no food or drinks, except water, at least 
8 hours prior to sample collection): CTX, P1NP, PTH, and 25-hydroxy vitamin D. If the 
subject has not fasted prior to the visit, the visit may proceed but the subject must return 
within 72 hours in a fasted state to provide a blood sample for bone biomarker assessment.

DXA scan of spine and hip at Week 96 (±10 days). A rescan for technical reasons is allowed 
within 2 weeks.
9.1.5.
Posttreatment Assessments
9.1.5.1.
Early Study Treatment Discontinuation Visit
Subjects who prematurely discontinue or change study treatment during the treatment phase 
(from Day 1 to Week 48) or during the extension phase (only between Week 48 and 96) will be 
required to complete the ESTD assessments within 72 hours of stopping/changing study 
treatment. 
Any evaluations at the ESTD visit showing abnormal results indicating that there is a possible or
probable causal relationship with study drug, need to be followed (as often as deemed prudent by 
the investigator) until satisfactory clinical resolution or stabilization.
The following procedures are to be completed and documented.

Review of AEs and changes in concomitant medications.

Complete physical examination (urogenital/anorectal examinations will be performed at the 
discretion of the investigator).

Vital signs measurement (blood pressure and pulse) and weight.

Midstream urine sample collection for the following laboratory procedures:
-
Urinalysis and urine chemistry (see also Section 9.1.2.1).
-
Urine renal biomarkers: required if the last test was more than 12 weeks before the 
ESTD visit (fasted, ie, no food or drinks, except water, at least 8 hours prior to urine
collection; if the subject has not fasted prior to the visit, the visit may proceed, but the 
subject must return within 72 hours in a fasted state to provide a urine sample for renal 
biomarkers) (see also Section 9.1.2.2).
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-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confirmed with a serum test. If the test is positive, see Section 12.4.3 for 
the procedure to follow.

Blood sample collection for the following laboratory analyses:
-
Chemistry profile (see also Section 9.1.2.1).
-
eGFRcr according to the Cockcroft-Gault formula, and the CKD-EPI formula (for 
details, see Section 9.5.4).
-
Hematology profile (see also Section 9.1.2.1).
-
Plasma HIV-1 RNA.
-
CD4+ cell count.
-
Blood sample for HIV-1 resistance testing. 
-
Plasma storage sample for possible additional clinical testing.
-
PBMC storage sample that will only be analyzed if deemed necessary by the study 
virologist to characterize archived viral resistance.

Pharmacokinetic sample collection for D/C/F/TAF arm only.

Document study drug accountability for all study drugs dispensed.
In subjects participating in the bone investigation substudy:

Bone biomarkers (collected fasted, ie, no food or drinks, except water, at least 8 hours prior 
to sample collection): CTX, P1NP, PTH, and 25-hydroxy vitamin D. If the subject has not 
fasted prior to the visit, the visit may proceed but the subject must return within 72 hours in a 
fasted state to provide a blood sample for bone biomarker assessment.

DXA scan of spine and hip: only to be performed at ESTF if the last scan is more than 
12 weeks from the date of the ESTD visit and the ESTD visit takes place before Week 48.
9.1.5.2.
30-Day Follow-Up Visit
A 30-day FU visit will be required for any subject who has an ongoing AE or SAE at the time of 
his/her last study visit (unless consent is withdrawn).
A time window of ±7 days of the protocol-specified visit date may be used for this 30-day FU
visit. The following evaluations are to be completed and documented.

Review of AEs and changes in concomitant medications.

Symptom-directed physical examination (physical examination for which symptoms have 
been reported by the subject) as needed.

Weight.
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
Midstream urine sample collection for the following laboratory procedures:
-
Urinalysis and urine chemistry (see also Section 9.1.2.1).
-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confirmed with a serum test. If the test is positive, see Section 12.4.3 for 
the procedure to follow.

Blood sample collection for the following laboratory analyses:
-
Chemistry profile (see also Section 9.1.2.1).
-
eGFRcr according to the Cockcroft-Gault formula, and the CKD-EPI formula (for 
details, see Section 9.5.4).
-
Hematology profile (see also Section 9.1.2.1).
-
Plasma HIV-1 RNA.
-
CD4+ cell count.
9.2.
Efficacy Evaluations
9.2.1.
Antiviral Efficacy and Immunologic Change
Samples for determination of plasma HIV-1 RNA viral load and immunologic parameters will be 
taken at the time points specified in the Time and Events Schedule. 
Plasma viral load levels will be measured using a validated assay, which will be conducted by 
the central laboratory.
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 (S)AE.
9.2.2.
Resistance Determinations 
Samples for HIV-1 genotypic/phenotypic resistance testing, as well as a PBMC sample will be 
taken at the time points specified in the Time and Events Schedule. 
For subjects with confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥50 copies/mL 
at a scheduled or unscheduled visit; confirmative testing 2 to 4 weeks after the date of initial 
viral load result of HIV-1 RNA ≥50 copies/mL, or last available HIV-1 RNA ≥50 copies/mL)
and with a HIV-1 RNA value ≥400 copies/mL, HIV-1 genotypic 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 protocol virologist. Phenotypic resistance testing may be done upon request of 
the study virologist. For further details on the management of virologic rebound, see Section 9.3.
PBMC samples will be taken for storage and will only be analyzed if deemed necessary by the 
study virologist to characterize archived viral resistance
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9.3.
Management of Virologic Rebound
Subjects will be considered to have virologic rebound if they have a confirmed (2 consecutive
tests) HIV-1 RNA ≥50 copies/mL at a scheduled or unscheduled visit after maintaining HIV-1 
RNA <50 copies/mL. 
Subjects with HIV-1 RNA ≥50 copies/mL will be managed as follows:
-
If a single viral load measurement is 50 copies/mL after having previously been 
<50 copies/mL, subjects 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 
counsellation). 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 ≥50 copies/mL. 
-
Upon confirmation of HIV-1 RNA ≥50 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 testing. Phenotypic resistance testing
may be done upon request of the study virologist (see also Section 9.2.2).
-
If genotypic/phenotypic resistance to study drugs is determined, study drugs may be 
discontinued at the discretion of the investigator. In case of early discontinuation, and HIV-1 
RNA ≥400 copies/mL, an HIV-1 genotypic resistance report, if available, will be forwarded 
to the investigator in order to assist in the selection of a new ARV regimen.
-
If no resistance is detected from genotypic/phenotypic testing, the subject may remain on 
study drug and the viral load will be further monitored. Genotype/phenotype testing at other 
time points may be requested if deemed necessary by the protocol virologist. Investigators 
should carefully evaluate the benefits and risks of remaining on study drug for each 
individual subject and document this assessment in the on-site medical record. Investigators 
who opt to discontinue study drugs for an individual subject must discuss this with the 
sponsor’s medical monitor prior to study drug discontinuation.
A schematic overview of the guidance for management of subjects who meet the criteria for 
virologic rebound is provided in Attachment 1.
9.4.
Safety Evaluations
The study will include the following evaluations of safety and tolerability according to the time 
points specified in the Time and Events Schedule: AE reporting, clinical laboratory tests 
(including biochemistry, hematology, urinalysis, urine chemistry, and renal biomarkers), vital 
signs, physical examinations (complete or symptom-directed), and bone biomarkers and DXA 
scans of spine and hip (only for subjects participating in the substudy). These protocol 
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procedures are described in Sections 9.4.1 through 9.4.5. In addition to these measurements, 
guidelines for the management of toxicities are described in Section 9.5.
Any clinically relevant abnormalities occurring at screening (from signing the ICF) and any 
clinically relevant changes occurring during the study must be recorded in the AE section of the 
eCRF.
Clinical events and clinically significant laboratory abnormalities will be graded according to the 
Division of AIDS (DAIDS) grading table (see Attachment 2).
Any evaluations showing abnormal results at any time during the study will be followed until 
satisfactory clinical resolution or stabilization. All grade 3 and grade 4 laboratory abnormalities 
and 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) (for further 
details, see Section 9.5.1). 
Any evaluations at the ESTD visit showing abnormal results indicating that there is a possible 
causal relationship with study drug, need to followed by the investigator (as often as deemed 
prudent) until satisfactory clinical resolution or stabilization. Certain long-term AEs of ARV 
therapy 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.
9.4.1.
Adverse Events/HIV-related Events
At each visit, from signing of the ICF, subjects will be asked about any untoward medical 
occurrences, and these will be recorded as AEs in the AE section of the eCRF. For detailed 
definitions and reporting procedures of AEs, please see Section 12.
Special attention will be paid to those subjects who discontinue the study for an AE, or who 
experience a severe AE (at least grade 3), or an SAE. For reported HIV events, further details 
will be recorded if these events are AIDS-defining illnesses (see World Health Organization 
[WHO] Clinical Staging of HIV/AIDS, Attachment 3). For subjects experiencing specific AEs, 
toxicity management should be done as described in Section 9.5. 
9.4.2.
Clinical Laboratory Tests
Blood samples for biochemistry, hematology and serum pregnancy testing (females only, at 
screening only or if urine pregnancy test is positive), and a urine sample for urinalysis by 
dipstick, urine chemistry, renal biomarkers, and urine pregnancy testing (except at screening) 
will be collected at the time points specified in the Time and Events Schedule.
For laboratory assessments that need to be performed fasted while the subject has not fasted prior 
to the visit, the visit may proceed, but the subject must return within 72 hours in a fasted state to 
provide the necessary sample(s) for the assessments.
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 report, document this review, and 
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record any clinically relevant findings at screening and changes occurring during the study in the 
AE section of the eCRF (see also Section 12.2). The laboratory reports must be filed with the 
source documents.
The central laboratory will send the investigator and the sponsor an alert form whenever a grade 
3 or 4 laboratory abnormality (see Attachment 2) has been 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 medication interruption or
discontinuation unless such delay is not consistent with good medical practice. 
If a grade 3 or 4 laboratory abnormality is well documented prior to the start of the study and is 
not considered a safety concern by 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 subjects with pre-existing diabetes;
-
Asymptomatic grade 3 or grade 4 triglyceride or cholesterol elevations.
For further details on the management of grade 3 or 4 laboratory toxicities, see Section 9.5.1 and 
Attachment 4.
The following tests will be performed by the central laboratory:
-
Urine chemistry panel: 
creatinine, sodium, phosphate, glucose, protein, albumin;
(quantitative measurement).
-
Urinalysis by dipstick: 
specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, and leukocyte esterase.
If dipstick result is abnormal, flow cytometry will be used to measure sediment. In case of 
discordance between the dipstick results and the flow cytometric 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.
-
Urine renal biomarkers: 
RBP and beta-2-microglobulin (collected fasted).
-
Cystatin C.
-
Serum Chemistry panel: 
ALP, AST, ALT, GGT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, CPK, bicarbonate, BUN, 
chloride, creatinine, glucose, phosphorus, potassium, sodium, 
uric acid, and amylase (reflex lipase testing is performed in 
subjects with total amylase >1.5 x ULN), and AAG.
At baseline, Weeks 24, 48, and every 24 weeks during the extension phase, analyses of 
glucose will be done as part of the fasting metabolic assessments and not as part of the 
chemistry profile.
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For the calculation of eGFRcr according to the Cockcroft-Gault and CKD-EPI formulas, and 
eGFRcyst according to the CKD-EPI formula see Section 9.5.4; the eGFR calculations will 
be performed by the central laboratory.
-
Metabolic panel: 
total, HDL
and
LDL
cholesterol, triglycerides, glucose;
(collected fasted).
-
Hematology panel: 
hemoglobin, hematocrit, RBC count and parameters (MCH, 
MCH concentration and MCV), WBC count with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), 
and platelet count.
-
Pregnancy testing:
The screening sample for biochemistry will include a serum 
pregnancy test for all female subjects of childbearing potential; a
urine pregnancy test will be performed at all other visits. 
Positive urine pregnancy tests will be confirmed with a serum 
pregnancy test. FSH testing is required for female subjects who 
have stopped menstruating for at least 2 years but do not have 
documentation of ovarian hormonal failure. The results of the 
serum and urine pregnancy tests should be recorded in the eCRF 
and in the subject’s medical records.
-
Hepatitis testing:
A sample will be taken for HBV and HCV testing (HBsAg,
HCV RNA, and HCV antibody) at screening. Whenever 
clinically relevant, the investigator can request additional tests at 
other visits.
-
Bone biomarkers: 
CTX, P1NP, PTH, and 25-hydroxy vitamin D (collected fasted)
(only for subjects participating in the bone investigation 
substudy).
-
In addition, in case of rash safety blood samples need to be taken, and are to be processed by 
the central laboratory. For details on rash management, see Section 9.5.2.
9.4.3.
Electrocardiogram
A local ECG will be taken locally at screening to determine subject eligibility for participation in 
the study.
During the collection of ECGs, subjects should be in a quiet setting without distractions (eg, no 
television or cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs.
Twelve-lead ECGs will be recorded until 4 regular consecutive complexes are available so that 
the different ECG intervals (RR if available, PR, QRS and QT) and heart rate can be measured. 
The QT intervals will be corrected for heart rate according to Bazett’s (QTcB) and Fridericia’s 
(QTcF) QT corrections.5,14
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Any clinically relevant findings at screening must be recorded in the AE section of the eCRF.
9.4.4.
Vital Signs 
Systolic and diastolic blood pressure (SBP, DBP), pulse rate (supine after at least 5 minutes rest),
and weight will be recorded in a quiet setting without distractions, at the time points specified in
the Time and Events Schedule.
Blood pressure and pulse/heart rate measurements will be assessed with a completely automated 
device if possible. Manual techniques will be used only if an automated device is not available.
To obtain the actual body weight, subjects should be weighed lightly clothed.
Any clinically relevant findings at screening and changes occurring during the study must be 
recorded in the AE section of the eCRF.
9.4.5.
Physical Examination 
Complete physical
examinations,
or symptom-directed physical
examinations
(physical 
examination for which symptoms have been reported by the subject) as needed, will be 
performed at the time points in the Time and Events Schedule.
A complete physical examination includes skin and mucous membranes, lymph nodes, 
respiratory system, cardiovascular system, abdomen, central nervous system, peripheral nervous 
system, musculoskeletal system, genitourinary system and head-neck examination. Urogenital or 
anorectal examination will be performed at the discretion of the investigator if clinically relevant.
Subjects should be undressed during these complete physical examinations, which should be
performed by a licensed medical doctor, a physician’s assistant or a nurse practitioner in 
accordance with local guidelines.
The height should be measured barefooted at the screening visit.
Any clinically relevant findings at screening and changes occurring during the study must be 
recorded in the AE section of the eCRF.
9.4.6.
Bone investigation substudy
A bone investigation substudy will be performed at selected study sites, to assess bone 
biomarkers and DXA scans, in approximately 300 subjects (200 in the D/C/F/TAF treatment arm 
versus 100 in the control arm) who provide informed consent for the substudy.
DXA scans will be performed in subjects participating in the DXA substudy, provided that all 
necessary local regulatory authority and ethics committee approvals have been obtained. DXA 
scans will be performed at the time points specified in the Time and Events Schedule and will 
cover the spine and hip to measure changes in BMD.
A complete description of the procedures for the DXA scans will be provided in the DXA 
manual.
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Reading of the DXA scans will be performed centrally and results will be sent to the investigator. 
The investigator must review the DXA scan report, document this review and record any 
clinically relevant findings at baseline and changes occurring during the study in the AE section 
of the eCRF. The DXA scan reports must be filed with the source documents. For the 
management of potential bone toxicity, see Section 9.5.5.
In subjects participating in the DXA substudy, blood will be collected for assessment of bone 
biomarkers (including CTX, P1NP, PTH, and 25-hydroxy vitamin D) at the time points specified 
in the Time and Events Schedule.
9.5.
Toxicity Management
The toxicity management guidelines in this section are applicable throughout the entire study, 
including the screening period and the 48-week treatment period. In addition, it is strongly
recommended that investigators follow these guidelines and apply the same safety measures for 
subjects in the 48-week extension phase.
A subject will not be excluded from the study in case a treatment interruption is needed during 
the screening period because of the toxicity management guidelines. The baseline visit can take 
place as soon as the toxicity has resolved.
General guidance for the management of toxicities is provided in Section 9.5.1. Guidance for 
specific toxicities is provided in Sections 9.5.2 through 9.5.9. Please, see also Sections 9.4 and 
12 for information on procedures concerning the measurement and reporting of clinically 
relevant abnormalities and toxicities.
Any questions regarding toxicity management should be directed to the sponsor’s medical 
monitor.
9.5.1.
General Guidance for the Management of Clinical Events and 
Laboratory Abnormalities
Grade 1 and 2
Continue study medication at the discretion of the investigator.
Grade 3 
-
For a grade 3 clinical event or clinically relevant laboratory abnormality, study medication 
may be continued if the event is considered to be unrelated to study medication.
-
For a grade 3 clinical event, or clinically relevant laboratory abnormality confirmed by 
repeat testing (see Section 9.4.2), that is considered to be related to study medication, study 
medication should be withheld until the toxicity returns to baseline or within 1 grade from 
baseline, ie, grade 2.
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Mandatory confirmation is not warranted for asymptomatic grade 3 glucose elevations in 
subjects with pre-existing diabetes, and asymptomatic grade 3 triglyceride or cholesterol 
elevations.
-
If a laboratory abnormality recurs to grade 3 following rechallenge with study medication 
and is considered related to be to study medication, study medication should be permanently 
discontinued and the subject managed according to local practice. Recurrence of laboratory 
abnormalities considered unrelated to study medication may not require permanent 
discontinuation.
Grade 4 
-
For a grade 4 clinical event or clinically relevant laboratory abnormality confirmed by repeat 
testing (see Section 9.4.2), that is considered to be related to study medication, study 
medication should be permanently discontinued and the subject managed according to local 
practice. The subject 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 
subjects with pre-existing diabetes, and asymptomatic grade 4 triglyceride or cholesterol 
elevations.
-
Study medication may be continued without dose interruption for a clinically nonrelevant
grade 4 laboratory abnormalities (eg, grade 4 CPK after strenuous exercise, or triglyceride 
elevation that is nonfasting or that can be medically managed), or a clinical event considered 
unrelated to study medication.
When restarting study medication following resolution of a clinical event or clinically relevant 
laboratory abnormality, the study drugs may need to be restarted at full dose or (in the control
arm) at modified dose, which is dependent upon discussion with the sponsor’s medical monitor.
A schematic overview of these guidelines is provided in Attachment 4 for clinically relevant 
laboratory toxicities.
9.5.2.
Cutaneous Events/Rash
DRV is a sulfonamide. Subjects who previously experienced a 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.
Cutaneous events/rash should be captured in the AE section of the eCRF.
Management will be at the discretion of the investigator, taking into account the following 
protocol-defined procedures (see also Table 3), 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.
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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.
Subjects experiencing a grade 1 or 2 rash or cutaneous event may continue treatment, or have 
their study medication interrupted at the investigator’s discretion. Safety sampling (to be 
processed by the central laboratory) at the time of the 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 AE.
Grade 3 and 4 Cutaneous Reaction/Rash
A grade 3 cutaneous reaction/rash is defined as:
-
Diffuse rash and vesicles or limited number of bullae or superficial ulceration of mucous 
membrane limited to 1 site;
For the purpose of this protocol, the sponsor considers qualifying as a grade 3 rash the following:
-
Cutaneous reaction/rash with at least 1 of the following:
-
elevations of ALT/AST >2 x baseline but ≥5 x ULN;
-
fever 38°C or 100°F;
-
serum sickness-like reaction;
-
eosinophil count >1,000/mm³.
-
The syndromes of Drug Reaction 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;
-
TEN.
Subjects experiencing a grade 3 or 4 rash or cutaneous event must have their study medication 
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. 
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 
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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 3:
Summary of Cutaneous Reaction/Rash Follow-up
DAIDS Toxicity Grade
Definitions
Investigator Action
Grade 1
Localized rash
Subject may continue study
medication 
Grade 2
Diffuse rash
Target lesions
Subject may continue study
medication 
Grade 3
Diffuse rash and vesicles or limited number 
of bullae or superficial ulcerations of 
mucous membrane limited to 1 site
For the purpose of this protocol, the 
sponsor considers qualifying as a grade 3 
rash the following:
Cutaneous reaction/rash with at least 1 of 
the following:
- Elevations in ALT and/or AST 
(>2 x baseline but ≥5 x ULN)
- Fever 38°C or 100 F
- Serum sickness-like reaction
- Eosinophils >1000/mm³
The syndromes of Drug Reaction with 
Eosinophilia and Systemic Symptoms 
(DRESS) and Acute Generalized 
Exanthematous Pustulosis (AGEP)
Permanently discontinue study 
medication 
Referral to a dermatologist and 
biopsy, preferably within 24 hours
after the site becomes aware of the 
cutaneous event/rash
Laboratory assessments need to be 
performed 
Grade 4
Extensive or generalized bullous lesions
SJS
Ulceration of mucous membrane involving 
at least 2 distinct mucosal sites 
TEN
Permanently discontinue study
medication
Referral to a dermatologist and 
biopsy, preferably within 24 hours
after the site becomes aware of the 
cutaneous event/rash
Laboratory assessments need to be 
performed
9.5.3.
Acute Systemic Allergic Reaction
Management will be at the discretion of the investigator, taking into account the following 
protocol-defined procedures (see also Table 4), and should follow generally accepted medical 
standards.
Grade 1
A grade 1 acute systemic allergic reaction is defined as localized urticaria (wheals) with no 
medical intervention indicated.
Subjects may continue study medication or have their study medication interrupted at the 
investigator’s discretion. The subject should be advised to contact the investigator immediately if 
there is any worsening of the pruritus, or if any systemic signs or symptoms develop. 
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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 8 or the local Prescribing 
Information of the ARVs.
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.
Subjects may continue study medication or have their study medication interrupted at the 
investigator’s discretion. If there is any worsening of the allergic reaction, the subject should be 
advised to contact the investigator immediately and to discontinue study medications. 
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 8 or the 
local Prescribing Information of the ARVs.
Grade 3
A grade 3 acute systemic allergic reaction is defined as generalized urticaria, or angioedema with 
intervention indicated or symptoms of mild bronchospasm.
Subjects will permanently discontinue study medication. Subjects 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.
Subjects will permanently discontinue study medication. Subjects will be treated as clinically 
appropriate. Standard management should be undertaken.
Table 4:
Summary of Allergic Reaction Follow-up
DAIDS Toxicity Grade
Definitions
Investigator Action
Grade 1
Localized urticaria (wheals) with no 
medical intervention indicated
Subject may continue study
medication 
Grade 2
Localized urticaria with intervention 
indicated, or
mild angioedema with no  intervention 
indicated
Subject may continue study
medication 
Grade 3
Generalized urticaria, or
angioedema with intervention indicated, or
symptoms of mild bronchospasm
Permanently discontinue study
medication
Grade 4
Acute anaphylaxis, or 
life-threatening bronchospasm, or
laryngeal edema
Permanently discontinue study
medication
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9.5.4.
Potential Renal Toxicity
Estimated glomerular filtration rate for creatinine clearance (eGFRcr calculated according to the 
Cockcroft-Gault formula and the CKD-EPI formula), and eGFR for cystatin C clearance 
(eGFRcyst calculated according to the CKD-EPI formula) will be followed postbaseline during 
the treatment phase of the study. The eGFRs calculations will be performed and provided to the 
investigator by the central laboratory.
During the extension phase of the study, eGFRcr according to the Cockcroft-Gault formula for 
creatinine clearance will be monitored. All subjects with eGFRcr <50 mL/min must have serum 
creatinine re-measured preferably within 3 calender days of receipt of results. At the time of this 
repeat serum creatinine assessment, cystatin C will also be measured and the eGFRcyst will be 
calculated and compared with the baseline measurement.
-
eGFRcr according to the Cockcroft-Gault formula:11
Male:
(140 – age in years) x (weight in kg) eGFRcr (mL/min)
  72 (serum creatinine in mg/dL)
Female:
(140 – age in years) x (weight in kg) 0.85 eGFRcr (mL/min)
  72 (serum creatinine in mg/dL)
-
eGFRcr and eGFRcyst according to the CKD-EPI formula:19
eGFRcr
Female: Scr ≤0.7 mg/dL
144 x (Scr/0.7)-0.329 x 0.993age
Scr >0.7 mg/dL
144 x (Scr/0.7)-1.209 x 0.993age
Male:
Scr ≤0.9 mg/dL
141 x (Scr/0.9)-0.411 x 0.993age
Scr >0.9 mg/dL
141 x (Scr/0.9)-1.209 x 0.993age
eGFRcyst
Scyst ≤0.8 mg/L
133 x (Scyst/0,8)-0.499 x 0.996age [x 0.932 if female]
Scyst >0.8 mg/L
133 x (Scyst/0,8)-1.328 x 0.996age [x 0.932 if female]
Scr = serum creatinine (mg/dL), Scyst = serum cystatin C (mg/L)
Any subjects who have an eGFRcr (by Cockcroft-Gault) <50 mL/min, and who also experience 
>20% reduction in eGFRcyst (by CKD-EPI) 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 drugs. For subjects with eGFRcr <50 mL/min who are 
not discontinued based on toxicity management procedures above and considered to have stable 
renal function per principal investigator and medical monitor, it is not mandatory to repeat eGFR
assessments within 3 days.
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All subjects with negative or trace proteinuria at baseline who develop >1+ proteinuria on 
urinalysis must have a urinalysis repeated, with a concurrent urine chemistry, within 2 weeks of 
receipt of results. Upon confirmation of proteinuria, subjects will be asked to return to the clinic 
for a scheduled or unscheduled FU visit. It is recommended that the investigator contact the 
sponsor’s medical monitor to discuss if further consultation with a nephrologist is clinically 
warranted.
Once an individual subject 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 subject to continue on treatment with standard visits as described 
in the protocol.
For subjects who are randomized to the control arm, please refer to the local Prescribing 
Information of Truvada® with regard to dose adjustment or treatment discontinuation in case of 
renal impairment.34
9.5.5.
Potential Bone Toxicity
As there is uncertainty surrounding the clinical significance and management of decreases in 
BMD for HIV-1 positive patients, the sponsor recommends that any subject who has a DXA scan 
that demonstrates a decrease from baseline of >5% in the spine region or >7% in the hip region 
should be followed per local medical practice at the discretion of the investigator.
9.5.6.
Potential Posterior Uveitis Cases
In a 9-month toxicology study conducted in dogs, some animals administered the highest dose of 
TAF (12-18 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. More than 3,000 HIV-positive subjects have been exposed to TAF as part of the
Phase 2 and 3 E/C/F/TAF clinical development program by GSI and no AEs consistent with 
posterior uveitis in humans have been reported. Nonetheless, if subjects 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 prompt referral of the subject for 
specialized ophthalmologic evaluation including dilated fundoscopy, and if required, optical 
coherence tomography. 
9.5.7.
Hyperglycemia
Grade 3: 13.89–27.75 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. 
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Subjects who experienced asymptomatic glucose elevations of grade 3 and subjects with pre-
existing diabetes who experienced asymptomatic glucose elevations of grade 4 may continue 
study medications unless clinical assessment foresees an immediate health risk to the subject. 
Appropriate clinical management of hyperglycemia must be started in a timely fashion if 
applicable. Subjects with persistent grade 3 or 4 glucose elevations despite appropriate anti-
hyperglycemic treatment should permanently discontinue study treatment.
9.5.8.
Hypertriglyceridemia and Hypercholesterolemia
Hypertriglyceridemia:
Grade 3:
5.7-11.4 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. 
Subjects who experienced asymptomatic triglyceride or cholesterol elevations of grade 3 or 4 
may continue study medications unless clinical assessment foresees an immediate health risk to 
the subject.
Hypertriglyceridemia and hypercholesterolemia should be treated according to the specific 
guidelines for treating HIV-positive subjects (see Attachment 5). Current treatment guidelines 
specify different lipid thresholds for intervention for different degrees of cardiovascular risk. The 
presence or absence of other significant cardiovascular risk factors, which include smoking, age, 
family history of premature cardiovascular disease, diabetes, hypertension, low HDL cholesterol, 
and prior history of cardiovascular disease should be taken into account. Appropriate clinical 
management of hyperlipidemia in the setting of HIV disease should be started in a timely fashion
if applicable.
9.5.9.
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
(see Attachment 2) 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.
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9.6.
Pharmacokinetic Evaluations
9.6.1.
Evaluations
Pharmacokinetic assessments (sparse sampling) will be performed for all subjects randomized to 
the D/C/F/TAF arm to evaluate the pharmacokinetics of DRV. The pharmacokinetic samples 
may also be used for evaluation of the pharmacokinetics of COBI, FTC, TAF, and/or TFV, if 
deemed necessary, upon request of the study pharmacologist. 
Single sparse blood samples will be collected on the Weeks 2 through 48 visits and the ESTD 
visit if applicable. Samples should be taken at least 15 minutes postdose if the regular dosing 
time coincides with the study visit or at any time during the visit if the dosing time does not 
coincide with the scheduled study visit.
All samples for pharmacokinetic analyses will be collected, identified and handled according to 
the laboratory manual. Exact dates and times of blood sampling, intake time of investigational 
medication, and whether this was taken with an accompanying meal, for the last 2 doses of 
investigational medication prior to the pharmacokinetic sampling must be recorded in the eCRF.
Pharmacokinetics of the ARVs in the control arm may also be evaluated (for which stored
plasma samples may be used; see Section 9.1.1.1), if deemed necessary and upon request of the 
study pharmacologist.
9.6.2.
Analytical Procedures
Plasma concentrations of DRV will be analyzed by the bioanalytical laboratory contracted by 
and under the supervision of the sponsor, using validated high-performance liquid 
chromatography-tandem mass spectroscopy (LC-MS/MS) methods. The bioanalyses will be 
performed in batches. Determination of the plasma concentrations of COBI, FTC, TAF, and/or
TFV or ARVs in the control arm may be done upon sponsor’s request, using validated methods,
in a similar manner.
A description of the assays and validation data will be included in separate reports.
Results of bioanalyses will not be made available to the investigators.
9.6.3.
Pharmacokinetic Parameters 
Based on the individual plasma concentration-time data, using the actual dose taken and the
actual intake and sampling times, the following pharmacokinetic parameters may be derived 
using population pharmacokinetic modeling and Bayesian feedback, if appropriate population 
pharmacokinetic models are available.
-
C0h and AUC24h for DRV;
-
C0h or CXh and AUC24h for COBI, FTC, TAF, and/or TFV, or AUC12h/AUC24h as applicable 
for ARVs in the control arm, if deemed necessary, upon request of the study pharmacologist.
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10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
In the period up to Week 96, subjects will be considered to have completed study treatment if he 
or she has continued study medication intake up to Week 96 and has completed assessments at 
Week 96. Subjects who prematurely discontinue study treatment for any reason before 
completion of the 96-week treatment period will not be considered to have completed treatment.
In the period after Week 96, subjects will be considered to have completed study treatment if he 
or she continued study medication intake until D/C/F/TAF becomes commercially available and 
is reimbursed, or can be accessed through another source in the country where he/she is living, or 
until the sponsor terminates clinical development and has completed assessments until that point.
Subjects who prematurely discontinue study treatment for any reason before that point, will not 
be considered to have completed the post Week 96 D/C/F/TAF treatment period.
10.2.
Withdrawal From the Study 
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Withdrawal of consent.

Subject request to stop study treatment for any reason.

The investigator or sponsor believes (eg, for safety or tolerability reasons such as an AE, or 
for efficacy reasons) it is in the best interest of the subject to stop study treatment. The 
sponsor should be contacted for further discussion and final decision.

Unacceptable toxicity, as defined in the toxicity management Section 9.5 of this protocol.

Toxicity that, in the judgment of the investigator, compromises the ability to continue study-
specific procedures.

Pregnancy has been determined in participating female subjects.

The subject develops clinical hepatitis.

Discontinuation of the study at the request of the sponsor, DMC, the concerned regulatory 
agency or Independent Ethics Committee (IEC)/ Institutional Review Board (IRB).
A subject’s study treatment may be discontinued if:

An SAE occurs

The subject fails to comply with the protocol or study staff requirements

The subject starts disallowed treatment 
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
Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 

The subject demonstrates virologic rebound; see also Section 9.3.
If an investigator considers withdrawing a subject from study treatment for 1 of the above 
reasons, he /she should contact the sponsor for further discussion and final decision, unless the 
medical condition requires immediate action that cannot await contact with the sponsor.
Subjects who prematurely discontinue or change study treatment during the treatment phase 
(from Day 1 to Week 48) or during the extension phase (only between Week 48 and 96) will be 
required to complete the ESTD assessments within 72 hours of stopping/changing study 
treatment.
In addition, a 30-day follow-up (FU) visit will be required for any subject has an ongoing AE or 
SAE at the time of his/her last study visit (unless consent is withdrawn).
If a subject is lost to follow-up, every reasonable effort must be made by the study-site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and the source document, at the final evaluation the Trial Termination 
section of the eCRF must be completed. Study drug assigned to the withdrawn subject may not 
be assigned to another subject. Subjects who withdraw will not be replaced.
Subjects who withdraw consent from the bone investigation substudy (see Section 16.2.3) can 
still continue to participate in the main study.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, Long-
Term Retention of Samples for Additional Future Research). 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.
11.
STATISTICAL METHODS
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 efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan.
The following analyses will be performed: 

A formal DMC analysis for monitoring purposes including a futility analysis for lack of 
(non-inferior) efficacy and a blinded sample size re-estimation (see also Section 11.9).
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
The planned Week 24 interim analysis: once all subjects have completed the Week 24
assessments or discontinued earlier. This analysis will be done mainly to evaluate the safety 
and tolerability of D/C/F/TAF. However, efficacy of the 2 treatment arms will also be looked 
at. Results of which will also be shared with the DMC.

The primary analysis: once all subjects from the D/C/F/TAF arm have completed the 
Week 48 assessments or all subjects from the control arm have completed the Week 52
assessments (whichever comes last), or discontinued earlier.

The Week 96 analysis: once all subjects have completed the Week 96 assessments or 
discontinued earlier.

The final analysis: once all subjects have completed the extension phase assessments and the 
30-day FU visit (if applicable), or discontinued earlier.

Additional statistical analyses may be done as needed to prepare for interactions with 
regulatory authorities.
11.1.
Analysis Objectives and Endpoints
An overview of the objectives and hypothesis tested in this analysis is provided in Section 2. The 
analysis endpoints are listed below. 
11.1.1.
Primary Endpoint
The primary endpoint is the proportion of subjects having confirmed virologic rebound 
(confirmed HIV-1 RNA ≥50 copies/mL through 48 weeks of treatment up to and including the 
upper bound of the Week 48 window, or in case of early discontinuation a last single viral load 
of HIV-1 RNA ≥50 copies/mL).
11.1.2.
Secondary Endpoints
Secondary endpoints in this study are:
-
The proportion of subjects having confirmed virologic rebound through 24 and 96 weeks of 
treatment;
-
The time to virologic rebound in weeks;
-
The proportion of subjects experiencing grade 3 and 4 AEs through 24, 48, and 96 weeks of 
treatment;
-
The proportion of subjects experiencing SAEs and premature discontinuations due to AEs 
through 24, 48, and 96 weeks of treatment;
-
The change from baseline in serum creatinine, eGFRcr (by Cockcroft-Gault and by CKD-
EPI) and eGFRcyst (by CKD-EPI) at Weeks 24, 48, and 96;
-
The change from baseline in renal biomarkers at Weeks 24, 48, and 96;
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-
The proportion of subjects with HIV-1 RNA <20, <50, and <200 copies/mL at Weeks 24,
48, and 96 as defined by the FDA snapshot analysis and TLOVR algorithm;
-
The change from baseline in CD4+ cell count at Weeks 24, 48, and 96;
-
Adherence to drug intake based on drug accountability through 24, 48, and 96 weeks;
-
Genotypic, and phenotypic if applicable, resistance to ARVs in the 2 treatment arms in 
subjects with confirmed HIV-1 RNA rebound through Weeks 24, 48, and 96;
-
Pharmacokinetic parameters for DRV in the D/C/F/TAF arm.
Secondary endpoints to be assessed in subjects participating in a bone investigation substudy at 
selected study sites:
-
The percent change from baseline in bone biomarkers CTX, P1NP, PTH, and 25-hydroxy 
vitamin D at Weeks 24, 48, and 96.
-
The percent change from baseline in spine and hip BMD and change from baseline in BMD 
T-score at Weeks 24, 48, and 96.
11.2.
Sample Size Determination
A sample size of 1,100 subjects will yield 89% power if it is assumed that both treatment arms 
will have an equal rebound rate of 4% (confirmed HIV-1 RNA ≥50 copies/mL up to, and 
including the upper bound of the Week 48 window or have discontinued prematurely, 
irrespective of reason, with the last available HIV-1 RNA ≥50 copies/mL), that the noninferiority 
margin is 4%, and that the significance level of the test is at a 1-sided, 0.025 level.
Table 5 provides rebound rates from historical switch studies in virologically suppressed subjects 
and from the treatment-naïve study TMC114-C211 (ARTEMIS) in a subset of subjects (n=286) 
being virologically suppressed for at least 6 months (data available on file).
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Table 5:
Rebound Rates (Snapshota or Confirmed ≥50 Copies/mL) From Historical Studies of 
Virologically Suppressed Patients
Study
Treatment Arm
Rebound Rate
(Snapshota or Confirmed HIV-1 
RNA ≥50 copies/mL)
Studied Patient Population
STRATEGY-PI
(E/C/F/TDF switch 
f/bPI)3
bPI + FTC/TDF 
(N=139)
1.4% (Snapshot Week 48)
bPI + FTC/TDF; 6 months 
suppressed; 1st or 2nd ART;
no history of VF and no 
RAMs to FTC/TDF in 
historical genotype
SPIRIT 
(RPV/FTC/TDF
switch f/bPI)24
bPI + 2 NRTIs 
(N=159)
5% (Snapshot Week 24)
bPI + NRTIs; 6 months 
suppressed; 1st or 2nd ART;
no history of VF and no 
RAMs to any study drug in 
historical genotype
SPIRAL
(raltegravir switch 
f/bPI)21
bPI + 2 NRTIs 
(N=140)
4.3% (Confirmed HIV-1 RNA 
≥50 copies/mL through 48 weeks)
6 months suppressed; VF on 
previous ART eligible
ARTEMISb
DRV/rtv + FTC/TDF 
(N=286)
3.8% (Confirmed HIV-1 RNA 
≥50 copies/mL through 48 weeks)
DRV/rtv + FTC/TDF; subset 
of patients at least 6 months 
suppressed
ART=antiretroviral therapy; VF=virologic failure; f/bPI=from boosted PI
a HIV-1 RNA ≥50 copies/mL through 48 weeks or discontinuation due to lack of efficacy or discontinuations due t
other reasons and last HIV-1 RNA ≥50 copies/mL.
b Efficacy analysis performed after at least 6 months HIV-1 RNA <50 copies/mL.
For the bone investigation substudy, with 300 subjects (200 in the D/C/F/TAF treatment arm 
versus 100 in the control arm) and assuming an inter-subject variability of 4%, there is
approximately 98% power to detect a 2% difference between the D/C/F/TAF treatment arm and 
the control arm in percent change from baseline in BMD at the spine. Other power calculations 
are presented in Table 6.
Table 6:
BMD at the Lumbar Spine, Power Calculations
Mean % Change from 
Baseline
Common Standard 
Deviation (%)
Power
N=300
2
3.5
>99%
4
98%
3
3.5
>99%
4
>99%
11.3.
Analysis Sets
The intent-to-treat (ITT) population 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 or control) to which they were randomized. 
The ITT analysis set is the primary analysis set for efficacy analysis. Efficacy data up to the last 
dose date of the randomized study treatment will be included. The safety analysis (including all 
data collected up to the 30-day FU visit) is also performed on this analysis set.
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Since an analysis on the ITT population may not be conservative in a noninferiority setting, 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 analysis results. The PP population will include all subjects who (1) are randomized into 
the study, (2) have received ≥1 dose of treatment in the study, (3) without any major protocol 
deviation that is considered to potentially affect efficacy outcomes (eg, previous DRV failure, 
use of concomitant medication interfering with antiviral efficacy, inadequate adherence to drug 
intake), and (4) have a baseline HIV-1 RNA value <50 copies/mL. Specific details will be 
provided in the Statistical Analysis Plan. The PP analysis set is the secondary analysis set for 
efficacy analysis.
The pharmacokinetic analysis set will include all subjects who are randomized to the D/C/F/TAF 
arm (and the control arm, if applicable) and have received at least 1 dose of investigational 
treatment (or control treatment, if applicable) in the study, and for whom plasma concentration 
data are available. 
11.4.
Subject Information
For all subjects who sign an ICF and are randomly assigned to a treatment arm and receive at 
least 1 dose of study drug, descriptive statistics will be provided. Demographic and baseline 
disease characteristics will be summarized using standard descriptive methods (eg, sample size 
[n], mean, SD, median, minimum, maximum, frequency) as appropriate. 
11.5.
Efficacy Analyses
Antiviral Efficacy 
The primary analysis will consist of a noninferiority evaluation of switching to the D/C/F/TAF 
single-tablet regimen (investigational treatment arm) versus maintaining the current regimen 
consisting of a bPI combined with FTC/TDF (control arm), with respect to the proportion of 
virologic rebounders through Week 48 after the start of treatment in this study. The rebounders 
are defined as

subjects who show confirmed HIV-1 RNA ≥50 copies/mL up to, and including the upper 
bound of the Week 48 window (ie, 54 weeks),

subjects who discontinued prematurely (irrespective of reason) for which the last
available (single) HIV-1 RNA ≥50 copies/mL.
It will be concluded that the D/C/F/TAF single-tablet regimen is noninferior to the control 
regimen if the upper bound of the 2-sided 95% confidence interval (CI) of the difference 
between treatment arms (D/C/F/TAF arm - control arm) in rebounder rate is less than 4% (ie, a 
margin of 4% is applied to noninferiority assessment). The 2-sided 95% CI will be constructed 
using the stratum-adjusted Mantel-Haenszel difference in proportions, where the stratification 
factor (bPI used at screening) determines the strata. 
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If noninferiority of the D/C/F/TAF arm to control arm is established, the upper bound of the 95% 
CI will be compared to 0; if the upper bound of the 95% CI is less than 0, then superiority of 
D/C/F/TAF over the control arm will be established.
The proportion of subjects having confirmed virologic rebound through 24 and 96 weeks of 
treatment. Treatment difference (with 95% CI) through 24 and 96 weeks will be derived similary 
as for the primary efficacy parameter.
The proportion of subjects with HIV-1 RNA <20, <50, <200 copies/mL at Weeks 24, 48, and 96, 
as defined by the FDA snapshot analysis will be analyzed. 
In addition, confirmed virologic response defined as HIV-1 RNA <20, <50, and <200 copies/mL 
at Weeks 24, 48, and 96 determined by the TLOVR algorithm will be analyzed.
The treatment arms will be compared by 95% CIs constructed using the stratum adjusted Mantel-
Haenszel difference in proportions at Weeks 24 and 48, where the stratification factor (bPI at 
screening) determines the strata.
Time to virologic rebound will be graphically presented by means of Kaplan-Meier curves and 
the treatment groups will be compared by means of the Cox proportional hazards model 
including terms for treatments and bPI at screening.
Immunologic Change
The changes from baseline in CD4+ cell count at Weeks 24, 48, and 96 will be summarized 
using descriptive statistics. The difference in changes from baseline in CD4+ cell count between 
the 2 treatment arms and the associated 95% CIs at Weeks 24 and 48 will be constructed using 
ANCOVA, including term for bPI used at screening in the model and baseline CD4+ value as a 
covariate.
Resistance 
HIV-1 genotypes, and phenotypes if applicable, will be analyzed from samples of subjects with 
confirmed virologic rebound (2 consecutive HIV-1 RNA values ≥50 copies/mL or last available 
HIV-1 RNA ≥50 copies/mL) and with HIV-1 RNA value ≥400 copies/mL. The number of PR
mutations (including International AIDS Society [IAS]-USA PI RAMs and IAS-USA primary PI 
mutations), and RT mutations (including IAS-USA NRTI RAMs and IAS-USA NNRTI RAMs), 
as well as specific mutations associated with resistance to DRV, FTC, TFV, and the PIs in the 
control treatment regimen (DRV, ATV, LPV) will be tabulated.42 Fold change (FC) in 50% 
effective concentration (EC50) of ARVs may be analyzed and tabulated.
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11.6.
Safety Analyses
Adverse Events
The original terms used by investigators to identify AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). All reported AEs with onset during the study
will be included in the analysis. For each AE, the percentage of subjects who experience at least 
1 occurrence of the given event will be summarized.
Summaries (number and percentage of subjects) of treatment-emergent AEs (by system organ 
class and preferred term) will be provided by treatment arm. Additional summaries will include 
summaries for AEs by severity grade (with special attention to grade 3 or 4 AEs), investigator’s 
assessment of relationship to treatment, SAEs, and AEs leading to discontinuation of study 
treatment.
Clinical Laboratory Tests
Laboratory data will be summarized by treatment arm and type of test. Descriptive statistics will 
be calculated for each laboratory analyte for observed values and changes from baseline at each 
scheduled time point. Graphical presentation of changes in laboratory parameters can be made as 
applicable. Abnormalities will be determined according to the DAIDS grading table (see 
Attachment 2) and in accordance with the normal ranges of the clinical laboratory. Maximum 
toxicity grade after baseline will be tabulated and special attention will be given to the subjects 
who develop grade 3 or 4 toxicities.
Serum Creatinine and Cystatin C 
The changes from baseline in serum creatinine, eGFRcr (by Cockcroft-Gault and by CKD-EPI) 
and eGFRcyst (by CKD-EPI) at Weeks 24, 48, and 96 will be summarized by treatment arm and 
using descriptive statistics.11,19 The difference between the 2 treatment arms in change from 
baseline in serum creatinine and eGFR at Weeks 24 and 48 will be tested using ANCOVA, 
including corresponding baseline value and other clinically relevant factors (if deemed 
necessary) in the model. A supportive repeated measures analysis will be performed to obtain an 
estimate of the between-treatment difference along with its 95% CI at Weeks 24 and 48. This 
model will include post-baseline change from baseline as a response variable, terms for 
treatment, visit, the interaction of visit and treatment and the corresponding baseline value as a 
covariate and other clinically relevant factors (if deemed necessary). An unstructured covariance 
matrix will be used to model the correlation among repeated measurements.
Renal Biomarkers
Selected renal biomarkers, including RBP and beta-2-microglobulin, will be summarized by 
treatment arm and visit using descriptive statistics. The comparison between the 2 treatment arms 
at Weeks 24 and 48 will be performed using the Van Elteren test stratified for bPI used at 
screening. The within-treatment comparison will be performed using Wilcoxon signed-rank test.
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Vital Signs
Descriptive statistics of vital sign (pulse rate, systolic and diastolic blood pressure) values and 
changes from baseline will be summarized at each scheduled time point. The percentage of
subjects with values beyond clinically important limits will be tabulated. For definitions of 
abnormalities of vital signs, refer to Attachment 6.
Physical examination
Physical examination findings and changes from baseline at each scheduled time point will be 
summarized.
Bone investigations
Baseline, post-baseline, and the percent change from baseline at Weeks 24, 48, and 96 for 
selected bone biomarkers, including CTX, P1NP, PTH, and 25-hydroxy vitamin D, will be 
summarized by treatment arm and visit using descriptive statistics. The within-treatment
comparison will be done using Wilcoxon signed-rank test. The comparison between the 2 
treatment arms will be performed using the Van Elteren test stratified for bPI used at screening.
The percent change from baseline at Weeks 24, 48, and 96 in spine and hip BMD as well as the 
change from baseline in BMD T-score will be summarized by treatment arm and visit using 
descriptive statistics. The between-treatment differences at Weeks 24 and 48 will be estimated 
using ANCOVA model, including baseline BMD value and other clinically relevant factors (if 
deemed necessary) in the model. The within-treatment comparison will be done using paired t-
test. A supportive longitudinal repeated measures analysis will be performed on this endpoint to 
obtain an estimate of the between-treatment difference along with its 95% CI at Weeks 24 and 
48. This model will include post-baseline percent change from baseline as a response variable, 
terms for treatment, visit, the interaction of visit and treatment and the corresponding baseline 
BMD value as a covariate and other clinically relevant factors (if deemed necessary). An 
unstructured covariance matrix will be used to model the correlation among repeated 
measurements.
The BMD T-score will be summarized descriptively. BMD status based on the T-score (normal:
≥-1; osteopenia: from <-1 to -2.5; osteoporosis: <-2.5) will be tabulated.
11.7.
Pharmacokinetic Analyses
Individual pharmacokinetic parameters will be derived with population pharmacokinetic analysis
(if appropriate population pharmacokinetic models are available) using the sparse samples 
collected at Weeks 2, 4, 8, 12, 24, 36, and 48, or ESTD (if applicable) for DRV, and other ARVs 
as requested by the sponsor. Model specifications will be described in separate report(s), as 
applicable.
Descriptive statistics will be calculated for the plasma concentrations of DRV by visit and for the 
derived pharmacokinetic parameters as available, and also for any of the ARVs analyzed upon 
sponsor’s request (COBI, FTC, TAF, TFV, ARVs in the control arm), if applicable. Summary 
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statistics include n, mean, SD, coefficient of variation (CV), geometric mean, median, minimum 
and maximum.
11.8.
Treatment Adherence
Treatment adherence based on pill count will be summarized by means of descriptive statistics 
and frequency tabulations.
11.9.
Data Monitoring Committee
An external DMC will be established to monitor the safety and efficacy information to ensure the 
safety of the subjects enrolled in this study, and to allow regular assessment of the risk/benefit 
profile of the applied therapy schemes. The details will be provided in a separate DMC charter.
A formal futility analysis for lack of (non-inferior) efficacy of the D/C/F/TAF regimen will be 
performed, using a conditional power approach, ie, probability of claiming non-inferiority at the 
completion of the study based on the available interim data. To this end, available interim data 
regarding virologic rebound will be used. Further details regarding the derivation of the 
conditional power and the choice of threshold for the conditional power to stop for futility will 
be provided in the DMC charter and DMC statistical analysis plan. The futility analysis will be 
guided by the DMC, and the sponsor and study team will remain blinded. It is not the intention to 
stop the study early in case of noninferiority/superiority of the D/C/F/TAF regimen versus the 
control group.
In addition, a blinded sample size re-estimation procedure will be applied to allow for an 
adjustment in sample size to maintain adequate power in case the overall rate of rebound is 
anticipated to be different than assumed. Details will be provided in the DMC charter.
The DMC will consist of 2 external medical experts in the relevant therapeutic area and 1 
external statistician. The DMC responsibilities, authorities, and procedures will be documented 
in its charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of subjects, 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.
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12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or noninvestigational) product. An AE does not necessarily have a causal 
relationship with the treatment. 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 noninvestigational) product, whether or not related to that 
medicinal (investigational or noninvestigational) product. (Definition per ICH)
This includes any occurrence that is new in onset, or aggravated in severity or frequency, or 
changed in nature from the baseline condition, abnormal results of protocol-mandated diagnostic 
procedures including laboratory test abnormalities (eg, venipuncture, biopsy), and complications 
and termination of pregnancy.
AE collecting starts with the signing of the ICF (see Section 12.4.1 for time of last AE
recording).
An AE does not include the following (see also Section 12.3 and 12.4.3):

Medical or surgical procedures if the condition that leads to the procedure is an AE

Pre-existing diseases or conditions or laboratory abnormalities present or detected before the 
screening visit that do not worsen; any medical condition or clinically significant laboratory 
abnormality with an onset date before the ICF is signed, is not an AE. It is considered to be 
pre-existing and should be documented in the medical history eCRF.

Situations where no untoward medical occurrence has occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae

Uncomplicated pregnancy

An induced elective abortion to terminate a pregnancy without medical reason
Serious Adverse Event
An 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; however, death is an outcome of an AE, and not an AE in itself

Is life threatening (The subject is at immediate risk of death at the time of the event; this
does not refer to an event that hypothetically might cause death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity
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
Is a congenital anomaly or birth defect in the offspring of a subject who received study drug

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 subject or may require intervention to prevent 1 of the other outcomes listed in the 
definition above. These should usually be considered serious. Examples of such events are:
-
Intensive treatment in an emergency room or at home for allergic bronchospasm
-
Blood dyscrasias or convulsions that do not result in hospitalization
-
Development of drug dependency or drug abuse
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug 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).
Additional clarification on AEs/SAEs:

Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is an SAE.

In-patient hospitalization means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time; this may or may not be overnight. It does not 
include presentation or care within an emergency department.

The investigator should attempt to establish diagnosis of an event on the basis of signs, 
symptoms and/or other clinical information; in such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms.

A distinction should be made between seriousness and severity of an AE. An AE that is 
assessed as grade 4 (potentially life-threatening) should not be confused with an SAE. 
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 ‘severe’ when it meets the predefined 
criteria as described the DAIDS toxicity grading table in Attachment 2 (see also Section
12.1.3).
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 the D/C/F/TAF tablet, the expectedness of an AE will be determined by whether or not it is 
listed in the IB.16 For the bPIs (DRV once daily with rtv or COBI, ATV with rtv or COBI, LPV 
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with rtv) and FTC/TDF used in the control arm, the expectedness of an AE will be determined by 
whether or not it is listed in the applicable USPI current at the time the AE is reported.
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the general categorical descriptors outlined 
in the DAIDS toxicity grading table in Attachment 2.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
A distinction should be made between seriousness and severity of AEs. An AE that is assessed as 
grade 4 (potentially life-threatening) should not be confused with an SAE. Severity is a category 
utilized for rating the intensity of an event, and both AEs and SAEs can be assessed as grade 4. 
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An event is defined as ‘serious’ when it meets 1 of the predefined outcomes described in 
Section 12.1.1.
12.2.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities independent of the underlying medical condition that require medical or surgical 
intervention or lead to study drug interruption or discontinuation must be recorded as an AE, as 
well as an SAE, if applicable. In addition, laboratory or other abnormal assessments (eg, DXA, 
vital signs) that are associated with signs and/or symptoms must be recorded as an AE or SAE if 
they meet the definition of an AE (or SAE) as described in Section 12.1.1. If the laboratory 
abnormality is part of a syndrome, the syndrome or diagnosis (ie, anemia) must be recorded and 
not the laboratory result (ie, decreased hemoglobin).
12.3.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study drug

Unexpected therapeutic or clinical benefit from use of a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)

Lack of effect reports

Pregnancy reports, whether or not maternal exposure to the product occurred (see also 
Section 12.4.3)

Reports of adverse reactions in infants following exposure from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
12.4.
Procedures
12.4.1.
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 subject's last study-related 
procedure (which may include contact for follow-up of safety). SAEs, including those 
spontaneously reported to the investigator within 30 days after the last dose of study drug, must 
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be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
All events that meet the definition of an SAE will be reported as serious SAEs, regardless of 
whether they are protocol-specific assessments. Anticipated events will be recorded and reported 
as described in Attachment 7.
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, 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.
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 SAEs that are unlisted (unexpected) and associated with the use of the study 
drug. The investigator (or sponsor where required) must report these events to the appropriate 
IEC/IRB that approved the protocol unless otherwise required and documented by the IEC/IRB. 
For all studies with an outpatient phase, including open-label studies, the subject 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 subject is participating in a clinical study

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

Subject number
12.4.2.
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 SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a physician from the study site, and transmitted to 
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by 
facsimile (fax).
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All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject'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 drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject 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 an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject’s participation in a study must be reported as an SAE, except hospitalizations 
for the following:

Hospitalizations not intended to treat an acute illness or AE (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 
eCRF). 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 SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.

For convenience the investigator may choose to hospitalize the subject for the duration of 
the treatment period.
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 (see Section 12.1.1).
12.4.3.
Pregnancy 
All initial reports of pregnancy 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. 
Any subject who becomes pregnant during the study must be promptly withdrawn from the 
study. The pregnancy itself is not considered an AE nor is an induced elective abortion to 
terminate a pregnancy without medical reasons.
Abnormal pregnancy outcomes (eg, spontaneous abortion, an induced therapeutic abortion due to 
complications or other medical reasons, stillbirth, and congenital anomaly) are considered SAEs
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and must be reported using the Serious Adverse Event Form. The underlying medical reason for 
this procedure should be recorded as the AE term.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported by the study-site personnel within 24 hours of 
their knowledge of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of pregnancy and any postnatal sequelae in the 
infant will be required, also if the outcome is poststudy.
Refer to Sections 4.1 and 8.1 for definition of female of childbearing potential, pregnancy 
precautions, and contraceptive recommendations.
12.5.
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.
13.
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 subjects, 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.
13.1.
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 an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (see Section 12.4.2). A sample of the suspected 
product should be maintained for further investigation if requested by the sponsor.
13.2.
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.
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14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
The investigational medication, D/C/F/TAF tablets, will be provided by the sponsor. 
The D/C/F/TAF tablets supplied for this study are yellow capsule-shaped, with ‘JG’ on one side 
and ‘8121’ on the other, film-coated tablets containing 800 mg of DRV (as 867 mg of darunavir 
ethanolate), 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (as 11.2 mg TAF fumarate). 
The D/C/F/TAF tablet cores contain silicon dioxide, croscarmellose sodium, microcrystalline 
cellulose, magnesium stearate  polyvinyl alcohol, polyethylene glycol, talc, iron oxide yellow, 
and titanium dioxide.
The bPIs (DRV once daily with rtv or COBI, ATV with rtv or COBI, LPV with rtv) and 
FTC/TDF for the regimens in the control arm will also be provided by the sponsor. If deemed 
necessary by the sponsor, and in case local regulations allow, local sourcing of any compounds 
in the comparator arm can be considered. For information on formulation and list of excipients, 
refer to the D/C/F/TAF IB or the applicable local Prescribing Information.16
14.2.
Packaging
The D/C/F/TAF tablets are packaged in white, high-density polyethylene bottles with a silica gel 
desiccant and polyester coil fiber in each bottle. Each bottle is capped with a white, continuous 
thread, child-resistant polypropylene screw cap fitted with an induction-sealed, aluminum-faced 
liner.
When provided by the sponsor, the bPIs (DRV once daily with rtv or COBI, ATV with rtv or 
COBI, LPV with rtv) and FTC/TDF for the regimens in the control arm will be provided in 
packaging that meets the applicable regulatory requirements.
No study medication can be repacked without prior approval from the sponsor.
14.3.
Labeling
The investigational medication labels will contain information to meet the applicable regulatory 
requirements. 
When provided by the sponsor, the bPIs (DRV once daily with rtv or COBI, ATV with rtv or 
COBI, LPV with rtv) and FTC/TDF for the regimens in the control arm will be labeled with a 
study-specific label that meets the applicable regulatory requirements.
No study medication can be relabeled without prior approval from the sponsor.
14.4.
Preparation, Handling, and Storage 
The D/C/F/TAF tablets, bPIs (DRV once daily with rtv or COBI, ATV with rtv or COBI, LPV 
with rtv) and FTC/TDF in the control arm, should be stored according to the storage conditions 
printed on the label.
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To ensure the stability of D/C/F/TAF tablets, the bPIs and FTC/TDF in the control arm, the drug 
products should not be dispensed into a container other than the container in which it is supplied.
Measures that minimize drug contact with the body should always be considered during 
handling, preparation, and disposal procedures. Any unused study drug should be disposed of in 
accordance with local requirements.
Refer to the pharmacy manual/study site investigational product manual for additional guidance on
study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented in the drug 
accountability form. Subjects, or their legally acceptable representatives where applicable, must 
be instructed to return all original containers, whether empty or containing study drug.
Investigational drug 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 investigational drug, and investigational drug 
returned by the subject, must be available for verification by the sponsor’s study-site monitor 
during on-site monitoring visits. The return to the sponsor of unused investigational drug, or used 
returned investigational drug for destruction, will be documented in the drug return form. When 
the study site is an authorized destruction unit and investigational drug supplies are destroyed 
on-site, this must also be documented in the drug return form.
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Whenever a subject brings his or her study drug to the study site for pill count, 
this is not seen as a return of supplies. Study drug may not be relabeled or reassigned for use by 
other subjects. The investigator agrees neither to dispense the study drug from, nor store it at, 
any site other than the study sites agreed upon with the sponsor.
The monitor will periodically check the supplies of study medication held by the investigator or 
pharmacist to ensure accountability and appropriate storage conditions of all study drug(s) used.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

IB of D/C/F/TAF

IWRS manual

Sample ICF 

eCRF completion guidelines;
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
Pharmacy manual/study site investigational product manual

Virologic rebound monitoring flowchart

Laboratory manual

DXA manual

Contact information page(s)
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during 
the study, subjects 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 subjects who are fully able to understand the risks, 
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
16.2.
Regulatory Ethics Compliance
16.2.1.
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.
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
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 (excluding the ones that are purely 
administrative, with no consequences for subjects, data or study conduct)

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

IB (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials
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
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

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 subjects

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 subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject 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.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
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must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s). 
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent
Each subject 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 subject 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 subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects 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 subject will receive for the treatment of his or her disease. Subjects will be 
told that alternative treatments are available 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 
subject 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 subject, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF the subject is authorizing such access, including permission to 
obtain information about his or her survival status, and agrees to allow his or her study physician 
to recontact the subject for the purpose of obtaining consent for additional safety evaluations, if 
needed, and subsequent disease-related treatments, or to obtain information about his or her 
survival status.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the subject.
Subjects willing to participate in the bone investigation substudy at selected study sites must 
provide informed consent for the substudy.
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16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects 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 subjects confidential.
The informed consent obtained from the subject 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 subject 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.
16.2.5.
Long-term Retention of Samples for Additional Future Research 
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 the D/C/F/TAF
FDC, to understand HIV-1 infection, and to understand differential drug responders. No future 
pharmacogenomic (DNA) research will be conducted. The research may begin at any time 
during the study or the post-study storage period. See also Section 9.1.1.1.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research.
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
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 
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approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, 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) involves only logistic or administrative aspects of the study, the 
IRB (and IEC 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 (see Contact Information page[s] provided separately). 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 eCRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
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.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

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, subject 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
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
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 subject:

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
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor’s study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject 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; drug receipt/dispensing/return records; study drug administration information; and 
date of study completion and reason for early discontinuation of study drug or withdrawal from 
the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
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Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
Data that will be recorded directly into the eCRF are specified in the Source Document 
Identification Form.
The study medication log booklets will be considered source data.
17.5.
Case Report Form Completion
CRFs are provided for each subject in electronic format. 
Electronic data capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic CRF (eCRF), and transmitted 
in a secure manner to the sponsor within the timeframe agreed upon between the sponsor and the 
study site. The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in 
English. Study site personnel must complete the eCRF as soon as possible after a subject visit, 
and the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible. The investigator must verify that all data entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool. The 
investigator or study-site personnel must adjust the eCRF (if applicable) and complete the query.
If corrections to an eCRF are needed after the initial entry into the CRF, this can be done in 3 
different ways:

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).

Study-site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
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, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor's data base.
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
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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 database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, 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.
17.8.
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 post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the eCRFs with the hospital or clinic records (source 
documents). 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 documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
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from this review of eCRFs and source documents 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 documentation 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 study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit for the last subject participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject visit at that study site, in the time frame specified in the Clinical Trial
Agreement.
17.9.2.
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:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local regulatory authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. 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 and comparison with the eCRFs. Subject 
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 agency concerning an upcoming inspection.
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17.11. Use of Information and Publication
All information, including but not limited to information regarding the D/C/F/TAF tablet or the
sponsor's operations (eg, patent application, formulas, manufacturing processes, basic scientific 
data, prior clinical data, formulation information) supplied by the sponsor to the investigator and
not previously published, and any 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 the D/C/F/TAF 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 eCRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. 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. Study subject 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 GPC and International Committee of Medical Journal Editors 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 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 combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), 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 Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
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contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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Summary of Product Characteristics for Viread® (eenofovir disoproxil fumarate). Gilead Sciences Inc; May 
2013.
36.
UNAIDS 2013. AIDS by the numbers. Available at: http://www.unaids.org/en/media/unaids/contentassets/ 
documents/unaidspublication/2013/JC2571_AIDS_by_the_ numbers _ en.pdf.
37.
US Prescribing Information for Emtriva® (emtricitabine). Gilead Sciences Inc; April 2013.
38.
US Prescribing Information for Truvada® (emtricitabine/tenofovir disoproxil fumarate). Gilead Sciences Inc; 
April 2013.
39.
US Prescribing Information for Viread® (tenofovir disoproxil fumarate). Gilead Sciences Inc; November 2012.
40.
WHO Case definitions of HIV for surveillance and revised clinical staging and immunological classification of 
HIV-related disease in adults and children (Table 3), 2007. Available at: http://www.who.int/hiv/pub/guidelines/ 
HIVstaging150307.pdf?ua=1. 
41.
WHO. The use of antiretroviral drugs for treating and preventing HIV infection. June 2013. Available at: 
http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
118
Approved, Date: 29 May 2015
42.
Wensing AM, Calvez V, Gunthard HF, et al. Update of the Drug Resistance Mutations in HIV-1: June/July 
2014. Top Antivir. Med. 2014;22:642-650.
43.
Willig JH, Abroms S, Westfall AO, Routman J, Adusumilli S, Varshney M, et al. Increased regimen durability 
in the era of once-daily fixed-dose combination antiretroviral therapy. AIDS. 2008;22(15):1951-1960. 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
119
Approved, Date: 29 May 2015
ATTACHMENTS
Attachment 1:
Management of Virologic Rebound
a
If HIV-1 RNA ≥50 copies/mL is not confirmed, subjects will remain on their current regimen and the viral load 
will be further monitored.
b
If HIV-1 RNA ≥50 copies/mL is confirmed and HIV-1 RNA value is ≥400 copies/mL, the blood sample from 
the retesting visit or a following visit with HIV-1 RNA ≥400 copies/mL will be used for HIV-1 genotypic 
testing. Phenotypic resistance testing may be done upon request of the study virologist.
c
The subject may remain on study drug and the viral load will be further monitored. Genotype/phenotype testing 
at other time points may be requested if deemed necessary by the protocol virologist. Investigators should 
carefully evaluate the benefits and risks of remaining on study drug for each individual subject and document 
this assessment in the on-site medical record. Investigators who opt to discontinue study drugs for an individual 
subject must inform the sponsor’s medical monitor prior to study drug discontinuation.
d
In case of early discontinuation, an HIV-1 genotypic resistance report, if available, will be forwarded to the 
investigator in order to assist in the selection of a new ARV regimen.
Screening
Treatment Period
Extension / ESTD /
30-Day Follow-up
HIV-1 genotype/ 
phenotypic testingb
If no resistance is determined, 
continue on study drugsc
If resistance is determined, study 
drugs may be discontinued and the 
ARV regimen may be changedd
Confirmed virologic rebound.
If HIV-1 RNA ≥50 copies/mL is confirmed, potential 
causes of virologic rebound should be documented. 
Assessment should include lack of adherence, 
concomitant medication, comorbidities (eg, active 
substance abuse, depression, or other intercurrent 
illnesses).
After 2 to 4 weeks after HIV-1 RNA 
result of ≥50 copies/mL, return for 
scheduled/ unscheduled HIV-1 RNA 
retesting, and bring back study medication 
for pill count and adherence booklet.
At any visit, after maintaining HIV-1 RNA 50 copies/mL, 
a single HIV-1 RNA measurement 50 copies/mL
Unconfirmed 
virologic rebound: 
remain on current 
regimena
Baseline (Day 1)
Remain 
on study
Contact the patient within 48 
hours, assess potential causes
and provide adherence 
counsellation as appropriate 
or take any other action as 
deemed appropriate.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
120
Approved, Date: 29 May 2015
Attachment 2: Division of AIDS 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 
(version 2.0, November 2014), or ‘DAIDS grading table’, is a descriptive terminology to be 
utilized for AE reporting in this study. A grading (severity) scale is provided for each AE term.
General Instructions
Estimating Severity Grade
If the need arises to grade a clinical AE that is not identified in the DAIDS grading table, use the 
category ‘Estimating Severity Grade’ located at the top of the table on the following page. In 
addition, all deaths related to an AE are to be classified as grade 5.
Grading Adult and Pediatric Adverse Events
The DAIDS grading table includes parameters for grading both adult and pediatric AEs. When a 
single set of parameters is not appropriate for grading specific types of AEs for both adult and 
pediatric populations, separate sets of parameters for adult and/or pediatric populations (with 
specified respective age ranges) are provided. If there is no distinction in the table between adult 
and pediatric values for a type of AE, then the single set of parameters listed is to be used for 
grading the severity of both adult and pediatric events of that type.
Determining Severity Grade
If the severity of an AE could fall under either 1 of 2 grades (eg, the severity of an AE could be 
either grade 2 or grade 3), select the higher of the 2 grades for the AE.
Laboratory normal ranges should be taken into consideration to assign gradings to a laboratory 
value.
Definitions
Basic self-care functions
Adults: activities such as bathing, dressing, toileting, 
transfer/movement, continence, and feeding
Young children: activities that are age and culturally appropriate 
(eg, feeding self with culturally appropriate eating implements)
Usual social & functional 
activities
Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for example:
Adults: adaptive tasks and desirable activities, such as going to 
work, shopping, cooking, use of transportation, or pursuing a hobby
Young Children: activities that are age and culturally appropriate 
(eg, social interactions, play activities, learning tasks)
Intervention
Medical, surgical, or other procedures recommended or provided by 
a healthcare professional for the treatment of an adverse event.
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
121
Approved, Date: 29 May 2015
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Clinical adverse event 
NOT identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or minimal 
interference with usual 
social & functional 
activities with 
intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities 
with intervention or 
hospitalization 
indicated 
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-
care functions with 
intervention indicated 
to prevent permanent 
impairment, persistent 
disability, or death 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
122
Approved, Date: 29 May 2015
MAJOR CLINICAL CONDITIONS
CARDIOVASCULAR
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Arrhythmia (by ECG 
or physical 
examination) 
Specify type, if 
applicable
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention indicated 
Non-life-threatening 
symptoms AND Non-
urgent intervention 
indicated 
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Blood Pressure 
Abnormalities1
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
≥18 years of age 
140 to <160 mmHg 
systolic OR 90 to 
<100 mmHg diastolic 
≥160 to <180 mmHg 
systolic OR ≥100 to 
<110 mmHg diastolic 
≥180 mmHg systolic 
OR ≥110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (eg, 
malignant 
hypertension) OR 
Hospitalization 
indicated 
<18 years of age 
>120/80 mmHg 
≥95th to <99th 
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥99th percentile + 
5 mmHg adjusted for 
age, height, and gender 
(systolic and/or 
diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (eg, 
malignant 
hypertension) OR 
Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected 
with oral fluid 
replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent with 
ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
No symptoms AND 
Laboratory or cardiac 
imaging abnormalities 
Symptoms with mild 
to moderate activity or 
exertion 
Symptoms at rest or 
with minimal activity 
or exertion (eg, 
hypoxemia) OR 
Intervention indicated 
(eg, oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (eg, 
vasoactive 
medications, 
ventricular assist 
device, heart 
transplant) 
Hemorrhage (with 
significant acute blood 
loss) 
NA 
Symptoms AND No 
transfusion indicated 
Symptoms AND 
Transfusion of ≤2 units 
packed RBCs indicated 
Life-threatening 
hypotension OR 
Transfusion of >2 units 
packed RBCs (for 
children, packed 
RBCs >10 cc/kg) 
indicated 
1 Blood pressure norms for children <18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 2011; DOI: 10.1542/peds.2009-
2107C.  
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
123
Approved, Date: 29 May 2015
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3 SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Prolonged PR 
Interval or AV Block 
Report only one 
>16 years of age 
PR interval 0.21 to 
<0.25 seconds 
PR interval 
≥0.25 seconds OR 
Type I 2nd degree AV 
block 
Type II 2nd degree AV 
block OR Ventricular 
pause ≥3.0 seconds 
Complete AV block 
≤16 years of age 
1st degree AV block 
(PR interval > normal 
for age and rate) 
Type I 2nd degree AV 
block 
Type II 2nd degree AV 
block OR Ventricular 
pause ≥3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2
0.45 to 0.47 seconds 
>0.47 to 0.50 seconds 
>0.50 seconds OR 
≥0.06 seconds above 
baseline 
Life-threatening 
consequences (eg, 
Torsade de pointes, 
other associated 
serious ventricular 
dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention indicated 
Symptoms AND 
Intervention indicated 
Life-threatening 
embolic event (eg, 
pulmonary embolism, 
thrombus) 
2 As per Bazett’s formula.  
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
124
Approved, Date: 29 May 2015
DERMATOLOGIC
PARAMETER 
GRADE 1 
MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Alopecia (scalp only) 
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with usual 
social & functional 
activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one area 
Localized to more than 
one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(eg, oral antibiotics, 
antifungals, antivirals) 
IV treatment indicated 
(eg, IV antibiotics, 
antifungals, antivirals) 
Life-threatening 
consequences (eg, 
sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or minimal 
interference with usual 
social & functional 
activities 
Marked or generalized 
causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or minimal 
interference with usual 
social & functional 
activities 
Marked or generalized 
causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one area 
Localized to more than 
one area 
Generalized 
NA 
Pruritus3 (without skin 
lesions) 
Itching causing no or 
minimal interference 
with usual social & 
functional activities 
Itching causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA
Rash 
Specify type, if 
applicable 
For the rash 
management applicable 
in this study, see 
Section 9.5.2.
Localized rash 
Diffuse rash OR Target 
lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or 
generalized bullous 
lesions OR Ulceration 
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis 
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section.  
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
125
Approved, Date: 29 May 2015
ENDOCRINE AND METABOLIC
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of current 
medication regimen 
Uncontrolled despite 
treatment modification 
OR Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (eg, 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end 
organ failure) 
Gynecomastia 
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with usual 
social & functional 
activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with usual 
social & functional 
activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social & 
functional activities 
NA
Hyperthyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform 
usual social &
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (eg, 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (eg, 
myxedema coma) 
Lipoatrophy4
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with usual 
social & functional 
activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy5
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with usual 
social & functional 
activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.  
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
126
Approved, Date: 29 May 2015
GASTROINTESTINAL
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3 SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Anorexia 
Loss of appetite 
without decreased oral 
intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive 
intervention indicated 
(eg, tube feeding, total 
parenteral nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention indicated 
(eg, 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 (eg, 
sepsis, perforation) 
Constipation 
NA 
Persistent constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (eg, 
obstruction) 
Diarrhea 
≥1 year of age 
Transient or 
intermittent episodes of 
unformed stools OR 
Increase of ≤3 stools 
over baseline per 24-
hour period 
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4 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 (eg, 
hypotensive shock) 
<1 year of age 
Liquid stools (more 
unformed than usual) 
but usual number of 
stools 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration 
Liquid stools with 
moderate dehydration 
Life-threatening 
consequences (eg, 
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 (eg, 
hypotensive shock) 
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 (eg, 
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 
(eg, IV fluids) 
Life-threatening 
consequences (eg, 
hypotensive shock) 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
127
Approved, Date: 29 May 2015
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated 
Life-threatening 
consequences (eg, 
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 (eg, 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
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 (eg, IV 
fluids) 
Life-threatening 
consequences (eg, 
hypotensive shock) 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
128
Approved, Date: 29 May 2015
MUSCULOSKELETAL
PARAMETER 
GRADE 1 
MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Arthralgia 
Joint pain causing no or 
minimal interference 
with usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing no or 
minimal interference 
with usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint 
stiffness or swelling 
causing inability to 
perform basic self-care 
functions 
Myalgia (generalized) 
Muscle pain causing no 
or minimal interference 
with usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but with 
radiographic findings 
AND No operative 
intervention indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care 
functions 
Osteopenia6
≥30 years of age 
BMD t-score -2.5 to -1 
NA 
NA 
NA 
<30 years of age 
BMD z-score -2 to -1 
NA 
NA 
NA 
Osteoporosis6
≥30 years of age 
NA 
BMD t-score <-2.5 
Pathologic fracture 
(eg, compression 
fracture causing loss of 
vertebral height) 
Pathologic fracture 
causing life-
threatening 
consequences 
<30 years of age 
NA 
BMD z-score <-2 
Pathologic fracture 
(eg, compression 
fracture causing loss of 
vertebral height) 
Pathologic fracture 
causing life-
threatening 
consequences 
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment of osteoporosis 
at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of 
Sheffield, UK. 2007: Printed by the University of Sheffield.  
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
129
Approved, Date: 29 May 2015
NEUROLOGIC
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Acute CNS Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (eg, stroke 
with neurological 
deficit) 
Altered Mental 
Status (for Dementia, 
see Cognitive, 
Behavioral, or 
Attentional 
Disturbance below) 
Changes causing no or 
minimal interference 
with usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Confusion, memory 
impairment, lethargy, 
or somnolence causing 
inability to perform 
usual social & 
functional activities 
Delirium OR 
Obtundation OR Coma 
Ataxia 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities OR No 
symptoms with ataxia 
detected on 
examination 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance (includes 
dementia and attention 
deficit disorder) 
Specify type, if 
applicable 
Disability causing no 
or minimal 
interference with usual 
social & functional 
activities OR 
Specialized resources 
not indicated 
Disability causing 
greater than minimal 
interference with usual 
social & functional 
activities OR 
Specialized resources 
on part-time basis 
indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated 
Disability causing 
inability to perform 
basic self-care 
functions OR 
Institutionalization 
indicated 
Developmental Delay
<18 years of age 
Specify type, if 
applicable 
Mild developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool
appropriate for the 
setting 
Developmental 
regression, either 
motor or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache 
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 
Symptoms causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated OR 
Headache with 
significant impairment 
of alertness or other 
neurologic function 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if 
applicable 
Minimal muscle 
weakness causing no 
or minimal 
interference with usual 
social & functional 
activities OR No 
symptoms with 
decreased strength on 
examination 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social & 
functional activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness impairing 
ventilation 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
130
Approved, Date: 29 May 2015
PARAMETER 
GRADE 1 
MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Neurosensory 
Alteration (includes 
paresthesia and painful 
neuropathy) 
Specify type, if 
applicable 
Minimal paresthesia 
causing no or minimal 
interference with usual 
social & functional 
activities OR No 
symptoms with 
sensory alteration on 
examination 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or 
paresthesia causing 
inability to perform 
basic self-care 
functions 
Seizures 
New Onset Seizure 
≥18 years of age 
NA 
NA 
1 to 3 seizures 
Prolonged and 
repetitive seizures (eg, 
status epilepticus) OR 
Difficult to control (eg, 
refractory epilepsy) 
<18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting 
<5 minutes with 
<24 hours postictal 
state 
Seizure lasting 5 to 
<20 minutes with 
<24 hours postictal 
state 
Seizure lasting 
≥20 minutes 
OR >24 hours postictal 
state 
Prolonged and 
repetitive seizures (eg, 
status epilepticus) OR 
Difficult to control (eg, 
refractory epilepsy) 
Pre-existing Seizure 
NA 
Increased frequency 
from previous level of 
control without change 
in seizure character 
Change in seizure 
character either in 
duration or quality (eg, 
severity or focality) 
Prolonged and 
repetitive seizures (eg, 
status epilepticus) OR 
Difficult to control (eg, 
refractory epilepsy) 
Syncope 
Near syncope without 
loss of consciousness 
(eg, pre-syncope) 
Loss of consciousness 
with no intervention 
indicated 
Loss of consciousness 
AND Hospitalization 
or intervention 
required 
NA 
PREGNANCY, PUERPERIUM, AND PERINATAL
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Fetal Death or 
Stillbirth (report using 
mother’s participant 
ID) 
Report only one 
NA 
NA 
Fetal loss occurring at 
≥20 weeks gestation 
NA 
Preterm Delivery7
(report using mother’s 
participant ID) 
Delivery at 34 to 
<37 weeks gestational 
age 
Delivery at 28 to 
<34 weeks gestational 
age 
Delivery at 24 to 
<28 weeks gestational 
age 
Delivery at <24 weeks 
gestational age 
Spontaneous 
Abortion or 
Miscarriage8 (report 
using mother’s 
participant ID) 
Report only one 
Chemical pregnancy 
Uncomplicated 
spontaneous abortion 
or miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
7 Definition: A delivery of a live-born neonate occurring at ≥20 to <37 weeks gestational age. 
8 Definition: A clinically recognized pregnancy occurring at <20 weeks gestational age.  
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
131
Approved, Date: 29 May 2015
PSYCHIATRIC
PARAMETER 
GRADE 1 
MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Insomnia 
Mild difficulty falling 
asleep, staying asleep, 
or waking up early 
Moderate difficulty 
falling asleep, staying 
asleep, or waking up 
early 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early 
NA 
Psychiatric Disorders 
(includes anxiety,
depression, mania, and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR Behavior 
causing no or minimal 
interference with usual 
social & functional 
activities 
Symptoms with 
intervention indicated 
OR Behavior causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms with 
hospitalization 
indicated OR Behavior 
causing inability to 
perform usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR 
Behavior causing 
inability to perform 
basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death AND 
No wish to kill oneself 
Preoccupied with 
thoughts of death AND 
Wish to kill oneself 
with no specific plan 
or intent 
Thoughts of killing 
oneself with partial or 
complete plans but no 
attempt to do so OR 
Hospitalization 
indicated 
Suicide attempted 
RESPIRATORY
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Acute Bronchospasm 
Forced expiratory 
volume in 1 second or 
peak flow reduced to 
≥70 to <80% OR 
Mild symptoms with 
intervention not 
indicated 
Forced expiratory 
volume in 1 second or 
peak flow 50 to <70% 
OR Symptoms with 
intervention indicated 
OR Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Forced expiratory 
volume in 1 second or 
peak flow 25 to <50% 
OR Symptoms 
causing inability to 
perform usual social 
& functional activities 
Forced expiratory 
volume in 1 second or 
peak flow <25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or 
Respiratory Distress 
Report only one 
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities OR 
Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
to <95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional activities 
OR Pulse oximetry 
<90% 
Respiratory failure with 
ventilator support 
indicated (eg, CPAP, 
BPAP, intubation) 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
132
Approved, Date: 29 May 2015
SENSORY
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Hearing Loss 
≥12 years of age 
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention indicated 
Profound bilateral 
hearing loss (>80 dB at 
2 kHz and above) OR 
Non-serviceable 
hearing (ie, >50 dB 
audiogram and <50% 
speech discrimination) 
<12 years of age 
(based on a 1, 2, 3, 
4, 6 and 8 kHz 
audiogram) 
>20 dB hearing loss at 
≤4 kHz 
>20 dB hearing loss at 
>4 kHz 
>20 dB hearing loss at 
≥3 kHz in one ear with 
additional speech 
language related 
services indicated 
(where available) OR 
Hearing loss sufficient 
to indicate therapeutic 
intervention, including 
hearing aids 
Audiologic indication 
for cochlear implant 
and additional speech-
language related 
services indicated 
(where available) 
Tinnitus 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities with 
intervention not 
indicated 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities with 
intervention indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Vertigo 
Vertigo causing no or 
minimal interference 
with usual social &
functional activities 
Vertigo causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from 
baseline) 
Visual changes 
causing no or minimal 
interference with usual 
social & functional 
activities 
Visual changes causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Visual changes 
causing inability to 
perform usual social & 
functional activities 
Disabling visual loss in 
affected eye(s) 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
133
Approved, Date: 29 May 2015
SYSTEMIC
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with no 
intervention indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of mild 
bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
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 
Cytokine Release 
Syndrome9
Mild signs and 
symptoms AND 
Therapy (ie, antibody 
infusion) interruption 
not indicated 
Therapy (ie, antibody 
infusion) interruption 
indicated AND 
Responds promptly to 
symptomatic treatment 
OR Prophylactic 
medications indicated 
for ≤24 hours 
Prolonged severe signs 
and symptoms OR 
Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (eg, 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
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 
Incapacitating 
symptoms of fatigue or 
malaise causing 
inability to perform 
basic self-care 
functions 
Fever (non-axillary 
temperatures only) 
38.0 to <38.6°C or 
100.4 to <101.5°F 
≥38.6 to <39.3°C or 
≥101.5 to <102.7°F 
≥39.3 to <40.0°C or 
≥102.7 to <104.0°F 
≥40.0°C or ≥104.0°F 
Pain10 (not associated 
with study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Pain causing inability 
to perform usual social 
& functional activities 
Disabling pain causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated 
Serum Sickness11
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention indicated 
(eg, antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(eg, steroids or IV 
fluids) 
Life-threatening 
consequences (eg, 
requiring pressor or 
ventilator support) 
Underweight12
>5 to 19 years of 
age 
NA 
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 of age 
NA 
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 of age 
NA 
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 
9 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
10 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section. 
11 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or dyspnea.  
12 WHO reference tables may be accesed 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 of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤5 years of age.  
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
134
Approved, Date: 29 May 2015
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
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 
(eg, tube feeding, total 
parenteral nutrition) 
URINARY
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Urinary Tract 
Obstruction 
NA 
Signs or symptoms of 
urinary tract 
obstruction without 
hydronephrosis or renal 
dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing 
life-threatening 
consequences 
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
135
Approved, Date: 29 May 2015
SITE REACTIONS TO INJECTIONS AND INFUSIONS
PARAMETER
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Injection Site Pain or 
Tenderness 
Report only one 
Pain or tenderness 
causing no or minimal 
limitation of use of 
limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb 
Pain or tenderness 
causing inability to 
perform usual social & 
functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization 
indicated 
Injection Site 
Erythema or 
Redness13
Report only one 
>15 years of age 
2.5 to <5 cm in 
diameter OR 6.25 to 
<25 cm2 surface area 
AND Symptoms 
causing no or minimal 
interference with 
usual social & 
functional activities 
≥5 to <10 cm in 
diameter OR ≥25 to 
<100 cm2 surface area 
OR Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
≥10 cm in diameter OR 
≥100 cm2 surface area 
OR Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (eg, 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
≤15 years of age 
≤2.5 cm in diameter 
>2.5 cm in diameter 
with <50% surface area 
of the extremity 
segment involved (eg, 
upper arm or thigh) 
≥50% surface area of 
the extremity segment 
involved (eg, upper 
arm or thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage 
Potentially life-
threatening 
consequences (eg, 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or 
Swelling 
Report only one 
>15 years of age 
Same as for Injection 
Site Erythema or 
Redness, >15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, >15 years of 
age 
Same as for Injection 
Site Erythema or 
Redness, >15 years of 
age 
Same as for Injection 
Site Erythema or 
Redness, >15 years of 
age 
≤15 years of age 
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
age 
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
age 
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
age 
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
age 
Injection Site Pruritus 
Itching localized to 
the injection site that
is relieved 
spontaneously or in 
<48 hours of 
treatment 
Itching beyond the 
injection site that is not 
generalized OR Itching 
localized to the 
injection site requiring 
≥48 hours treatment 
Generalized itching 
causing inability to 
perform usual social & 
functional activities 
NA 
13 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area.  
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
136
Approved, Date: 29 May 2015
LABORATORY VALUES
CHEMISTRIES
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Acidosis 
NA 
pH ≥7.3 to <LLN 
pH <7.3 without life-
threatening 
consequences 
pH <7.3 with life-
threatening 
consequences 
Albumin, Low (g/dL; 
g/L) 
3.0 to <LLN 
30 to <LLN 
≥2.0 to <3.0 
≥20 to <30 
<2.0 
<20 
NA 
Alkaline 
Phosphatase, High 
1.25 to <2.5 x ULN 
2.5 to <5.0 x ULN 
5.0 to <10.0 x ULN 
≥10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤7.5 
pH >7.5 without life-
threatening 
consequences 
pH >7.5 with life-
threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25 to <2.5 x ULN 
2.5 to <5.0 x ULN 
5.0 to <10.0 x ULN 
≥10.0 x ULN 
Amylase (Pancreatic) 
or Amylase (Total), 
High 
Report only one 
1.1 to <1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to <5.0 x ULN 
≥5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25 to <2.5 x ULN 
2.5 to <5.0 x ULN 
5.0 to <10.0 x ULN 
≥10.0 x ULN 
Bicarbonate, Low 
(mEq/L; mmol/L) 
16.0 to <LLN 
16.0 to <LLN 
11.0 to <16.0
11.0 to <16.0 
8.0 to <11.0 
8.0 to <11.0 
<8.0 
<8.0 
Bilirubin 
Direct Bilirubin14, 
High 
>28 days of age 
NA 
NA 
>ULN 
>ULN with life-
threatening 
consequences (eg, 
signs and symptoms of 
liver failure) 
≤28 days of age 
ULN to ≤1 mg/dL 
>1 to ≤1.5 mg/dL 
>1.5 to ≤2 mg/dL 
>2 mg/dL 
Total Bilirubin, 
High 
>28 days of age 
1.1 to <1.6 x ULN 
1.6 to <2.6 x ULN 
2.6 to < 5.0 x ULN 
≥5.0 x ULN 
≤28 days of age 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
Calcium, High 
(mg/dL; mmol/L) 
≥7 days of age 
10.6 to <11.5 
2.65 to <2.88 
11.5 to <12.5 
2.88 to <3.13 
12.5 to <13.5 
3.13 to <3.38 
≥13.5 
≥3.38 
<7 days of age 
11.5 to <12.4 
2.88 to <3.10 
12.4 to <12.9 
3.10 to <3.23 
12.9 to <13.5 
3.23 to <3.38 
≥13.5 
≥3.38 
Calcium (Ionized), 
High (mg/dL; 
mmol/L) 
>ULN to <6.0 
>ULN to <1.5 
6.0 to <6.4 
1.5 to <1.6 
6.4 to <7.2 
1.6 to <1.8 
≥7.2 
≥1.8 
Calcium, Low 
(mg/dL; mmol/L) 
≥7 days of age 
7.8 to <8.4 
1.95 to <2.10 
7.0 to <7.8 
1.75 to <1.95 
6.1 to <7.0 
1.53 to <1.75 
<6.1 
<1.53 
<7 days of age 
6.5 to <7.5 
1.63 to <1.88 
6.0 to <6.5 
1.50 to <1.63 
5.50 to <6.0 
1.38 to <1.50 
<5.50 
<1.38 
Calcium (Ionized), 
Low (mg/dL; mmol/L) 
<LLN to 4.0 
<LLN to 1.0 
3.6 to <4.0 
0.9 to <1.0 
3.2 to <3.6 
0.8 to <0.9 
<3.2 
<0.8 
Cardiac Troponin I, 
High 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory 
14 Direct bilirubin >1.5 mg/dL in a participant <28 days of age should be graded as grade 2, if <10% of the total bilirubin.  
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
137
Approved, Date: 29 May 2015
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Creatine Kinase, 
High 
3 to <6 x ULN 
6 to <10 x ULN 
10 to <20 x ULN 
≥20 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
>1.3 to 1.8 x ULN OR 
Increase of >0.3 mg/dL 
above baseline 
>1.8 to <3.5 x ULN 
OR Increase of 1.5 to 
<2.0 x above baseline 
≥3.5 x ULN OR 
Increase of ≥2.0 x 
above baseline 
Creatinine 
Clearance15 or 
eGFR, Low 
Report only one 
NA 
<90 to 60 ml/min or 
ml/min/1.73 m2 OR 10 
to <30% decrease from 
baseline 
<60 to 30ml/min or 
ml/min/1.73 m2 OR 
≥30 to <50% decrease 
from baseline 
<30 ml/min or 
ml/min/1.73 m2 OR 
≥50% decrease from 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
110 to 125 
6.11 to <6.95 
>125 to 250 
6.95 to <13.89 
>250 to 500 
13.89 to <27.75 
>500 
≥27.75 
Nonfasting, High 
116 to 160 
6.44 to <8.89 
>160 to 250 
8.89 to <13.89 
>250 to 500 
13.89 to <27.75 
>500 
≥27.75 
Glucose, Low 
(mg/dL; mmol/L) 
≥1 month of age 
55 to 64 
3.05 to 3.55 
40 to <55 
2.22 to <3.05 
30 to <40 
1.67 to <2.22 
<30 
<1.67 
<1 month of age 
50 to 54 
2.78 to 3.00 
40 to < 50 
2.22 to <2.78 
30 to <40 
1.67 to <2.22 
< 30 
<1.67 
Lactate, High 
ULN to <2.0 x ULN 
without acidosis 
≥2.0 x ULN without 
acidosis 
Increased lactate with 
pH <7.3 without life-
threatening 
consequences 
Increased lactate with 
pH <7.3 with life-
threatening 
consequences 
Lipase, High 
1.1 to <1.5 x ULN 
1.5 to <3.0 x ULN 
3.0 to <5.0 x ULN 
≥5.0 x ULN 
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, 
Fasting, High 
≥18 years of age 
200 to <240 
5.18 to <6.19 
240 to <300 
6.19 to <7.77 
≥300 
≥7.77 
NA 
<18 years of age 
170 to <200 
4.40 to <5.15 
200 to <300 
5.15 to <7.77 
≥300 
≥7.77 
NA 
LDL, Fasting, High 
≥18 years of age 
130 to <160 
3.37 to <4.12 
160 to <190 
4.12 to <4.90 
≥190 
≥4.90 
NA 
>2 to <18 years of 
age 
110 to <130 
2.85 to <3.34 
130 to <190 
3.34 to <4.90 
≥190 
≥4.90 
NA 
Triglycerides, 
Fasting, High 
150 to 300 
1.71 to 3.42 
>300 to 500 
>3.42 to 5.7 
>500 to <1,000 
>5.7 to 11.4 
>1,000 
>11.4 
Magnesium16, Low 
(mEq/L; mmol/L) 
1.2 to <1.4 
0.60 to <0.70 
0.9 to <1.2 
0.45 to <0.60 
0.6 to <0.9 
0.30 to <0.45 
<0.6 
<0.30 
Phosphate, Low 
(mg/dL; mmol/L) 
>14 years of age 
2.0 to < LLN 
0.81 to < LLN 
1.4 to < 2.0 
0.65 to < 0.81 
1.0 to <1.4 
0.32 to <0.65 
<1.0 
<0.32 
1 to 14 years of age 
3.0 to <3.5 
0.97 to <1.13 
2.5 to <3.0 
0.81 to <0.97 
1.5 to <2.5 
0.48 to <0.81 
<1.5 
<0.48 
<1 year of age 
3.5 to <4.5 
1.13 to <1.45 
2.5 to <3.5 
0.81 to <1.13 
1.5 to <2.5 
0.48 to <0.81 
<1.5 
<0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to <6.0 
5.6 to <6.0 
6.0 to <6.5 
6.0 to <6.5 
6.5 to <7.0 
6.5 to <7.0 
≥7.0 
≥7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to <3.4 
3.0 to <3.4 
2.5 to <3.0 
2.5 to <3.0 
2.0 to <2.5 
2.0 to <2.5 
<2.0 
<2.0 
15 Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).  
16 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.  
NCT02269917

D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Sodium, High 
(mEq/L; mmol/L) 
146 to <150 
146 to <150 
150 to <154 
150 to <154 
154 to <160 
154 to <160 
≥160 
≥160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to <135 
130 to <135 
125 to <130 
125 to <135 
121 to <125 
121 to <125 
≤120 
≤120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to <10.0 
0.45 to <0.59 
10.0 to <12.0 
0.59 to <0.71 
12.0 to <15.0 
0.71 to <0.89 
≥15.0
≥0.89 
NCT02269917

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HEMATOLOGY
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Absolute CD4+ 
Count, Low 
(cell/mm3; cells/L) 
>5 years of age 
(not HIV infected) 
300 to <400 
300 to <400 
200 to <300 
200 to <300 
100 to <200 
100 to <200 
<100 
<100 
Absolute Lymphocyte 
Count, Low 
(cell/mm3; cells/L) 
>5 years of age 
(not HIV infected) 
600 to <650 
0.600 x 109 to <0.650 
x 109
500 to <600 
0.500 x 109 to <0.600 
x 109
350 to <500 
0.350 x109 to <0.500 x 
109
<350 
<0.350 x 109 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
>7 days of age 
800 to 1,000 
0.800 x 109 to 1.000 x 
109
600 to 799 
0.600 x 109 to 0.799 x 
109
400 to 599 
0.400 x 109 to 0.599 x 
109
<400 
<0.400 x 109
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 1.500 x 
109
1,000 to 1,249 
1.000 x 109 to 1.249 x 
109
750 to 999 
0.750 x 109 to 0.999 x 
109
<750 
<0.750 x 109
≤1 day of age 
4,000 to 5,000 
4.000 x 109 to 5.000 x 
109
3,000 to 3,999 
3.000 x 109 to 3.999 x 
109
1,500 to 2,999 
1.500 x 109 to 2.999 x 
109
<1,500 
<1.500 x 109
Fibrinogen, 
Decreased (mg/dL; 
g/L) 
100 to <200 
1.00 to <2.00 
OR 
0.75 to <1.00 x LLN 
75 to <100 
0.75 to <1.00 
OR 
≥0.50 to <0.75 x LLN 
50 to <75 
0.50 to <0.75 
OR 
0.25 to <0.50 x LLN 
<50 
<0.50 
OR 
<0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin17, Low 
(g/dL; mmol/L)18
≥13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to <10.0 
5.57 to <6.19 
7.0 to <9.0 
4.34 to <5.57 
<7.0 
<4.34 
≥13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to <9.5 
5.25 to <5.88 
6.5 to <8.5 
4.03 to <5.25 
<6.5 
<4.03 
57 days of age to 
<13 years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to <9.5 
5.25 to <5.88 
6.5 to <8.5 
4.03 to <5.25 
<6.5 
<4.03 
36 to 56 days of 
age (male and 
female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to <8.5 
4.32 to <5.26 
6.0 to <7.0 
3.72 to <4.32 
<6.0 
<3.72 
22 to 35 days of 
age (male and 
female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to <9.5 
4.94 to <5.88 
6.7 to <8.0 
4.15 to <4.94 
<6.7 
<4.15 
8 to ≤21 days of 
age (male and 
female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to <11.0 
5.57 to <6.81 
8.0 to <9.0 
4.96 to <5.57 
<8.0 
<4.96 
≤7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to <13.0 
6.19 to <8.05 
9.0 to <10.0 
5.59 to <6.19 
<9.0 
<5.59 
INR, High 
(not on anticoagulation 
therapy) 
1.1 to <1.5 x ULN 
1.5 to <2.0 x ULN 
2.0 to <3.0 x ULN 
≥3.0 x ULN 
Methemoglobin (% 
hemoglobin) 
5.0 to <10.0% 
10.0 to <15.0% 
15.0 to <20.0% 
≥20.0% 
17 Male and female sex are defined as sex at birth. 
18 The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. For grading hemoglobin 
results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate 
conversion factor for the particular laboratory.  
NCT02269917

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Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
PTT, High 
(not on anticoagulation 
therapy) 
1.1 to <1.66 x ULN 
1.66 to <2.33 x ULN 
2.33 to <3.00 x ULN 
≥3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000 to <124,999
100.000 x 109 to 
<124.999 x 109
50,000 to <100,000 
50.000 x 109 to 
<100.000 x 109
25,000 to <50,000 
25.000 x 109 to 
<50.000 x 109
<25,000 
<25.000 x 109
PT, High 
(not on anticoagulation 
therapy 
1.1 to <1.25 x ULN 
1.25 to <1.50 x ULN 
1.50 to <3.00 x ULN 
≥3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
>7 days of age 
2,000 to 2,499 
2.000 x 109 to 2.499 x 
109
1,500 to 1,999 
1.500 x 109 to 1.999 x 
109
1,000 to 1,499 
1.000 x 109 to 1.499 x 
109
<1,000 
<1.000 x 109
≤7 days of age 
5,500 to 6,999 
5.500 x 109 to 6.999 x 
109
4,000 to 5,499 
4.000 x 109 to 5.499 x 
109
2,500 to 3,999 
2.500 x 109 to 3.999 x 
109
<2,500 
<2.500 x 109
URINALYSIS
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤250 mg 
2+ or ˃250 to ≤500 mg 
>2+ or >500 mg 
NA 
Hematuria (not to be 
reported based on 
dipstick findings or on 
blood believed to be of 
menstrual origin) 
6 to <10 RBCs per 
high power field 
≥10 RBCs per high 
power field 
Gross, with or without 
clots OR With RBC 
casts OR Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+ or higher 
NA 
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APPENDIX A: TOTAL BILIRUBIN TABLE FOR TERM AND PRETERM NEONATES
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Total Bilirubin19, 
High (mg/dL; 
μmol/L)20
Term Neonate21
<24 hours of age 
4 to <7 
68.4 to <119.7 
7 to <10 
119.7 to <171 
10 to <17 
171 to <290.7 
≥17 
≥290.7 
24 to <48 hours of 
age 
5 to <8 
85.5 to <136.8 
8 to <12 
136.8 to <205.2 
12 to <19 
205.2 to <324.9 
≥19 
≥324.9 
48 to <72 hours of 
age 
8.5 to <13 
145.35 to <222.3 
13 to <15 
222.3 to <256.5 
15 to <22 
256.5 to <376.2 
≥22 
≥376.2 
72 hours to 
<7 days of age 
11 to <16 
188.1 to <273.6 
16 to <18 
273.6 to <307.8 
18 to <24 
307.8 to <410.4 
≥24 
≥410.4 
7 to 28 days of age 
(breast feeding) 
5 to <10 
85.5 to <171 
10 to <20 
171 to <342 
20 to <25 
342 to <427.5 
≥25 
≥427.5 
7 to 28 days of age 
(not breast 
feeding) 
1.1 to <1.6 x ULN 
1.6 to <2.6 x ULN 
2.6 to <5.0 x ULN 
≥5.0 x ULN 
Preterm Neonate20
35 to <37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
32 to <35 weeks 
gestational age 
and <7 days of age 
NA 
NA 
10 to <14 
171 to <239.4 
≥14 
≥239.4 
28 to <32 weeks 
gestational age 
and <7 days of age 
NA 
NA 
6 to <10 
102.6 to <171 
≥10 
≥171 
<28 weeks 
gestational age 
and <7 days of age 
NA 
NA 
5 to <8 
85.5 to <136.8 
≥8 
≥136.8 
7 to 28 days of age 
(breast feeding) 
5 to <10 
85.5 to <171 
10 to <20 
171 to <342 
20 to <25 
342 to <427.5 
≥25 
≥427.5 
7 to 28 days of age 
(not breast 
feeding) 
1.1 to <1.6 x ULN 
1.6 to <2.6 x ULN 
2.6 to <5.0 x ULN 
≥5.0 x ULN 
19 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first week of life 
followed by the benign phenomenon of breast milk jaundice after the first week of life. Severity grading in this appendix corresponds 
approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 4. 
20 A laboratory value of 1 mg/dL is equivalent to 17.1 μmol/L. 
21 Definitions: Term is defined as ≥37 weeks gestational age; near-term, as ≥35 weeks gestational age; preterm, as <35 weeks gestational age; and 
neonate, as 0 to 28 days of age.  
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Attachment 3: 
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]) 27,40
Clinical Stage 1
Clinical Stage 1 consists of 1 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 of symptomatic conditions in an HIV-infected adolescents or adults that 
are not included among conditions listed in Clinical Stage 3, and that meet ≥1 of the following 
criteria: a) the conditions are attributed to HIV infection or are indicative of a 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 of conditions 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
NCT02269917

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-
Unexplained persistent fever (above 37.6°C intermittent or constant, for longer than 
1 month)
-
Persistent oral candidiasis
-
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 (<0.5 × 109/L) or chronic thrombocytopenia
(<50 × 109/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
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Attachment 4: 
Management of Clinically Significant Laboratory Toxicities
a
Mandatory confirmation is not warranted for asymptomatic grade 3 or grade 4 glucose elevations in subjects with pre-existing diabetes, and asymptomatic 
grade 3 or grade 4 triglyceride or cholesterol elevations.
Grade 1
Grade 4
Grade 3
Grade 2
May continue dosing 
at the discretion of 
the investigator
Repeat lab to 
confirm toxicity 
gradea
Repeat lab to 
confirm toxicity 
grade
If confirmed and at least possibly related to study medication:
-
Withhold to study medication until Grade 2
-
Restart to study medication at full dose
If confirmed and unrelated to study 
medication, dosing may continue at 
the discretion of the investigator
If confirmed and at 
least possibly related to 
study medication, 
discontinue study 
medication dosing 
permanently and follow 
at periodic intervals at 
least weekly until a 
return to baseline or is 
otherwise explained
If Grade 3 or 4 recurrence that is confirmed and at least possibly 
related to study medication, discontinue all study medication dosing 
permanently
If Grade 3 or 4 recurrence that is considered unrelated to study 
medication, continue study medication at the same dose at the 
discretion of the investigator
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Attachment 5:
Management of Dyslipidemia 
RECOMMENDATIONS
(Adapted from: Guidelines for the evaluation and management of dyslipidemia in human 
immunodeficiency virus [HIV]-Infected adults receiving ARV therapy: Recommendations of the 
HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS 
Clinical Trials Group.2)
Clinicians should monitor patients receiving ARV therapy for dyslipidemia by obtaining a 
fasting lipid profile before and after starting ARV therapy. Frequent monitoring may be indicated 
by the presence of persistent lipid elevation, cardiovascular risk factors, or cardiovascular 
symptoms.
Clinicians should recommend lifestyle modifications, such as increased exercise, weight loss, 
nutrition therapy, smoking cessation, and drug addiction treatment.
Pharmacologic treatment of dyslipidemia should be guided by currently available clinical 
guidelines.
Lipid 
abnormalities 
in 
HIV-infected 
patients, 
specifically 
hypocholesterolemia 
and 
hypertriglyceridemia, were described before the advent of ARV therapy; however, the number of 
patients with lipid abnormalities appears to be increasing in the HAART era. Patients often 
develop lipid abnormalities within 3 months of initiation of ARV therapy. The full clinical 
significance of these laboratory abnormalities is not yet clear, although the abnormalities may be 
associated with premature coronary artery disease (CAD) in some patients, especially those with 
other risk factors for coronary heart disease (CHD) or the metabolic syndrome previously 
referred to as syndrome X.
Major risk factors (LDL cholesterol excluded) that modify LDL goals* are:
-
cigarette smoking;
-
hypertension (blood pressure ≥140/90 mmHg or on antihypertensive medication);
-
low HDL cholesterol (<40 mg/dL)†;
-
family 
history 
of 
premature 
CHD
(CHD in male first-degree relative <55 years; CHD in female first-degree relative <65 years)
-
age (men ≥45 years; women ≥55 years)
*
All these risk factors are captured in the eCRF.
†
HDL cholesterol ≥60 mg/dL counts as a ‘negative’ risk factor; its presence removes one risk factor from the 
total count
Hypertriglyceridemia, low HDL cholesterol levels, and elevated LDL cholesterol levels have 
been described in patients receiving ARV therapy, especially PIs. NNRTI use has been 
associated with hypercholesterolemia. The mechanism by which PIs cause dyslipidemia is 
unclear. Hypertriglyceridemia seems to be most significant in patients with regimens that include 
NCT02269917

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Clinical Protocol TMC114IFD3013 Amendment 4
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Approved, Date: 29 May 2015
low-dose rtv. Significant hypertriglyceridemia (>500 mg/dL) is associated with an increased risk 
of pancreatitis, particularly in patients with other risk factors for pancreatitis eg, alcohol or 
didanosine use).
Lipid abnormalities in HIV-infected patients receiving ARV therapy may occur in conjunction 
with body fat changes. Secondary causes of dyslipidemia, including diabetes, hypothyroidism, 
liver disease, chronic renal failure, and other medications, such as progestins, anabolic steroids, 
and corticosteroids, should be considered in patients with new onset dyslipidemia.
A fasting lipid profile (total, LDL and HDL cholesterol, triglycerides) should be obtained prior to 
starting ARV treatment (ideally at baseline visit). A fasting lipid profile should be obtained 3 to 
6 months after starting or changing ARV therapy (ideally at each visit of the study protocol).
Alternatively, if collection of a fasting sample is not feasible, a nonfasted total cholesterol and 
HDL cholesterol may be obtained. The clinician should proceed with a fasting lipoprotein profile 
when the nonfasted total cholesterol is >200 mg/dL or HDL cholesterol is <40 mg/dL.
The management of lipid disorders in HIV-infected patients parallels management in non-HIV-
infected patients (see Table 7 and Table 8). Individual risk assessments for an acute coronary 
event and management of lipid disorders can be accomplished by following current guidelines 
for assessment and management, such as those published by the National Cholesterol Education 
Program (NCEP) and the Adult AIDS Clinical Trial Group (ACTG) Cardiovascular Disease 
Focus Group (see Table 7 and Table 8). Treatment of dyslipidemia should include lifestyle and 
risk modification with or without pharmacological therapies.
For patients without known CAD, therapeutic lifestyle changes should be the first intervention 
for the treatment of lipid disorders. These changes include increased physical exercise, weight 
reduction when indicated, smoking cessation and dietary changes. Consultation with a registered 
dietitian may be helpful in achieving dietary goals [restriction of total fat to 25%-30% of total 
caloric intake, and dietary cholesterol to <200 mg/day; use of plant sterols (2 gm/d) found in 
commercial margarines (eg,, Benecol or Basikol), and increased soluble fiber (10-25 g/d)].
Lipid-lowering agents should be considered for hyperlipidemias that do not respond to changes 
in ARV therapy or therapeutic lifestyle changes, or for patients in whom such modifications are 
not appropriate. The first-line pharmacological treatment for patients with isolated elevation of 
LDL cholesterol is statin therapy (see Table 8). Pravastatin is the safest drug for treating 
hyperlipidemia during concurrent therapy with currently FDA approved PIs. Atorvastatin can be 
used cautiously at lower doses (5- 10 mg) with careful titration. Rosuvastatin will not likely 
interact with PIs and NNRTIs. Use of other statins, particularly lovastatin and simvastatin, is 
contraindicated.
Fibric acid derivatives, such as gemfibrozil and fenofibrate, are the first-line treatment for 
isolated elevation of fasting triglyceride levels. The threshold suggested for intervention is 
500 mg/dL.
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Gemfibrozil and fenofibrate are not metabolized via the CYP system and are generally safe to 
use in patients receiving ARV therapy. For patients with high triglycerides in whom LDL 
cholesterol cannot be measured, the non-HDL cholesterol level may be calculated to guide 
initiation of therapy (total – HDL cholesterol). 
Patients with persistent high-grade hypertriglyceridemia (>1000 mg/dL) may benefit from a very 
low-fat diet, even if they are not overweight.
Table 7:
LDL and non-HDL Cholesterol Goals and Thresholds for Therapeutic Lifestyle Changes and 
Drug Therapy in Different Risk Categories
Risk Category
LDL Goal 
(mg/dL)
LDL Level at 
Which to Initiate 
Lifestyle 
Changes 
(mg/dL)
LDL Level at 
Which to 
Consider Drug 
Therapy 
(mg/dL)
Non-HDL Goal 
(mg/dL)*
CHD or CHD risk 
equivalents: diabetes mellitus, 
atherosclerotic disease (CAD 
or stroke), or multiple risk 
factors (10-year risk >20%)
<100
≥100
<130 (100-129: 
drug optional)†
≥130
2+ risk factors: HDL <40, 
strong
family history, age >45 years, 
and
smoking (10-year risk >20%)
<130
≥130
10-year risk
10%-20%: ≥130
10-year risk 
<10%: ≥160
<160
0-1 risk factor‡
<160
≥160
≥190 (160-189: 
LDL-lowering 
drug optional)
<190
*
Non-HDL cholesterol = (total – HDL cholesterol). When LDL cholesterol cannot be measured because the 
triglyceride level is >200 mg/dL, non-HDL cholesterol may be used as a secondary goal. The non-HDL 
cholesterol goal is 30 mg/dL higher than the LDL cholesterol goal.
†
Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol level of 
<100 mg/dL cannot be achieved by therapeutic lifestyle changes (dietary and exercise intervention). Others prefer 
use of drugs that primarily modify triglycerides and HDL cholesterol (eg, nicotine acid or fibrate). Clinical 
judgment also may suggest deferring drug therapy in this subcategory.
‡
Almost all people with 0 or 1 risk factors have a 10-year risk <10%; thus, 10-year risk assessment in people with 
0 or 1 risk factors is not necessary.
For those with both elevated serum LDL cholesterol and triglyceride levels, combination therapy 
with a statin and fibrate may be needed but should be used with extreme caution because of 
overlapping toxicity (rhabdomyolysis) profiles. Therapy should begin first with a statin, followed 
by the addition of the fibric acid derivative if response to the maximal statin dose is suboptimal 
after 3 to 4 months of treatment. Routine monitoring for hepatic and muscle toxicity should be 
performed in these situations.
The use of additional drugs, such as nicotinic acid or bile sequestrants, may be necessary to 
manage dyslipidemia. Nicotinic acid may cause hepatotoxicity and elevated serum glucose 
levels. Therefore, low-dose therapy with incremental dose increases is advisable for those 
patients who require this drug. Bile acid sequestrants (eg, colesevelam 3 tablets twice daily or 
ezetimibe 10 mg once daily) may also be used but may interfere with absorption of oral 
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medications; therefore, proper timing of the dosing of this drug is important when used in 
conjunction with ARV medications (ie, 1 hour before or 4 hours after).
Table 8:
Choice of Drug Therapy for Dyslipidemia in HIV-infected Individuals Receiving HAART
Lipid Abnormality
First Choice
Second Choice (or if 
Additional Treatment is 
Needed)
Comments
Isolated high LDL
cholesterol
Statin*
Fibrate
Start with low doses of statins 
and titrate upward.
Patients receiving PIs may be at 
increased risk of statin-induced 
myopathy.
Combined 
hyperlipidemia (high 
cholesterol and high 
triglycerides)
Fibrate or statin*
If starting with fibrate, add 
statin*
If starting with statin*, add 
fibrate
Combining statin and a fibrate 
may increase risk for myopathy
Isolated 
hypertriglyceridemia
Fibrate
Statin*
Combining statin and a fibrate 
may increase risk for myopathy.
* Statins should be dosed at bedtime. Simvastatin and lovastatin are not allowed in patients receiving DRV.
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Attachment 6:
Cardiovascular Safety: Definitions of Abnormalities
Vital Signs
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 AEs related to hypotension/hypertension should be done according to the DAIDS grading 
table (Attachment 2).
ECG
Abnormality Code
Heart Rate (bpm)
PR
(ms)
QRS
(ms)
QTca
(ms)
Abnormally low
50 bpm
N/A
50 ms
-
Abnormally high
120 bpm
210 ms
120 ms
-
]450 ms, 480 ms]
-
-
-
450 <QTc 480 
]480 ms, 500 ms]
-
-
-
480 <QTc 500
More than 500 ms
-
-
-
QTc >500 
a
Categories for QTc parameters are defined based on the ICH E14 Guidance.9
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Attachment 7:
Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen. For 
the purposes of this study the following events will be considered anticipated events:

AIDS dementia (PT AIDS dementia complex)

Bacterial infections, multiple or recurrent* 

Candidiasis of bronchi, trachea, or lungs 

Candidiasis of esophagus†

Cervical cancer, invasive§

Coccidioidomycosis, disseminated or extrapulmonary 

Cryptococcosis, extrapulmonary 

Cryptosporidiosis, chronic intestinal (>1 month's duration) 

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month 

Cytomegalovirus retinitis (with loss of vision)†

Encephalopathy, HIV related 

Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or esophagitis 
(onset at age >1 month) 

Herpes zoster infections

Histoplasmosis, disseminated or extrapulmonary 

Isosporiasis, chronic intestinal (>1 month's duration) 

Kaposi sarcoma†

Leishmaniasis

Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex*†

Lymphoma, Burkitt (or equivalent term) 

Lymphoma, immunoblastic (or equivalent term) 

Lymphoma, primary, of brain 

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary†

Mycobacterium tuberculosis of any site, pulmonary,†§ disseminated,† or extrapulmonary†

Mycobacterium, other species or unidentified species, disseminated† or extrapulmonary†

Oral candidiasis 

Peripheral neuropathy  

Pneumocystis jirovecii pneumonia†

Pneumonia, recurrent†§

Progressive multifocal leukoencephalopathy 
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
Salmonella septicemia, recurrent 

Toxoplasmosis of brain, onset at age >1 month†

Tuberculosis

Wasting syndrome attributed to HIV
* Only among children aged <13 years28
† 
Condition that might be diagnosed presumptively
§ 
Only among adults and adolescents aged >13 years27
Reporting of Anticipated Events
These events will be captured on the CRF and in the database, and will be reported to the sponsor as 
described in Section 12.4.1, All Adverse Events. Any event that meets serious adverse event criteria will 
be reported to the sponsor within the appropriate timeline as described in Section 12.4.2, Serious Adverse 
Events. These anticipated events are exempt from expedited reporting as individual single cases to Health 
Authorities, Investigators and Independent Ethics Committee/Institutional Review Board. However if 
based on an aggregate review, it is determined that an anticipated event is possibly related to study drug, 
the sponsor will report these events in an expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
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INVESTIGATOR AGREEMENT
I have read this document 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 drug, 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):
M. Opsomer
Institution:
Janssen Research & Development
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.
LAST PAGE
NCT02269917

 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Magda Opsomer
29May2015, 15:29:10 PM, UTC
Document Approval
NCT02269917

CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 14 May 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Phase 3, randomized, active-controlled, open-label study to evaluate the efficacy, safety 
and tolerability of switching to a darunavir/cobicistat/emtricitabine/tenofovir alafenamide 
(D/C/F/TAF) once-daily single-tablet regimen versus continuing the current regimen 
consisting of a boosted protease inhibitor (bPI) combined with emtricitabine/tenofovir 
disoproxil fumarate (FTC/TDF) in virologically-suppressed, human immunodeficiency 
virus type 1 (HIV-1) infected subjects.
Protocol TMC114IFD3013; Phase 3
D/C/F/TAF  (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, 
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used 
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact 
Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
EudraCT NUMBER:         2014-003052-31
Status:
Approved  
Date:
14 May 2020
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
EDMS number:
EDMS-RIM-47474, 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.
NCT02269917

COVID-19 Appendix
D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 14 May 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 judgement 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 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 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. 
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.

COVID-19 Appendix
D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 14 May 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL
Drug Supply and Drug Return

Normal study drug shipment from the Janssen depots to the sites will continue until further 
notice.

Normal study drug dispensation to subject by site.

If study treatment dispensation to subject at site might be impacted local sponsor team should 
be informed by site. Direct-to-patient (DTP) process, when permitted by local regulations in 
the country, to allow sites to ship study treatment to the subjects will be initiated and only 
after approval by the sponsor, the granted site may ship treatment to subject with support of 
sponsor supply team. Where DTP shipments are deemed necessary, the process must be 
coordinated between the site and sponsor staff following standard DTP procedures for 
arranging shipment and adhering to associated approvals and documentation requirements.

Where necessary upon local guidance, subjects will consent upfront before the DTP process 
will be implemented.

In case of remote visits, return of study drug will be postponed and both used and unused kits 
should be kept home by the subject at a secure location. The subject will be requested to bring 
the used and un-used kits back to site at a next on-site visit, in or outside the study.

There will be no central study drug return organized by the sponsor.
Subject Visits and Assessments
On-site Visits
Where possible and allowed subjects will come to site to have their Every 6 Month Follow-up 
(Every 6M FU) visit performed as required per protocol and all assessments done as per Time and
Events schedule.
Delaying on-site visits might be considered. On-site visits conducted outside of visit windows 
(±7 days) is considered a minor protocol deviation. Due to the projected timeframe of the 
COVID-19 pandemic, this is not considered a viable approach. Note that the treatment continuity
of the subject should be guaranteed when subjects are coming to site outside the visit window.
The relationship to COVID-19 for delayed or missing protocol-specified information/procedures 
will be documented in the patient source documents.
Remote Assessment Visits
Where subjects do not have the option to come to site (per local health authority restriction) or 
sites are not able to accommodate the Every 6M FU visits, site staff will be asked to collect any 
assessments that can be made remotely. These assessments are important for the continued 
evaluation of safety and efficacy as patients complete the study period. Conducting remote 
assessment visits enables this important data to be collected without risking patient, family, and 
site staff safety. As allowable per local regulations, these remote assessments can be conducted 
via telephone with patients in their homes. Assessments that can be completed remotely include a 

COVID-19 Appendix
D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 14 May 2020
collection of adverse events, concomitant medications. Site staff will be asked to adhere to the 
Time and Events Schedule outlined in the protocol, to the extent feasible, when scheduling remote 
assessments.
Where necessary upon local guidance, subjects will consent upfront before remote visits will be 
implemented.
Many of the assessments required in the Time and Events Schedule are not in scope for remote 
visits. Physical examinations, vital signs and laboratory assessments (urine & blood sample 
collection) will not possible to be collected in a remote setting. This data will be missing for 
patients that are unable to attend site visits.
In cases where local labs were done at the discretion of the principal investigator, significant 
abnormalities should be discussed with the SRP, if necessary, and entered in the electronic Data 
Capture (eDC). An extra comment should be entered in the eDC to document the local laboratory
sampling. Laboratory sampling and non-significant laboratory abnormalities will not be entered.
The relationship to COVID-19 for missing protocol-specified information/procedures will be 
documented in the patient source documents.
Early Withdrawal From the Study
If a subject is lost to follow-up, or is unwilling to have a remote assessment performed, the subject 
will be considered an early withdrawal. Sites will be reminded to follow the procedures outlined 
in the protocol.
Protocol Deviations
All COVID-19 related protocol deviations will be reported and will be summarized in the Clinical 
Study Report.

COVID-19 Appendix
D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114IFD3013
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 14 May 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):
Erika Van Landuyt
Institution:
Janssen Research & Development 
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.