Clinical trial NCT02431247
Conditions: Immunodeficiency Virus Type 1, Human
Keywords: Immunodeficiency Virus Type 1, Human Darunavir Cobicistat Tenofovir Alafenamide Emtricitabine Tenofovir Disoproxil Fumarate
Sponsor: Janssen Sciences Ireland UC
Start date: 2015-07-06; Completion date: 2020-09-30
Enrollment: 725 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to demonstrate non-inferiority in efficacy of a darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed dose combination (FDC) tablet versus Darunavir/Cobicistat (DRV/COBI) FDC coadministered with Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) FDC in human immunodeficiency virus-1 (HIV-1) infected, antiretroviral (ARV) treatment naive adult participants.

Detailed description:
This is a Phase 3, multicenter (when more than one hospital or medical school team work on a medical research study), randomized (study drug assigned by chance), double-blind (a medical research study in which neither the researchers nor the participant know what treatment the participant is receiving), active-controlled (study in which the experimental treatment or procedure is compared to a standard \[control\] treatment or procedure) study. The study consists of 5 periods: a Screening period, Double-blind treatment period, Single-arm treatment period, Extension period and a Follow-up period. Participants will receive either darunavir (DRV)/ cobicistat (COBI)/emtricitabine (FTC) /tenofovir alafenamide (TAF) fixed dose combination (D/C/F/TAF FDC) or DRV/COBI FDC along with FTC/TDF FDC. Primarily percentage of participants with human immunodeficiency virus (HIV) -1 Ribonucleic acid (RNA) less than (\<) 50 copies per milliliter (copies/ml) defined by snapshot analysis will be evaluated. Participants' safety will be monitored throughout the study.

Arms: arm 1: Subject will receive a single oral tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF fixed dose combination \[FDC\]) once daily along with DRV/COBI FDC-matching and FTC/TDF FDC-matching placebo tablets once daily up to Week 48 analysis unblinding visit (i.e. after last subject has reached Week 48). After Week 48 analysis unblinding visit, subjects will receive a single tablet containing D/C/F/TAF FDC once daily up to Week 96. arm 2: Subject will receive DRV 800 mg/COBI 150 mg FDC and FTC 200 mg/TDF 300 mg FDC along with D/C/F/TAF FDC-matching placebo tablet once daily up to Week 48 analysis unblinding (i.e. after last subject has reached Week 48). After Week 48 analysis unblinding, subjects will receive a single tablet containing D/C/F/TAF FDC once daily up to Week 96.
Interventions: intervention 1: Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide FDC intervention 2: DRV/COBI FDC intervention 3: FTC/TDF FDC intervention 4: D/C/F/TAF FDC - Matching Placebo intervention 5: FTC/TDF FDC Matching Placebo intervention 6: DRV/COBI FDC Matching Placebo
Intervention descriptions: intervention 1: A tablet containing DRV 800 mg, COBI 150 mg, FTC 200 mg and TAF) 10 mg will be administered once daily. intervention 2: A tablet containing DRV 800 mg and COBI 150 mg will be administered once daily. intervention 3: A tablet containing FTC 200 mg and TDF 300 mg will be administered once daily. intervention 4: Matching placebo of D/C/F/TAF FDC will be administered once daily. intervention 5: Matching placebo of FTC/TDF FDC will be administered once daily. intervention 6: Matching placebo of DRV/COBI FDC will be administered once daily.

Protocol documents:
Prot_002.pdf: 
1
Status: Approved, Date: 18 April 2017
Janssen Research & Development *
Clinical Protocol
A Phase 3, randomized, active-controlled, double-blind study to evaluate efficacy and 
safety of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) once daily 
fixed dose combination regimen versus a regimen consisting of darunavir/cobicistat fixed 
dose combination coadministered with emtricitabine/tenofovir disoproxil fumarate fixed 
dose combination in antiretroviral treatment-naïve human immunodeficiency virus type 1 
infected subjects.
Protocol TMC114FD2HTX3001 Amendment 2; 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 
Sciences Ireland UC; 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.  
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: 2015-000754-38
Status:
Approved
Date:
18 April 2017
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
EDMS number:
EDMS-ERI-97893189, 11.0
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
2
Approved, Date: 18 April 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENT ......................................................................................................................... 6
SYNOPSIS.................................................................................................................................................... 9
TIME AND EVENT SCHEDULE................................................................................................................. 18
PERIOD....................................................................................................................................................... 18
ABBREVIATIONS ...................................................................................................................................... 23
DEFINITIONS OF TERMS.......................................................................................................................... 26
1.
INTRODUCTION................................................................................................................................ 27
1.1.
Background .................................................................................................................................... 27
1.2.
Darunavir (PREZISTA®)................................................................................................................ 28
1.3.
Cobicistat (Tybost®)....................................................................................................................... 29
1.4.
Emtricitabine (Emtriva®) ................................................................................................................ 30
1.5.
Tenofovir Alafenamide ................................................................................................................... 30
1.5.1.
General Information.................................................................................................................... 30
1.5.2.
Preclinical Pharmacology and Toxicology.................................................................................. 31
1.5.3.
Preclinical Pharmacokinetics...................................................................................................... 32
1.5.4.
Nonclinical Toxicology ................................................................................................................ 33
1.5.5.
Clinical Studies ........................................................................................................................... 34
1.6.
Comparator Drug ........................................................................................................................... 38
1.7.
Overall Rationale and Risks Assessment for the Study ................................................................ 38
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 40
2.1.
Objectives ...................................................................................................................................... 40
2.2.
Hypothesis ..................................................................................................................................... 41
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 41
3.1.
Overview of Study Design.............................................................................................................. 41
3.2.
Study Design Rationale.................................................................................................................. 45
3.3.
Dose Selection Rationale............................................................................................................... 46
4.
SUBJECT POPULATION.................................................................................................................. 47
4.1.
Inclusion Criteria ............................................................................................................................ 47
4.2.
Exclusion Criteria ........................................................................................................................... 50
4.3.
Prohibitions and Restrictions ......................................................................................................... 52
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 52
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 53
7.
TREATMENT COMPLIANCE............................................................................................................ 55
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 55
8.1.
Disallowed and Cautioned Concomitant Therapy.......................................................................... 56
9.
STUDY EVALUATIONS .................................................................................................................... 60
9.1.
Study Procedures........................................................................................................................... 60
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
3
Approved, Date: 18 April 2017
9.1.1.
Overview..................................................................................................................................... 60
9.1.2.
Pre-treatment Phase................................................................................................................... 62
9.1.2.1.
Screening Visit......................................................................................................................... 62
9.1.2.2.
Baseline Visit (Day 1) .............................................................................................................. 63
9.1.3.
Double-blind Treatment Phase................................................................................................... 65
9.1.4.
Open-label Single-arm Phase .................................................................................................... 67
9.1.5.
Extension Phase......................................................................................................................... 68
9.1.6.
Post-treatment Phase................................................................................................................. 69
9.1.6.1.
Early Study Treatment Discontinuation Visit ........................................................................... 69
9.1.6.2.
30-Day Follow-up Visit............................................................................................................. 71
9.2.
Efficacy Evaluations....................................................................................................................... 71
9.2.1.
Antiviral Efficacy and Immunologic Change ............................................................................... 71
9.2.2.
Resistance Determinations......................................................................................................... 72
9.2.2.1.
Virologic Failure....................................................................................................................... 72
9.2.2.2.
Subjects Eligible for Resistance Testing ................................................................................. 72
9.3.
Pharmacokinetics Evaluations ....................................................................................................... 77
9.3.1.
Evaluations ................................................................................................................................. 77
9.3.2.
Analytical Procedures................................................................................................................. 77
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 77
9.4.
Safety Evaluations ......................................................................................................................... 78
9.4.1.
Adverse Events........................................................................................................................... 78
9.4.2.
Clinical Laboratory Tests ............................................................................................................ 79
9.4.3.
Electrocardiogram....................................................................................................................... 81
9.4.4.
Vital Signs................................................................................................................................... 81
9.4.5.
Physical Examination.................................................................................................................. 82
9.4.6.
Bone Investigation Substudy ...................................................................................................... 82
9.5.
Toxicity Management..................................................................................................................... 83
9.5.1.
General Guidance for the Management of Clinical Events and Laboratory Abnormalities ........ 83
9.5.2.
Cutaneous Events/Rash............................................................................................................. 84
9.5.3.
Acute Systemic Allergic Reaction............................................................................................... 86
9.5.4.
Potential Renal Toxicity .............................................................................................................. 88
9.5.5.
Potential Bone Toxicity ............................................................................................................... 89
9.5.6.
Potential Posterior Uveitis Cases ............................................................................................... 89
9.5.7.
Hyperglycemia............................................................................................................................ 89
9.5.8.
Hypertriglyceridemia and Hypercholesterolemia........................................................................ 90
9.5.9.
Lipodystrophy/Fat Redistribution/Body Changes ....................................................................... 90
9.6.
Sample Collection and Handling.................................................................................................... 90
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 91
10.1.
Completion ..................................................................................................................................... 91
10.2.
Withdrawal From the Study............................................................................................................ 91
11.
STATISTICAL METHODS................................................................................................................. 93
11.1.
Analysis Objectives and Endpoints................................................................................................ 93
11.2.
Subject Information ........................................................................................................................ 94
11.3.
Sample Size Determination ........................................................................................................... 95
11.4.
Efficacy Analyses ........................................................................................................................... 95
11.4.1.
Primary Analysis ......................................................................................................................... 95
11.4.2.
Secondary Analyses................................................................................................................... 96
11.5.
Pharmacokinetic Analyses............................................................................................................. 96
11.6.
Safety Analyses ............................................................................................................................. 97
11.7.
Treatment Adherence .................................................................................................................... 98
11.8.
Data Monitoring Committee ........................................................................................................... 99
12.
ADVERSE EVENT REPORTING ...................................................................................................... 99
12.1.
Definitions ...................................................................................................................................... 99
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 99
12.1.2.
Attribution Definitions................................................................................................................ 102
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
4
Approved, Date: 18 April 2017
12.1.3.
Severity Criteria ........................................................................................................................ 102
12.2.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events 
or Serious Adverse Events .......................................................................................................... 102
12.3.
Special Reporting Situations........................................................................................................ 103
12.4.
Procedures................................................................................................................................... 103
12.4.1.
All Adverse Events.................................................................................................................... 103
12.4.2.
Serious Adverse Events ........................................................................................................... 104
12.4.3.
Pregnancy................................................................................................................................. 105
12.5.
Contacting Sponsor Regarding Safety......................................................................................... 106
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 106
13.1.
Procedures................................................................................................................................... 106
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 106
14.
STUDY DRUG INFORMATION....................................................................................................... 106
14.1.
Physical Description of Study Drug(s) ......................................................................................... 106
14.2.
Packaging .................................................................................................................................... 107
14.3.
Labeling........................................................................................................................................ 108
14.4.
Preparation, Handling, and Storage............................................................................................. 108
14.5.
Drug Accountability ...................................................................................................................... 108
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 109
16.
ETHICAL ASPECTS ....................................................................................................................... 109
16.1.
Study-specific Design Considerations ......................................................................................... 109
16.2.
Regulatory Ethics Compliance..................................................................................................... 109
16.2.1.
Investigator Responsibilities ..................................................................................................... 109
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 110
16.2.3.
Informed Consent ..................................................................................................................... 111
16.2.4.
Privacy of Personal Data .......................................................................................................... 112
16.2.5.
Long-term Retention of Samples for Additional Future ............................................................ 113
16.2.6.
Country Selection ..................................................................................................................... 113
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 113
17.1.
Protocol Amendments.................................................................................................................. 113
17.2.
Regulatory Documentation .......................................................................................................... 114
17.2.1.
Regulatory Approval/Notification .............................................................................................. 114
17.2.2.
Required Prestudy Documentation........................................................................................... 114
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 115
17.4.
Source Documentation................................................................................................................. 115
17.5.
Case Report Form Completion .................................................................................................... 115
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 116
17.7.
Record Retention ......................................................................................................................... 116
17.8.
Monitoring .................................................................................................................................... 117
17.9.
Study Completion/Termination..................................................................................................... 118
17.9.1.
Study Completion ..................................................................................................................... 118
17.9.2.
Study Termination..................................................................................................................... 118
17.10.
On-site Audits............................................................................................................................... 118
17.11.
Use of Information and Publication.............................................................................................. 118
REFERENCES.......................................................................................................................................... 121
ATTACHMENTS....................................................................................................................................... 124
INVESTIGATOR AGREEMENT ............................................................................................................... 157
LAST PAGE.............................................................................................................................................. 157
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
5
Approved, Date: 18 April 2017
LIST OF ATTACHMENTS
Attachment 1: 
Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events ........................................................................................................ 125
Attachment 2: 
WHO Clinical Staging of HIV/AIDS .......................................................................... 147
Attachment 3: 
Management of Clinically Significant Laboratory Toxicities ..................................... 149
Attachment 4:
Management of Dyslipidemia ................................................................................... 150
Attachment 5:
Cardiovascular Safety: Definitions of Abnormalities ................................................ 154
Attachment 6:
Anticipated Events.................................................................................................... 155
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Exclusionary Concomitant Medications ........................................................................ 51
Table 2:
Concomitant Therapy: Disallowed and Cautioned Use ................................................ 56
Table 3:
Summary of Cutaneous Reaction/Rash Follow-up ....................................................... 86
Table 4:
Summary of Allergic Reaction Follow-up ...................................................................... 87
Table 5:
BMD at the Lumbar Spine, Power Calculations............................................................ 95
Table 6:
LDL and non-HDL Cholesterol Goals and Thresholds for Therapeutic 
Lifestyle Changes and Drug Therapy in Different Risk Categories............................. 152
Table 7:
Choice of Drug Therapy for Dyslipidemia in HIV-infected Individuals 
Receiving HAART ....................................................................................................... 153
FIGURES
Figure 1:
Schematic Overview of the Study ................................................................................. 44
Figure 2:
Virologic Nonresponse Schema.................................................................................... 74
Figure 3:
Virologic Rebound Schema........................................................................................... 76
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
6
Approved, Date: 18 April 2017
PROTOCOL AMENDMENT
Protocol History
TMC114FD2HTX3001_Protocol
Document Type and
File Name
Issued Date
Amendment
Type
Comments
Initial Clinical Protocol
TMC114FD2HTX3001_Protocol
10-Mar-2015
-
-
Protocol Amendment 1
TMC114FD2HTX3001_Protocol_Amend_1
23-Jul-2015
Substantial
For details, please refer to 
Section Amendment_1
Protocol Amendment 2
TMC114IFD2HTX3001_Protocol_Amend_2
This document
Non-
Substantial
For details, please refer to 
Section Amendment_2
Amendment_2 (this document)
The overall reason for the amendment: The main reason for this amendment is to clarify that the 
appearance of the D/C/F/TAF FDC tablets provided in the open-label treatment phase is different from 
the appearance of the D/C/F/TAF FDC tablets provided in the double-blind treatment phase. Debossed 
D/C/F/TAF FDC tablets are only provided once patients roll over from the double-blind treatment 
phase, in which plain-faced D/C/F/TAF FDC tablets are used, to the open-label treatment phase. Further 
changes have been made to the protocol for clarification or correction.
The changes made to the clinical protocol amendment 1, TMC114FD2HTX3001_Protocol Amend_1, 
dd. 23-Jul-2015, are listed below, including rationale of each change and a list of all applicable sections.
Rationale: Debossed D/C/F/TAF FDC tablets were added to support the transition from plain-faced 
D/C/F/TAF FDC tablets in the double-blind treatment phase to debossed D/C/F/TAF FDC tablets in the 
open-label treatment phase.
14.1 Physical Description of Study Drug(s)
Rationale: A writing error was made: An incorrect power of 86% was provided in the text, and was 
therefore corrected to 90% power, consistent with what is presented in Table 5.
11.3 Sample Size Determination
Rationale: Section “ECG” in section 11.6 on safety statistical analyses was corrected as there is no data 
collected in the CRF for HR, RR, PR, QRS, QTcB, or QTcF but only an overall interpretation (normal 
or abnormal) for the ECG.
11.6 Safety Analyses
Rationale: Correction to the description of the randomization procedure.
5 TREATMENT ALLOCATION AND BLINDING
Rationale: Minor editorial changes were made for clarity and consistency.
3.3 Dose Selection Rationale
5 TREATMENT ALLOCATION AND BLINDING
14.1 Physical Description of Study Drug(s)
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
7
Approved, Date: 18 April 2017
Amendment_1 (23-Jul-2015)
The overall reason for the amendment: Following Health Authority feedback on the clinical protocol 
TMC114FD2HTX3001, dd. 10-Mar-2015, the requested changes have been implemented. Further 
changes have been made to the protocol for clarification or correction.
The changes made to the clinical protocol TMC114FD2HTX3001, dd. 10-Mar-2015, are listed below, 
including rationale of each change and a list of all applicable sections.
Rationale: Due to the high rate of discontinuations observed in Gilead's study GS-US-236-0118 
(3/12 subjects) among subjects with baseline CrCl <70 mL/min because of renal adverse events, the 
creatinine clearance threshold for eligibility has therefore been increased from 50 to 70 mL/min.
SYNOPSIS
1.7 Overall Rationale and Risks Assessment for the Study
4.1 Inclusion Criteria
9.1.2.1 Screening Visit
Rationale: Subjects treated with post-exposure prophylaxis and/or pre-exposure prophylaxis who 
became HIV-1 infected are not considered treatment-naïve and may have resistance to emtricitabine 
and/or tenofovir disoproxil fumarate that may be undetectable 30 days following treatment. Following 
Health Authority feedback, subjects previously treated with post-exposure prophylaxis and/or pre-
exposure prophylaxis will therefore no longer be allowed in the study.
4.1 Inclusion Criteria
Rationale: For completeness, it has been added in inclusion criterion 13 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
Rationale: For completeness, penile intra-epithelial neoplasia has been added to the exceptions in 
exclusion criterion 6.
4.2 Exclusion Criteria
Rationale: To ensure a DXA scan is available prior to starting study medication and to allow more 
flexibility in the timing of the DXA scan at baseline, the DXA scan can be performed between screening 
and baseline before study eligibility has been confirmed. Furthermore, it has been clarified that absence 
of pregnancy needs to be confirmed prior to performing the scan. 
Time and Event Schedule
9.1.2.2 Baseline Visit (Day 1)
Rationale: To allow more flexibility in the timing of the DXA scans, but still ensure sufficient time 
between two consecutive DXA scans to evaluate potential changes, the time windows for the planned 
study visit scans at Week 24, 48 and 96 and technical rescans have been adjusted.
Time and Event Schedule
9.1.3 Double-blind Treatment Phase
9.1.4 Open-label Single-arm Phase
9.1.6.1 Early Study Treatment Discontinuation Visit
Rationale: The assessment of parathyroid hormone and 25-hydroxy vitamin D at the early study 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
8
Approved, Date: 18 April 2017
treatment discontinuation visit (if applicable) has been added for completeness.
Time and Event Schedule
9.1.6.1 Early Study Treatment Discontinuation Visit
Rationale: Since drug dispensation at baseline covers the treatment period up to Week 4, drug 
accountability at the Week 2 visit has been removed.
SYNOPSIS
Time and Event Schedule
3.1 Overview of Study Design
9.1.3 Double-blind Treatment Phase
Rationale: For clarification, the conditions when the use of lidocaine is disallowed have been specified.
4.2 Exclusion Criteria
8.1 Disallowed and Cautioned Concomitant Therapy
Rationale: For clarification it has been specified that in case of persistent low level viremia between 50 
and 400 HIV-1 RNA copies/mL, study drugs may be discontinued at the investigator’s discretion and 
the subject should subsequently be withdrawn from the study.
9.2.2.2 Subjects Eligible for Resistance Testing
Rationale: For clarification, it has been specified that subjects will be given the opportunity to receive 
D/C/F/TAF treatment after Week 96 in order to collect long-term safety and efficacy data on 
D/C/F/TAF.
SYNOPSIS
3.2 Study Design Rationale
6 DOSAGE AND ADMINISTRATION
Rationale: Minor modifications and clarifications to the text. 
SYNOPSIS
Time and Event Schedule
DEFINITIONS OF TERMS
1.3 Cobicistat (Tybost®)
3.1 Overview of Study Design
8.1 Disallowed and Cautioned Concomitant Therapy
9.1.1 Overview
9.1.2.2 Baseline Visit (Day 1)
9.1.6.1 Early Study Treatment Discontinuation Visit
9.2.2.1 Virologic Failure
9.2.2.2 Subjects Eligible for Resistance Testing
9.4.2 Clinical Laboratory Tests
11.1 Analysis Objectives and Endpoints
11.8 Data Monitoring Committee
Attachment 4 Management of Dyslipidemia
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
9
Approved, Date: 18 April 2017
SYNOPSIS
A Phase 3, randomized, active-controlled, double-blind study to evaluate efficacy and safety of 
darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) once daily fixed dose combination 
regimen versus a regimen consisting of darunavir/cobicistat fixed dose combination coadministered with 
emtricitabine/tenofovir disoproxil fumarate fixed dose combination in antiretroviral treatment-naïve 
human immunodeficiency virus type 1 infected subjects.
EudraCT NUMBER: 2015-000754-38
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective is to demonstrate noninferiority in efficacy of a D/C/F/TAF fixed dose 
combination
(FDC) tablet
versus darunavir/cobicistat (DRV/COBI)
FDC coadministered
with 
emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) FDC in human immunodeficiency virus type 1 
(HIV-1) infected, antiretroviral (ARV) treatment-naïve adult subjects, as determined by the proportion of 
virologic responders defined as having HIV-1 RNA <50 copies/mL at Week 48 (FDA-defined snapshot 
analysis), with a maximum allowable difference of 10%.
Secondary Objectives
The secondary objectives of this study are:

To evaluate superiority of a D/C/F/TAF FDC tablet versus DRV/COBI FDC coadministered with 
FTC/TDF FDC as determined by the proportion of virologic responders defined as having HIV-1 
RNA <50 copies/mL at Week 48 (FDA-defined snapshot analysis), in case noninferiority is 
established;

To evaluate the immunologic response (CD4+ cell count) of the 2 treatment arms through Week 48;

To evaluate the incidence of grade 3 and 4 adverse events (AEs), serious adverse events (SAEs), and 
premature discontinuations due to AEs in the 2 treatment arms through Week 48;

To evaluate the change from baseline in serum creatinine, estimated glomerular filtration rate
(eGFR) based on creatinine clearance (eGFRcreatinine, by Cockcroft-Gault and by Chronic Kidney 
Disease Epidemiology Collaboration [CKD-EPI] formulas) and eGFR based on cystatin C clearance 
(eGFRcystatin C, by CKD-EPI) in the 2 treatment arms at Week 48;

To evaluate the change from baseline in renal biomarkers at Week 48;

To assess the development of viral resistance in the 2 treatment arms through Week 48;

To evaluate the steady-state pharmacokinetics of DRV and TAF;

To evaluate long-term efficacy, resistance, and safety of the D/C/F/TAF FDC regimen (Week 96 and 
beyond).
Objectives of a bone investigation substudy performed at selected study sites:

To evaluate the safety in the 2 treatment arms as determined by the percentage change from baseline 
in hip and spine bone mineral density (BMD) and change from baseline in T-score at Week 48;

To evaluate the change from baseline in bone biomarker levels at Week 48. 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
10
Approved, Date: 18 April 2017
Hypothesis
Null hypothesis: D/C/F/TAF FDC is inferior to DRV/COBI FDC coadministered with FTC/TDF FDC by 
at least 10% with respect to the proportion of subjects having HIV-1 RNA <50 copies/mL at Week 48 (as 
defined by the FDA-defined snapshot analysis).
Alternative hypothesis: D/C/F/TAF FDC is noninferior to DRV/COBI FDC coadministered with 
FTC/TDF FDC by less than 10% with respect to the proportion of subjects having HIV-1 RNA 
<50 copies/mL at Week 48 (as defined by the FDA-defined snapshot analysis).
OVERVIEW OF STUDY DESIGN
Study TMC114FD2HTX3001 is a 96-week multicenter, Phase 3 study consisting of a 48-week 
randomized, double-blind active-controlled treatment period, to evaluate a D/C/F/TAF FDC versus 
DRV/COBI FDC coadministered with FTC/TDF FDC in ARV treatment-naïve HIV-1 infected adult 
subjects, followed by an open-label single-arm D/C/F/TAF treatment period for all subjects up to 
Week 96 to asses long-term efficacy, resistance, and safety.
A target of 670 subjects will be randomly assigned in this study with 335 subjects planned per treatment 
arm.
Prior to or at the baseline visit (Day 1), subjects who meet all eligibility criteria will be randomized in a 
1:1 ratio to 1 of the following 2 treatment arms:
-
D/C/F/TAF Arm:
Regimen of a single tablet containing DRV 800 mg/ COBI 150 mg/ 
FTC 200 mg/ TAF 10 mg (D/C/F/TAF FDC) once daily, (n=335) 
+ DRV/COBI FDC-matching and FTC/TDF FDC-matching placebo tablets 
once daily;
-
Control Arm : 
Regimen of DRV 800 mg/ COBI 150 mg FDC coadministered with FTC 
200 mg/ TDF 300 mg FDC once daily, (n=335)
+ D/C/F/TAF FDC-matching placebo tablet once daily.
Randomization will be stratified by HIV-1 RNA level (≤100,000 copies/mL or 100,000 copies/mL) and
by CD4+ cell count (<200 cells/µL or ≥200 cells/µL) at screening. 
Subjects will be treated for 96 weeks, and will return for study visits at Weeks 2, 4, 8, 12, 24, 36, 48, 
every 12 weeks thereafter until and including a Week 96 visit. 
After Week 48, subjects will continue to take their blinded study drug and attend visits every 12 weeks 
until all subjects have reached Week 48, the database for the primary analysis has been locked, and 
treatment assignments have been unblinded. Provided the results from the primary analysis do not 
preclude (further) exposure of subjects to D/C/F/TAF, all subjects will return for an unblinding visit and 
will receive the D/C/F/TAF FDC tablet treatment during an open-label single-arm treatment phase up to 
Week 96. Subjects from the control arm who switch to the D/C/F/TAF regimen after the 48-week double-
blind treatment will be required to return to the clinic for an additional visit 3 to 7 weeks after the 
unblinding visit.
After Week 96, subjects will be given the opportunity to continue D/C/F/TAF treatment during an
extension phase until the D/C/F/TAF FDC tablet 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. During the extension phase subjects will attend visits every 6 months. 
Subjects who prematurely discontinue, either during the double-blind treatment phase (from Day 1 to 
Week 48) or during the single-arm D/C/F/TAF treatment phase (between Week 48 and Week 96) will be 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
11
Approved, Date: 18 April 2017
required to return to the clinic within 72 hours of stopping study treatment for the early study treatment 
discontinuation (ESTD) visit.
In addition, a 30-day follow-up (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).
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), double-blind active-controlled treatment 
for at least 48 weeks, an open-label single-arm D/C/F/TAF treatment up to Week 96 and an extension 
phase. A 30-day FU visit may take place as described above.
Assessment and reporting of drug adherence and accountability, concomitant medications, and AEs, 
laboratory evaluations for efficacy and safety (viral load, CD4+ cell count, biochemistry, hematology, 
urinalysis, urine chemistry), vital signs and (complete or symptom-directed) physical examinations will 
be performed at each visit, except drug accountability at Week 2. At screening, a 12-lead
electrocardiogram (ECG) and an HIV-1 genotype test will be performed. Urine for assessments of 
selected renal biomarkers, including retinol binding protein and beta-2-microglobulin, will be collected at 
baseline and at several visits during the study.
Screening genotype testing will be performed for all subjects to assess sensitivity to DRV, TDF and FTC. 
Further HIV-1 protease (PR) and reverse transcriptase (RT) genotype/phenotype testing will be performed 
at later time points for subjects that are eligible for resistance testing (subjects with virologic rebound, 
virologic nonresponse, and discontinuations with last available viral load measurement ≥400 copies/mL). 
If resistance to the study drugs is documented, study drugs may be discontinued.
Pharmacokinetic assessments (sparse sampling) will be performed for all subjects (single sample from 
Weeks 4 through 48 or the ESTD visit, except at Weeks 8 and 36 visits, when 2 samples will be collected 
≥2.5 hours apart). 
A bone investigation substudy will be performed at selected study sites, to assess bone biomarkers, 
including C-type collagen sequence (CTX), procollagen type 1 N-terminal propeptide (P1NP), 
parathyroid hormone (PTH) and 25-hydroxy vitamin D, and dual energy x-ray absorptiometry (DXA) 
scans, in at least 170 subjects (85 subjects per treatment arm) who provide informed consent for the 
substudy.
The safety and tolerability, as well as efficacy, of the enrolled subjects and treatment regimens will be 
monitored by an independent Data Monitoring Committee (DMC). In addition to the Week 48, Week 96
and final analyses, formal DMC analyses 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 670 subjects will be randomized in a 1:1 ratio to 1 of the 2 treatment arms. 
The key inclusion and exclusion criteria are summarized below.
Key Inclusion Criteria
Subjects must be ARV treatment-naïve (never treated with an ARV including post-exposure prophylaxis and pre-
exposure prophylaxis); no prior use of any approved or experimental anti-HIV drug for any length of time.
Screening plasma HIV-1 RNA level 1,000 copies/mL
CD4+ cell count 50 cells/L.
Screening HIV-1 genotype report must show full sensitivity to DRV, TDF and FTC.
Screening eGFRcreatinine ≥70 mL/min according to the Cockcroft-Gault formula for creatinine clearance.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
12
Approved, Date: 18 April 2017
Key Exclusion Criteria
Subject has been diagnosed with a new AIDS-defining condition within the 30 days prior to screening.
Subject has proven or suspected acute hepatitis within 30 days prior to screening.
Subject is hepatitis C or hepatitis B positive
Subject has a history of cirrhosis.
DOSAGE AND ADMINISTRATION
Prior to the baseline visit (Day 1), eligible subjects will be randomized in a 1:1 ratio to the investigational 
treatment arm (D/C/F/TAF FDC tablet) or the active control arm (DRV/COBI FDC coadministered with 
FTC/TDF FDC). 
-
D/C/F/TAF Arm (n=335):
Regimen of a single-tablet containing DRV 800 mg/ COBI 150 mg/ FTC 
200 mg/ TAF 10 mg (D/C/F/TAF FDC) once daily 
+ DRV/COBI FDC-matching and FTC/TDF FDC-matching placebo tablets 
once daily;
-
Control Arm (n=335): 
Regimen of DRV 800 mg/ COBI 150 mg FDC coadministered with 
FTC 200 mg/ TDF 300 mg FDC once daily 
+ D/C/F/TAF FDC-matching placebo tablet once daily.
All baseline tests and procedures must be completed prior to the administration of the first dose of study 
treatment. Initiation of study treatment must take place within 24 hours after the baseline visit.
The investigational medication, D/C/F/TAF FDC tablets, the control DRV/COBI FDC tablets and the 
D/C/F/TAF FDC- and DRV/COBI FDC–matching placebo tablets (identical in physical appearance), will 
be manufactured, packaged and provided by the sponsor. The control FTC/TDF FDC tablets and 
matching placebo tablets will be manufactured, packaged by Gilead Sciences, Inc. (GSI) and provided to 
the sponsor for distribution. 
All study drugs and matching placebo tablets must be administered orally, once daily in the morning with 
food, at approximately the same time each day. Study drugs should be taken on site with food during
study site visits (except Week 8 and Week 36), after all safety assessments that require fasting are taken.
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 >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 when such 
temporary interruption occurs.
After Week 48, subjects will continue to take their blinded study drug and attend visits every 12 weeks 
until all subjects have reached Week 48 and treatment assignments have been unblinded. Provided the 
results from the primary analysis do not preclude (further) exposure of subjects to D/C/F/TAF, all 
subjects will return for an unblinding visit and will receive the D/C/F/TAF treatment during an open-label
single-arm treatment phase up to Week 96. In order to collect long-term safety and efficacy data on 
D/C/F/TAF, subjects will be given the opportunity to continue the D/C/F/TAF treatment after Week 96 
during an extension phase until the D/C/F/TAF FDC tablet 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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
13
Approved, Date: 18 April 2017
EVALUATIONS
Efficacy 
Samples for determination of plasma HIV-1 RNA viral load, immunologic parameters, and for HIV-1 
genotype/phenotype resistance testing will be taken at the time points specified in the Time and Events 
Schedule.
Pharmacokinetics 
Pharmacokinetic assessments (sparse sampling) will be performed for all subjects at the time points 
specified in the Time and Events Schedule.
Plasma concentrations of DRV, COBI and TAF of samples from subjects in the D/C/F/TAF treatment 
arm will be analyzed under the responsibility of the sponsor, using validated analytical methods. Plasma 
concentrations of FTC and/or TFV of samples from subjects in the D/C/F/TAF treatment arm and plasma 
concentrations of the ARVs in the control arm may be determined, using validated analytical methods, at 
the sponsor’s discretion.
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;

Follow-up on specific toxicities.
Treatment Adherence
Treatment adherence will be assessed by pill count at the time points specified in the Time and Events 
Schedule. 
STATISTICAL METHODS
The following analyses will be performed: 

Independent DMC analyses for monitoring purposes, including a formal futility analysis for lack of 
(non-inferior) efficacy and a blinded sample size re-estimation.

The primary analysis: once all subjects have completed the Week 48 assessments or discontinued 
earlier.

The Week 96 analysis: once all subjects have completed the Week 96 assessments or discontinued 
earlier.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
14
Approved, Date: 18 April 2017

The final analysis: once all subjects have completed the extension phase 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. 
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects who have HIV-1 RNA <50 copies/mL at 
Week 48 as defined by the FDA snapshot analysis.
Secondary Endpoints
The secondary endpoints of this study are:

The proportion of subjects with HIV-1 RNA <50 copies/mL at Week 96 as defined by the FDA 
snapshot analysis;

The proportion of subjects with HIV-1 RNA <20 and <200 copies/mL at Weeks 48 and 96 as 
defined by the FDA snapshot analysis;

The proportion of subjects with HIV-1 RNA <20, <50, and <200 copies/mL at Weeks 48 and 96 as 
defined by the time to loss of virologic response (TLOVR) algorithm;

The change from baseline in log10 HIV-1 RNA at Weeks 48 and 96;

The change from baseline in CD4+ cell count at Weeks 48 and 96;

The change from baseline in serum creatinine, eGFRcreatinine (by Cockcroft-Gault and by CKD-EPI) 
and eGFRcystatin C (by CKPD-EPI) at Weeks 48 and 96;

The proportion of subjects experiencing grade 3 and 4 AEs, SAEs, and premature discontinuations 
due to AEs through Weeks 48 and 96.

The change from baseline in renal biomarkers at Week 48 and 96;

The development of viral resistance through Weeks 48 and 96;

Pharmacokinetic parameters (by population pharmacokinetic analysis) for DRV and TAF.  
The endpoints of the bone investigation substudy are:

The percentage change from baseline in hip and spine BMD and change from baseline in T-score at 
Weeks 24, 48, and 96;

The change from baseline in bone biomarkers at Weeks 24, 48, and 96.
Subject Information

The intent-to-treat (ITT) population will include all the subjects who were randomized and received 
≥1 dose treatment 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 30 days after subjects permanently discontinue 
their study treatment) 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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
15
Approved, Date: 18 April 2017
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, and (3) without any major protocol deviation 
that is considered to potentially affect efficacy outcomes (eg, inadequate baseline resistance profile, 
use of concomitant medication interfering with antiviral efficacy, inadequate adherence to drug
intake). 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 ≥1 dose of investigational treatment in the 
study, and for whom plasma concentration data of any analytes of interest are available.
Sample Size Determination
A sample size of 670 subjects (335 subjects in D/C/F/TAF arm and 335 subjects in the control arm) will 
yield 90% power. It is assumed that both treatment arms have a response rate of 80% (HIV-1 RNA 
<50 copies/mL at Week 48 as defined by the FDA snapshot analysis), that the noninferiority margin is 
10%, and that the significance level of the test is at a 1-sided, 0.025 level.
A minimum of 170 subjects (85 per treatment arm) is targeted to be included in the bone investigation 
substudy. Assuming a 4% inter-subject variability in BMD and a 1-sided alpha level of 2.5%, 85 subjects 
per treatment arm is sufficient to detect at least an absolute difference of 2% between the treatment arms 
with 90% power.
Statistical Analyses 
Efficacy 

The primary analysis will consist of a noninferiority evaluation of the D/C/F/TAF FDC tablet
(investigational treatment arm) versus DRV/COBI FDC coadministered with FTC/TDF FDC 
(control arm), with respect to the proportion of subjects with HIV-1 RNA <50 copies/mL at Week 48 
after the start of treatment in this study (as defined by the FDA snapshot analysis). It will be 
concluded that the D/C/F/TAF FDC tablet is not inferior to the control regimen if the lower bound of 
the 2-sided 95% confidence interval (CI) of the difference between treatment arms (D/C/F/TAF arm 
- control arm) in the response rate is greater than -10% (ie, a margin of 10% is applied to 
noninferiority assessment). The difference (with associated 95% confidence interval) will be 
constructed using the stratum-adjusted Mantel-Haenszel difference in proportions, where the 
stratification factors (HIV-1 RNA level [≤100,000 copies/mL or >100,000 copies/mL] and CD4+ 
cell count [<200 cells/µL or ≥200 cells/µL] at screening) determine the strata. 
If noninferiority of the D/C/F/TAF arm to control arm is established, the lower bound of the 95% CI 
will be compared to 0; if the lower bound of the 95% CI is greater than 0, then superiority of 
D/C/F/TAF over the control arm will be established. 

The proportion of subjects with HIV-1 RNA <20 and <200 copies/mL at Week 48 as defined by the 
FDA snapshot analysis will be analyzed using the same method as for the primary efficacy endpoint 
to compare treatment arms. 

Confirmed virologic response defined as HIV-1 RNA <20, <50, and <200 copies/mL at Week 48
determined by the TLOVR algorithm will be analyzed using the same method as for the primary 
efficacy endpoint to compare treatment arms. 

The changes from baseline in CD4+ cell count at Week 48 and 96 will be summarized using 
descriptive statistics. The differences in changes from baseline in CD4+ cell count at Week 48 
between the 2 treatment arms and the associated 95% confidence intervals will be constructed using 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
16
Approved, Date: 18 April 2017
analysis of covariance (ANCOVA), including CD4+ cell count at baseline as continuous covariate in 
the model.

Screening HIV-1 PR/RT genotype analysis will be performed for all subjects. Post-screening HIV-1 
PR/RT genotype/phenotype testing will be available from subjects who are eligible for resistance 
testing (subjects with virologic rebound, virologic nonresponse, and discontinuations with last 
available viral load measurement ≥400 copies/mL). The number and type of amino acid changes, of 
HIV-1 PR (including IAS-USA PI RAMs and IAS-USA primary PI mutations), and RT (including 
IAS-USA NRTI RAMs and IAS-USA NNRTI RAMs), as well as specific mutations associated with 
resistance to DRV, FTC, and TDF will be tabulated. Available fold change (FC) in 50% effective 
concentration (EC50) of ARVs will be tabulated. In subjects with paired screening or baseline and 
post-baseline genotypes/phenotypes, development of resistance will be analyzed.
Pharmacokinetic Analyses 
The plasma concentration data of DRV, TAF, and COBI of subjects randomized to the D/C/F/TAF 
treatment arm will be evaluated. Plasma concentration data for each analyte may be subjected to 
population pharmacokinetic modeling, if appropriate population pharmacokinetic models are available. 
Model specifications will be described in separate report(s), as applicable.
The pharmacokinetics of other ARVs in the D/C/F/TAF arm (eg, FTC and TVF) and their metabolites, as 
well as the ARVs in samples from subjects in the control arm, may be analyzed, if deemed necessary, 
upon sponsor’s request. 
Descriptive statistics will be calculated for the plasma concentrations of DRV, COBI, and TAF by visit 
and for the derived pharmacokinetic parameters (as available), and also for any of the other ARVs in the 
study analyzed upon sponsor’s request, if applicable. Summary statistics include n, mean, SD, coefficient 
of variation (CV), geometric mean, median, minimum and maximum.
Safety Analyses
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 ≥1 occurrence of the given event will 
be summarized.
Summaries (number and percentage of subjects) of treatment-emergent AEs (by system organ class 
[SOC] and preferred term [PT]) 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.
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 Division of AIDS (DAIDS) grading table 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 developed grade 3 or 4 toxicities.
The changes from baseline in serum creatinine, eGFRcreatinine (by Cockcroft-Gault and by CKD-EPI) and 
eGFRcystatin C (by CKPD-EPI) at Weeks 48 and 96 will be summarized by treatment arm and using 
descriptive statistics. The difference in changes from baseline at Week 48 in serum creatinine between the 
2 treatment arms will be tested using ANCOVA, including baseline serum creatinine in the model. 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
17
Approved, Date: 18 April 2017
Selected renal biomarkers, including retinol binding protein and beta-2-microglobulin, will be 
summarized by treatment arm and visit using descriptive statistics. The difference in change from 
baseline in these biomarkers at Week 48 between 2 treatment arms will be tested using the Wilcoxon 
rank-sum test.
Descriptive statistics of vital signs (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.
Physical examination findings and changes from baseline at each scheduled time point will be listed.
Bone Investigation Substudy 
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 at Weeks 24 and 48 will be performed 
using the Wilcoxon rank-sum test.
Percent change from baseline in spine and hip BMD at Weeks 24, 48, and 96, 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. 
Treatment Adherence
Treatment adherence based on pill count will be summarized by means of descriptive statistics and 
frequency tabulations.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
18
Approved, Date: 18 April 2017
TIME AND EVENT SCHEDULE
PERIOD
Double-blind 
Active-controlled 
Treatment Periodc,d
Open-label Single-arm 
D/C/F/TAF 
Treatment Periodf
Extension 
Periodh ESTDi
30-
Day 
FUj
Visit   Screeninga Baseline
Day 1b Week 
2
Week 
4
Week 
8
Week 
12
Week 
24
Week 
36
Week 48d
and
Unblinding 
Visite
3-7 weeks 
after 
Unblinding 
Visitg
Every 12 
weeks
Week 
96
Every 6 
months
Study Procedures
Screening/Administrative
Informed consentk
X
Medical history
X
12-Lead ECG (local)
X
Height
X
HBV and HCV testing
X
Serum pregnancy testl
X
FSH testm
X
Inclusion/exclusion 
criteria
X
Check clinical statusn
X
Study Drug Administration
Randomizationo
X
Adherence 
(log booklet)p
X
X
X
X
X
X
X
Xq
X
X
X
X
Drug dispensation & 
accountability
X
X
X
X
X
X
Xq,r
Xs
X
X
Xt
Xs
Safety Evaluations
Adverse events
X
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
Vital signs and weight
X
X
X
X
X
X
X
X
Xq
X
X
X
X
X
Xu
Complete physical 
examination
X
X
X
X
X
Symptom-directed 
physical examination
X
X
X
X
X
Xv
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
19
Approved, Date: 18 April 2017
PERIOD
Double-blind 
Active-controlled 
Treatment Periodc,d
Open-label Single-arm 
D/C/F/TAF 
Treatment Periodf
Extension 
Periodh ESTDi
30-
Day 
FUj
Visit   Screeninga Baseline
Day 1b Week 
2
Week 
4
Week 
8
Week 
12
Week 
24
Week 
36
Week 48d
and
Unblinding 
Visite
3-7 weeks 
after 
Unblinding 
Visitg
Every 12 
weeks
Week 
96
Every 6 
months
Clinical Laboratory Evaluationsw
Chemistry profilex
X
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
Metabolic profiley
X
X
Xq
X
Hematology profilez
X
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
Cystatin C and 
eGFRcystatin C
X
X
X
X
X
X
X
X
Xq
X
eGFRcreatinine
aa
X
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
Urinalysis and urine 
chemistrybb
X
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
Urine pregnancy testk
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
Renal biomarkerscc
X
X
X
X
X
Xq
X
X
X
X
Efficacy Evaluations
Plasma HIV-1 RNAdd
X
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
CD4+ cell count
X
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
HIV-1
genotype/phenotypeee
X
X
X
X
X
X
X
X
Xq
X
X
X
X
X
PBMC sampleff
X
X
Xgg
X
X
Pharmacokinetic Evaluations
Pharmacokinetic 
samplehh
X
X
X
X
X
X
Xff
X
Other
Plasma sample 
storageii
X
X
X
X
X
X
X
X
X
X
X
Bone investigation substudy
DXA scansjj
X
X
Xgg
X
X
Bone biomarkersll
X
X
X
X
X
Xkk
X
Xkk
X
X
DXA: dual energy x-ray absorptiometry; ECG: electrocardiogram; eGFR: estimated glomerular filtration rate; ESTD: Early Study Treatment Discontinuation visit; 
FSH: follicle-stimulating hormone; FU: Follow-up; HBV: hepatitis B; HCV: hepatitis C; HIV-1: human immunodeficiency virus type 1; ICF: informed consent 
form; PBMC: peripheral blood mononuclear cells; RNA: ribonucleic acid.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
20
Approved, Date: 18 April 2017
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, and every 12 weeks thereafter until 
the unblinding visit. The visit window is ±2 days of the protocol-specified visit date at Week 2, ±7 days of the protocol-specified date through Week 48, and every 
12 weeks thereafter until the unblinding visit. 
d
After Week 48, subjects will continue to take their blinded study drug and attend visits every 12 weeks until all subjects have reached Week 48. 
e
Once all subjects have reached Week 48 and unblinded treatment assignments have been provided to the investigators, all subjects will return to the clinic for an 
unblinding visit, preferably at the next planned visit. At the unblinding visit, provided the results from the primary analysis do not preclude (further) exposure of
subjects to D/C/F/TAF, all subjects will discontinue their blinded study drugs and will receive the D/C/F/TAF FDC tablet in a single-arm treatment period up to 
Week 96.
f
Study visits during the open-label single-arm D/C/F/TAF treatment period are to be completed within ±7 days of the protocol-specified visit date. 
g
Subjects from the control arm who switch to the D/C/F/TAF treatment after the 48-week double-blind treatment will be required to return to the clinic for an 
additional visit 3 to 7 weeks after the unblinding visit. If this additional visit would take place within a ±4 week window of a normal planned schedule visit, the 
additional visit can take place during this planned visit.
h
Visits in the extension period will occur every 6 months, until the D/C/F/TAF treatment 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. Study visits during the extension period are to be 
completed within ±14 days of the protocol-specified visit date.
i
ESTD visit to occur within 72 hours of last dose of study treatment for subjects who prematurely discontinue, either during the double-blind treatment period (from 
Day 1 to Week 48), or during the open-label single-arm D/C/F/TAF treatment period (between Week 48 and Week 96). 
j
Required for any subject who has an ongoing AE or SAE at the time of his/her study visit (unless consent is withdrawn); ±7 days window may be used. 
k
Signing of the ICF needs to be done before the first study-related activity.
l
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.
m
FSH test for female subjects who have stopped menstruating for at least 2 years but do not have documentation of ovarian failure.
n
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.
o
Randomization should be performed during the baseline visit, provided that all screening procedures have been completed and subject eligibility has been 
confirmed.
p
Dispensation of the study medication log booklet at the baseline visit, in which 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.
q
At Week 48, every 12 weeks following Week 48 until unblinding, and the unblinding visit.
r
The first open-label study drug dispensation will occur at the unblinding visit.
s
Drug accountability only; study drug will not be dispensed at this visit.
t
Subjects might return to the clinic more frequently during the extension period for drug dispensation only.
u
Weight only.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
21
Approved, Date: 18 April 2017
v
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 the every 12 weeks visits between Week 48 and the unblinding visit.
w
Study drugs should be taken on site with food during all visits up to Week 96 after all laboratory assessments which require fasting are performed (except for the 
Week 8 and 36 visits, where fasting is not required).
x
Chemistry profile: alpha1-acid glycoprotein (AAG), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (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, 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. 
y
Fasting metabolic profile (total, high-and low-density lipoprotein [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.
z
Hematology profile: hemoglobin, hematocrit, red blood cell (RBC) count and parameters (mean corpuscular hemoglobin [MCH], MCH concentration and mean 
corpuscular volume), white blood cell (WBC) count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count.
aa
At screening only eGFRcreatinine by Cockcroft-Gault, at other visits during the treatment and extension phase also eGFRcreatinine by CKD-EPI. 
bb 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.
cc
Urine sample for selected renal biomarkers (including retinol binding protein 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.
dd Leftover blood samples from the viral load determinations could be used for protocol-related testing (virology, safety, pharmacokinetic analysis) at additional time 
points.
ee
At screening, only genotypic analysis of the HIV-1 (protease [PR] and reverse transcriptase [RT]) will be conducted for all subjects. Genotype/phenotype testing at 
later time points will be requested by the study virologist, based on subject’s viral load. 
ff
A PBMC sample will be taken for storage for exploratory analysis (eg to characterize archived viral resistance) if deemed necessary by the study virologist. 
gg Sample only to be taken at Week 48.
hh At Weeks 2, 4, 12, 24, 48, and the ESTD visit, subjects will have a single pharmacokinetic blood sample collected at least 30 minutes to maximum 4 hours
postdose. At the Week 8 and 36 visits, 2 pharmacokinetic samples will be collected with at least 2.5 hours in between sampling. The first pharmacokinetic sample 
should be taken between 1 and 4 hours postdose (dosing may occur prior to the study site visit). 
ii
Plasma samples drawn will be frozen and stored. Plasma storage samples will be banked for possible additional protocol-related testing (virology, safety, 
pharmacokinetic analysis). 
Bone investigation substudy at selected sites only (provided the necessary approvals have been obtained and informed consent is provided for the substudy):
jj
DXA scan of spine and hip: to be performed between screening and baseline (+2 weeks), at Weeks 24, 48, 96 and at the ESTD visit (±2 weeks) (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 96). A rescan for technical 
reasons is allowed within 2 weeks for the baseline visit, and within 4 weeks for all other visits. The time interval between the evaluable DXA scans at baseline and 
Week 24, baseline and Week 48, baseline and Week 96 is recommended to be at least 20, 44, and 92 weeks, respectively.
kk To be performed every 24 weeks.
ll
The blood sample for selected bone biomarkers (including CTX, P1NP, 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. Biomarkers PTH and 25-hydroxy 
vitamin D should be assessed at Day 1, Week 24, 48, 96, and ESTD (if applicable) only.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
22
Approved, Date: 18 April 2017
Note : During screening, retesting of abnormal laboratory values that may lead to exclusion will be allowed once.
Unscheduled visit(s) may be required for safety reasons, for technical issues, or for confirmation of virologic failure in case of unconfirmed virologic failure 
(virologic nonresponse or virologic rebound [see Section 9.2.2, Figure 2, and Figure 3]). When an HIV-1 RNA repeat testing is required at an unscheduled 
visit, an HIV-1 genotype/phenotype plasma sample and a plasma storage sample should also be drawn at the same unscheduled visit.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
23
Approved, Date: 18 April 2017
ABBREVIATIONS
3TC
lamivudine
AAG
alpha1-acid glycoprotein 
ABC
abacavir
ACTG
AIDS Clinical Trial Group
ADR
adverse drug reaction
AE
adverse event
AGEP
acute generalised exanthematous pustulosis 
AK
adenylate kinase
AIDS
acquired immunodeficiency syndrome
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
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
C0h
trough plasma concentration
Cmax
maximum plasma concentration
Cxh
plasma concentrations x hours after dosing
COBI
cobicistat
CPK
creatine phosphokinase
CTX
C-type collagen sequence
CV
coefficient of variation
CYP
cytochrome P450
DAIDS
Division of AIDS
DBP
diastolic blood pressure 
D/C/F/TAF
darunavir/cobicistat/emtricitabine/tenofovir alafenamide
DMC
Data Monitoring Committee
DP
diphosphate
DRESS
Drug reaction 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
eGFR
estimated glomerular filtration rate 
eGFRcreatinine
eGFR for creatinine clearance 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
24
Approved, Date: 18 April 2017
eGFRcystatin C
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
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
HDPE
high-density polyethylene 
hERG
human ether-à-go-go-related gene
HDL
high-density lipoprotein
HIV-1
human immunodeficiency virus type 1
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
IWRS
interactive web response system
LC-MS/MS
liquid chromatography/mass spectrometry/mass spectrometry
LDL
low-density lipoprotein
LLN
lower limit of normal range
LPV
lopinavir
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
NCEP
National Cholesterol Education Program 
NNRTI
non-nucleoside reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NR
(virologic) nonresponse
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
P1NP
procollagen type N-terminal propeptide 
PBMC
peripheral blood mononucleated cell
PDE
phosphodiesterase 
PI
protease inhibitor
PP
per protocol
PQC
Product Quality Complaint
PR
protease 
PT
preferred term
PTH
parathyroid hormone 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
25
Approved, Date: 18 April 2017
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
RB
(virologic) rebound 
RBC
red blood cell
RBP
retinol binding protein
RNA
ribonucleic acid
RPV
rilpivirine
RT
reverse transcriptase
rtv
low-dose ritonavir
SAE
serious adverse event
SBP
systolic blood pressure 
SD
standard deviation
SJS
Stevens-Johnson syndrome
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
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
TVD
Truvada (emtricitabine/tenofovir disoproxil fumarate)
UGT1A1
uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1
ULN
upper limit of normal range
US
United States of America
VF
virologic failure
WBC
white blood cell
WHO
World Health Organization
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
26
Approved, Date: 18 April 2017
DEFINITIONS OF TERMS
Investigational treatment (medication)
D/C/F/TAF FDC tablet
Control/Comparator treatment (regimen, medications)
DRV/COBI FDC coadministered with FTC/TDF FDC
Study treatment (medication)
Any ARV regimen and matching placebo tablets received in 
the investigational treatment arm or control arm in the current 
study
Virologic nonresponse (NR)*:
HIV-1 RNA <1 log10
reduction from baseline and 
≥50 copies/mL at the Week 8 visit, confirmed at the 
scheduled or unscheduled visit following Week 8.
Virologic Rebound (RB)*:

At any visit, after achieving confirmed (consecutive)
HIV-1 RNA <50 copies/mL, a rebound in HIV-1 RNA to 
≥50 copies/mL, which is subsequently confirmed at the 
following scheduled or unscheduled visit; 
or

At any visit, a >1 log10 increase in HIV-1 RNA from the 
nadir which is subsequently confirmed at the following 
scheduled or unscheduled visit.
                                                
* Protocol defined for the purpose of the resistance analysis. 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
27
Approved, Date: 18 April 2017
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.34
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.21,22,28
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).23,40
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.22 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.8,29,30 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.12,20,38
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
28
Approved, Date: 18 April 2017
pharmacokinetic enhancer (booster) COBI (developed by Gilead Sciences, Inc. [GSI]), the NRTI 
FTC, 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 FDC, is intended to be 
indicated for the treatment of HIV-1 infected adults who are either treatment-naïve or treatment-
experienced with no DRV RAMs (V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, 
I84V and L89V).
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 (formerly known as TMC114) is an inhibitor of the catalytic activity of HIV-1 protease
(PR) with potent in vitro antiviral activity against both wild-type and PI-resistant HIV-1 strains. 
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. In combination with low-dose ritonavir (rtv) as a pharmacokinetic booster and other 
ARVs, it has shown significant efficacy in treatment-naïve and treatment-experienced patients. 
DRV, in combination with other ARVs, 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 for use in treatment-naïve patients and treatment-experienced patients who have 
no DRV resistance-associated mutations (RAMs). COBI-boosted DRV is only approved for use 
in adults.
DRV was first registered in the US (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 taken with a booster
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
29
Approved, Date: 18 April 2017
For the most comprehensive nonclinical and clinical information regarding DRV available at the 
time of protocol writing, refer to the Investigator’s Brochure (IB) for D/C/F/TAF and its
addendum.16,17
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 by GSI and the sponsor), ATV/COBI 
(codeveloped by GSI and Bristol-Myers Squibb), 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 FDC DRV/COBI (PREZCOBIXTM/REZOLSTA®) 
has recently been approved in Canada, Europe and the United States, and is indicated in 
combination with other ARV medicinal products for the treatment of HIV-1 infection in adults 
aged 18 years or older.
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-
naïve 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% to 15%) decreases in estimated glomerular filtration rate (eGFR) calculated 
using the Cockcroft-Gault calculation occurred within the first few weeks of COBI initiation (in 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
30
Approved, Date: 18 April 2017
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 eGFR 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. 
For the most comprehensive nonclinical and clinical information regarding COBI and COBI/
DRV FDC, available at the time of protocol writing, 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 pyrimidine 2′-deoxycytidine. 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 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 less than 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 (see below). 
For further nonclinical and clinical information regarding FTC, refer to the Prescribing 
Information for FTC.31,35
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, developed by GSI. TAF has been coformulated with 
other ARVs, such as E/C/F/TAF and F/TAF (developed by GSI) and D/C/F/TAF (codeveloped 
by GSI and the sponsor), for the treatment of HIV-1 infection because of its potential for 
enhanced distribution of TFV into peripheral blood mononucleated cells (PBMCs) and to 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
31
Approved, Date: 18 April 2017
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 1.7) without compromising antiviral activity. 
Based on nonclinical data, the clinical safety and resistance 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-
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®; [TVD]).
For the most comprehensive nonclinical and clinical information regarding TAF and the 
D/C/F/TAF FDC tablet, 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.32,33,36,37
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
32
Approved, Date: 18 April 2017
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 (1,000 mg/kg), the 
renal system of the rat (1,000 mg/kg), or the cardiovascular system of the dog (100 mg/kg). TAF 
monofumarate (at 1,000 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.
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
33
Approved, Date: 18 April 2017
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).
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: area
under the concentration-time curve [AUC]=3,758 ng·h/mL); the 9-month dog study defined a 
NOAEL of 2 mg/kg/day (TFV AUC=1,180 ng·h/mL), and the 28-day nonhuman primate study 
defined a NOAEL of 30 mg/kg/day (TFV AUC = 5,870 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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
34
Approved, Date: 18 April 2017
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.
1.5.5.
Clinical Studies
Clinical studies entailing the use of TAF for the treatment of 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 RPV 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 bPI or unboosted integrase inhibitor in healthy subjects (completed).
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
35
Approved, Date: 18 April 2017
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 
300 mg once daily (n=10 per group). TAF was rapidly absorbed into the systemic circulation, 
and following attainment of maximum plasma concentration (Cmax), was eliminated rapidly with 
a short plasma half-life (20 to 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 1,814 versus 383 ng.h/mL). TAF monofumarate 150 mg provided lower Cmax
(42 ng/mL), but comparable AUCinf (1,740 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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
36
Approved, Date: 18 April 2017
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 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.7
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
37
Approved, Date: 18 April 2017
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 RPV 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.
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 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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
38
Approved, Date: 18 April 2017
1.6.
Comparator Drug
The control treatment in this study consists of the bPI regimen DRV/COBI FDC (see 
Section 1.3) coadministered with FTC/TDF FDC (TVD).
Truvada® (Emtricitabine/tenofovir disoproxil fumarate FDC)
For information on FTC, see Section 1.4. 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-type and nucleoside resistant strains of HIV-1. 
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). TDF has also been coformulated and marketed in several 
coformulations with other HIV-1 ARV drugs, such as FTC/TDF FDC (TVD). TVD, in 
combination with other ARVs, is indicated for the treatment of HIV-1 infection in adults and in 
pediatric patients 12 years of age or older. 
The most frequently reported adverse reactions considered possibly or probably related to FTC
and/or TDF were nausea (12%) and diarrhea (7%) in an open-label, randomized clinical trial 
(GS-01-934). The safety profiles of FTC and TDF in this study were consistent with the previous 
experience with these agents when each was administered with other ARV agents.32,36
For further information regarding TDF and FTC/TDF FDC, refer to the Prescribing Information 
for TDF and FTC/TDF FDC.32,33,36,37
1.7.
Overall Rationale and Risks Assessment for the Study
The success of HAART and the apparent benefits of maximally suppressed viremia have 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.5,6 In addition, young, newly infected patients are diagnosed earlier, 
initiate therapy earlier, and look ahead towards lifelong therapy, often more than 50 years.24
Incomplete adherence to ARV regimens is a critical factor contributing to the development of 
viral resistance and treatment failure and is thus a primary barrier to successful long-term 
treatment. Studies have shown that once-daily single-tablet regimens improve adherence, 
treatment satisfaction, and virologic outcomes for patients infected with HIV-1.1,10,14,18 Due to a
longer duration of high adherence, patients taking single-tablet regimens also have better clinical 
outcomes, such as fewer hospitalizations, when compared with multiple pill regimens.27
To improve care for HIV-infected patients and maximize tolerability, safety, clinical efficacy, 
and adherence, the sponsor is developing DRV with COBI, FTC and TAF into a FDC tablet 
(D/C/F/TAF). This new formulation would provide an additional single tablet option, in 
particular for subjects requiring PI-based regimens, and would be an attractive new once-daily 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
39
Approved, Date: 18 April 2017
simplified regimen. The D/C/F/TAF FDC tablet also represents a new alternative for 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 
FDC tablet is postulated to provide greater delivery to lymphatic tissues of TFV and 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 levels of TFV.4,18
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-daily 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 pharmacokinetic enhancer (rtv or 
COBI), a 10 mg dose TAF is used as opposed to a TAF 25 mg dose currently in development for 
use with other (non-boosted) ARV agents (see also Section 3.3).
Administration of DRV with COBI as a pharmacokinetic enhancer, FTC, and TAF in a single 
tablet is not expected to change the antiviral activity and, by extension, the resistance profiles of 
DRV, FTC, and TAF.
The combination of D/C/F/TAF is not anticipated to exacerbate known toxicities or lead to new 
toxicities compared to DRV/COBI FDC coadministered with FTC/TDF FDC. 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 to 18 mg/kg) in dogs. 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 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 to 89 mL/min).16 The combination of D/C/F/TAF is not anticipated to 
have an effect on actual glomerular filtration rate, monitoring of creatinine along with other 
standard clinical tests for renal and bone disorders is planned in all clinical studies with the 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
40
Approved, Date: 18 April 2017
D/C/F/TAF FDC tablet. The eligibility criteria for study TMC114FD2HTX3001 with the 
D/C/F/TAF FDC tablet allow the inclusion of subjects with a screening eGFR of ≥70 mL/min. 
Changes from baseline in serum creatinine, in eGFR based on creatinine clearance (eGFRcreatinine) 
and in eGFR based on cystatin C clearance (eGFRcystatin C) will be measured in this study. In 
addition, a renal management algorithm to optimally evaluate and determine the benefit/risk 
balance for continued participation of subjects whose eGFRcreatinine would decrease <50 mL/min 
is also included in the study protocol. As recent data suggest that the combined use of COBI and 
TDF might increase proteinuria (expected to be less with TAF), this study will also assess the 
effects of the D/C/F/TAF FDC tablet on proteinuria, albuminuria, beta-2-microglobulinuria, and 
urine retinol-binding protein (RBP).
In addition, assessment of bone mineral density (BMD) is included in the study protocol as a 
substudy, and follow-up per local medical practice at the discretion of the investigator will be 
recommended in case a decrease from baseline of >7% in the hip region or >5% in the spine 
region is demonstrated. Selected bone biomarkers, including C-type collagen sequence (CTX), 
procollagen type N-terminal propeptide (P1NP), parathyroid hormone (PTH), and 25-hydroxy 
vitamin D, will be monitored in the substudy.
Two clinical studies to date have been performed with the D/C/F/TAF FDC tablet regimen (GS-
US-299-0101 in healthy volunteers [N=102], and GS-US-299-0102 in ARV treatment-naïve 
HIV-1 infected subjects [N=153]).16 No new or unexpected adverse drug reactions were 
identified in these studies.
The aim of study TMC114FD2HTX3001 is to evaluate the efficacy and safety of the D/C/F/TAF 
FDC tablet in ARV treatment-naïve HIV-1 infected subjects. The active control in this 
randomized, double-blind, comparative study is DRV/COBI FDC coadministered with FTC/TDF 
FDC.
Week 48 is the primary analysis time point. An additional analysis will be performed when all 
subjects have completed the Week 96 visit or discontinued earlier. Final analysis will be 
conducted when all subjects have completed the extension phase or discontinued earlier (see also 
Section 3.1). 
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective is to demonstrate noninferiority in efficacy of a D/C/F/TAF FDC tablet 
versus DRV/COBI FDC coadministered with FTC/TDF FDC in HIV-1 infected, ARV
treatment-naïve adult subjects, as determined by the proportion of virologic responders defined 
as having HIV-1 RNA <50 copies/mL at Week 48 (FDA-defined snapshot analysis), with a 
maximum allowable difference of 10%.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
41
Approved, Date: 18 April 2017
Secondary Objectives
The secondary objectives of this study are:

To evaluate superiority of a D/C/F/TAF FDC tablet versus DRV/COBI FDC coadministered 
with FTC/TDF FDC as determined by the proportion of virologic responders defined as 
having HIV-1 RNA <50 copies/mL at Week 48 (FDA-defined snapshot analysis), in case 
noninferiority is established;

To evaluate the immunologic response (CD4+ cell count) of the 2 treatment arms through 
Week 48;

To evaluate the incidence of grade 3 and 4 AEs, serious adverse events (SAEs), and 
premature discontinuations due to AEs in the 2 treatment arms through Week 48;

To evaluate the change from baseline in serum creatinine, eGFRcreatinine (by Cockcroft-Gault 
and by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formulas) and 
eGFRcystatin C (by CKD-EPI) in the 2 treatment arms at Week 48;9,19

To evaluate the change from baseline in renal biomarkers at Week 48;

To assess the development of viral resistance in the 2 treatment arms through Week 48;

To evaluate the steady-state pharmacokinetics of DRV and TAF;

To evaluate long-term efficacy, resistance, and safety of the D/C/F/TAF regimen (Week 96 
and beyond).
Objectives of a bone investigation substudy performed at selected study sites:

To evaluate the safety in the 2 treatment arms as determined by the percentage change from 
baseline in hip and spine BMD and change from baseline in T-score at Week 48;

To evaluate the change from baseline in bone biomarker levels at Week 48. 
2.2.
Hypothesis
Null hypothesis: D/C/F/TAF FDC is inferior to DRV/COBI FDC coadministered with FTC/TDF 
FDC by at least 10% with respect to the proportion of subjects having HIV-1 RNA <50 
copies/mL at Week 48 (as defined by the FDA-defined snapshot analysis).
Alternative hypothesis: D/C/F/TAF FDC is noninferior to DRV/COBI FDC coadministered with 
FTC/TDF FDC by less than 10% with respect to the proportion of subjects having HIV-1 RNA 
<50 copies/mL at Week 48 (as defined by the FDA-defined snapshot analysis).
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a 96-week multicenter, Phase 3 study consisting of a 48-week randomized, double-blind 
active-controlled treatment period, to evaluate a D/C/F/TAF FDC tablet versus DRV/COBI FDC 
coadministered with FTC/TDF FDC in ARV treatment-naïve HIV-1 infected adult subjects, 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
42
Approved, Date: 18 April 2017
followed by an open-label single-arm D/C/F/TAF treatment period for all subjects up to Week 96 
to asses long-term efficacy, resistance, and safety.
A target of 670 subjects will be randomly assigned in this study with 335 subjects planned per 
treatment arm. 
Prior to or at the baseline visit (Day 1), subjects who meet all eligibility criteria will be 
randomized in a 1:1 ratio to 1 of the following 2 treatment arms:
-
D/C/F/TAF Arm: Regimen of a single tablet containing DRV 800 mg/ COBI 150 mg/ 
FTC 200 mg/ TAF 10 mg (D/C/F/TAF FDC) once daily, (n=335) 
+ DRV/COBI FDC-matching and FTC/TDF FDC-matching placebo 
tablets once daily;
-
Control Arm : 
Regimen of DRV 800 mg/ COBI 150 mg FDC coadministered with FTC 
200 mg/ TDF 300 mg FDC once daily, (n=335)
+ D/C/F/TAF FDC-matching placebo tablet once daily.
Randomization will be stratified by HIV-1 RNA level (≤100,000 copies/mL or 
100,000 copies/mL) and CD4+ cell count (<200 cells/µL or ≥200 cells/µL) at screening. 
Subjects will be treated for 96 weeks, and will return for study visits at Weeks 2, 4, 8, 12, 24, 36, 
48, every 12 weeks thereafter until and including a Week 96 visit. 
After Week 48, subjects will continue to take their blinded study drug and attend visits every 
12 weeks until all subjects have reached Week 48, the database for the primary analysis has been 
locked, and treatment assignments have been unblinded. Provided the results from the primary 
analysis do not preclude (further) exposure of subjects to D/C/F/TAF, all subjects will return for 
an unblinding visit and will receive the D/C/F/TAF FDC tablet treatment during an open-label 
single-arm treatment phase up to Week 96. Subjects from the control arm who switch to the 
D/C/F/TAF regimen after the 48-week double-blind treatment will be required to return to the 
clinic for an additional visit 3 to 7 weeks after the unblinding visit.
After Week 96, subjects will be given the opportunity to continue D/C/F/TAF treatment during 
an extension phase until the D/C/F/TAF FDC tablet 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. During the extension phase subjects will 
attend visits every 6 months. 
Subjects who prematurely discontinue, either during the double-blind treatment phase (from 
Day 1 to Week 48) or during the single-arm D/C/F/TAF phase (between Week 48 and Week 96) 
will be required to return to the clinic within 72 hours of stopping study treatment for the early 
study treatment discontinuation (ESTD) visit.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
43
Approved, Date: 18 April 2017
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), double-blind active-
controlled treatment for at least 48 weeks, an open-label single-arm D/C/F/TAF treatment up to 
Week 96 and an extension phase. A 30-day FU visit may take place as described above. 
The primary analysis of this study will be performed when all subjects have completed 
the Week 48 visit or discontinued earlier. An additional analysis will be performed when all 
subjects have completed the Week 96 visit. The final analysis will be performed once all subjects 
have completed the extension phase (and the 30-day FU visit if applicable), or discontinued 
earlier.
The safety and tolerability, as well as efficacy, of the enrolled subjects and treatment regimens 
will be monitored by an independent Data Monitoring Committee (DMC). Refer to Section 11.8
for details. In addition to the Week 48, Week 96, and final analyses, formal DMC analyses will 
be performed for monitoring purposes, including a futility analysis for lack of (non-inferior) 
efficacy and a blinded sample size re-estimation.
A diagram of the study design is provided in Figure 1.
Assessment and reporting of drug adherence and accountability, concomitant medications, and 
AEs, laboratory evaluations for efficacy and safety (viral load, CD4+ cell count, biochemistry, 
hematology, urinalysis, urine chemistry), vital signs and (complete or symptom-directed) 
physical examinations will be performed at each visit, except for drug accountability at Week 2.
At screening, a 12-lead electrocardiogram (ECG) and an HIV-1 genotype test will be performed.
Urine for assessments of selected renal biomarkers, including RBP and beta-2-microglobulin,
will be collected at baseline and at the time points specified in the Time and Event Schedule.
Screening genotype testing will be performed for all subjects to assess sensitivity to DRV, TDF 
and FTC. Further HIV-1 PR and RT genotype/phenotype testing will be performed at later time 
points for subjects that are eligible for resistance testing (subjects with virologic rebound, 
virologic nonresponse, and discontinuations with last available viral load measurement 
≥400 copies/mL). If resistance to the study drugs is documented, study drugs may be 
discontinued. 
Pharmacokinetic assessments (sparse sampling) will be performed for all subjects (single sample 
from Weeks 4 through 48 or the ESTD visit, except at Weeks 8 and 36 visits, when 2 samples 
will be collected ≥2.5 hours apart). 
A bone investigation substudy will be performed at selected study sites, to assess bone 
biomarkers and dual energy x-ray absorptiometry (DXA) scans, in at least 170 subjects 
(85 subjects in each treatment arm) who provide informed consent for the substudy. 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
44
Approved, Date: 18 April 2017
To determine BMD of the hip and spine, consenting subjects will have DXA scans performed at 
the time points specified in the Time and Event Schedule. In subjects participating in the DXA 
substudy, blood will be collected for assessment of bone biomarkers at the time points specified 
in the Time and Event Schedule.
Figure 1:
Schematic Overview of the Study 
Baseline 
(Day 1)a
Week 24
DMCb
Week 48c,d
Primary analysis
Week 96e
Analysis
Screening
Double-Blind Treatment Phasef
Single-arm 
Treatment
Phasec,d,f
Extension 
Phasee
Follow-up
≤30 days 
prior
to baseline
Treatment arm 1 (Test) (n=335): 
D/C/F/TAF FDC once dailyg
DRV/COBI FDC-matching and FTC/TDF FDC-
matching placebo tablets once dailyg
D/C/F/TAF
FDC
D/C/F/TAF
FDC
ESTDf and
30-day
FU visith
Treatment arm 2 (Control) (n=335): 
DRV/COBI FDC coadministered with FTC/TDF 
FDC once dailyg
D/C/F/TAF FDC-matching placebo tablet once 
dailyg
a
Following the baseline visit, subjects will return for study visits at Weeks 2, 4, 8, 12, 24, 36, 48, and every 12 
weeks thereafter until and including a Week 96 visit.
b
Formal DMC interim analyses will be performed for monitoring purposes, including a futility analysis for 
lack of (non-inferior) efficacy and a blinded sample size re-estimation.
c
Subjects will continue to take their blinded study drug and to attend visits every 12 weeks following Week 48 
until treatment assignment is unblinded.
d
After unblinding, provided the results from the primary analysis do not preclude (further) exposure of 
subjects to D/C/F/TAF, all subjects will receive D/C/F/TAF treatment during a single-arm treatment phase up 
to Week 96. Subjects from the control arm who switch to the D/C/F/TAF regimen after the 48-week double-
blind treatment will be required to return to the clinic for an additional visit 3 to 7 weeks after the unblinding 
visit.
e
After Week 96, subjects will be given the opportunity to continue D/C/F/TAF treatment during an extension 
phase until the D/C/F/TAF FDC tablet 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. During the extension phase subjects will attend visits every 6 months. 
f
Subjects who prematurely discontinue, either during the double-blind treatment phase (from Day 1 to 
Week 48) or during the single-arm D/C/F/TAF treatment phase (between Week 48 and Week 96) will be 
required to complete the ESTD assessments within 72 hours of stopping study treatment. 
g
All study drugs and matching placebo tablets must be administered orally, once daily in the morning with food, 
at approximately the same time each day.
h
Any subject who has an ongoing AE or SAE at the time of his/her last study visit will be required to return to 
the clinic 30 days after the completion their his/her study visit for a 30-day FU visit (unless consent is 
withdrawn).
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
45
Approved, Date: 18 April 2017
3.2.
Study Design Rationale
Control, Blinding, Randomization and Stratification 
A bPI in combination with 2 NRTIs, an established regimen for treatment-naïve HIV-infected 
patients, is the active control treatment in this study. The active control treatment consists of the 
DRV/COBI FDC (PREZCOBIX/REZOLSTA) coadministered with FTC/TDF FDC (TVD). In 
addition, since TAF is substituted by TDF in the comparator treatment, the active control 
treatment will allow a direct comparison of these 2 ARVs for safety assessments.
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints.
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. Equal randomization will be done because this 
requires a lower total sample size to attain the same power versus randomization with unequal 
division.
Two stratification factors (HIV-1 RNA level [≤100,000 copies/mL or >100,000 copies/mL] and 
CD4+ cell count [<200 cells/µL or ≥200 cells/µL] at screening) will be applied in the 
randomization process and will subsequently be used in the statistical analysis as covariates in 
the models. Since previous publications have shown that baseline viral load can be a predictive 
factor for outcome, this will ensure a balanced distribution of subjects across treatment arms.11,15
Study Period and Primary Analysis Time Point
A double-blind, active-controlled treatment duration up to 48 weeks was chosen to evaluate the 
sustained efficacy, tolerability and safety of the D/C/F/TAF FDC tablet regimen in the selected 
population. To assure continued follow-up of the study participants and gain further safety 
information, subjects who prematurely discontinue study treatment during the double-blind
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, provided the results from the primary analysis do not preclude (further) 
exposure of subjects to D/C/F/TAF, subjects of both treatment arms will receive the D/C/F/TAF 
FDC tablet in an open-label single-arm treatment phase and attend visits every 12 weeks up to 
Week 96. In order to collect long-term safety and efficacy data on D/C/F/TAF, subjects will be 
given the opportunity to continue D/C/F/TAF treatment after Week 96 during an extension phase 
and attend visits every 6 months, 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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
46
Approved, Date: 18 April 2017
The primary analysis of this study will be performed when all subjects have completed 
the Week 48 visit or discontinued earlier. An additional analysis will be performed when all 
subjects have completed the Week 96 visit. 
Primary analysis at Week 48, double-blind active-controlled treatment duration of 48 weeks and 
longer term follow-up up to 96 weeks are in line with FDA Guidance for Industry Human 
Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment (draft 
guidance June 2013).
Toxicity Management
The combination of D/C/F/TAF is not anticipated to exacerbate known toxicities or lead to new 
toxicities (see also Section 1.7). Measures and guidelines for the monitoring and management of 
specific toxicities with DRV, COBI, FTC, TAF or TDF are included in this protocol (see 
Section 9.5). The presented toxicity management guidelines are applicable throughout the entire 
study starting from baseline through the 96-week treatment period and the extension phase.
Safety and Efficacy Monitoring
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 independent 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 11.8).
3.3.
Dose Selection Rationale
DRV 800 mg boosted by COBI 150 mg, and FTC 200 mg in the D/C/F/TAF FDC tablet 
represent the marketed doses. The dose of TAF 10 mg in the D/C/F/TAF FDC 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. A TAF 10 mg dose is also being used 
for other TAF regimens including a pharmacoenhancer (rtv or COBI), currently in development.
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, -1.7±0.22 log10 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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
47
Approved, Date: 18 April 2017
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 D/C/F/TAF 
FDC tablet 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 studies 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 
FDC tablet.
4.
SUBJECT POPULATION
Approximately 670 subjects will be randomized in a 1:1 ratio to 1 of the 2 treatment arms. 
Screening for eligible subjects will be performed within approximately 30 days (up to maximum 
6 weeks) 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, refer to Section 11.3, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study.
1.
Subject must be medically stable on the basis of physical examination, medical history, 
vital signs, and 12-lead ECG performed at screening. If there are abnormalities, they must 
be consistent with the underlying illness in the study population. This determination must 
be recorded in the subject's source documents and initialed by the investigator.
2.
Subjects must have documented HIV-1 infection. 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
48
Approved, Date: 18 April 2017
3.
Subjects must be ARV treatment-naïve (never treated with an ARV including post-
exposure prophylaxis and pre-exposure prophylaxis); no prior use of any approved or 
experimental anti-HIV drug for any length of time.
4.
Screening plasma HIV-1 RNA level 1,000 copies/mL.
5.
CD4+ cell count 50 cells/L.
6.
Screening HIV-1 genotype report must show full sensitivity to DRV, TDF and FTC.
7.
Screening eGFRcreatinine ≥70 mL/min according to the Cockcroft-Gault formula for 
creatinine clearance.9
8.
Screening hepatic transaminases (alanine aminotransferase [ALT] and AST) ≤5 x upper 
limit of the normal range (ULN). 
9.
Screening direct bilirubin ≤1.5 x ULN. 
Note: Subjects with documented Gilbert's Syndrome may have total bilirubin up to 
5 x ULN. 
10.
Adequate hematologic parameters at screening: platelets ≥50,000 /µL, hemoglobin 
≥8.5 g/dL, absolute neutrophil count ≥1,000/µL.
11.
Screening serum amylase ≤2 x ULN (subjects with serum amylase >2 x ULN will remain
eligible if serum lipase is ≤2 x ULN). 
12.
For the other clinical laboratory tests performed at screening and not specified in the 
inclusion criteria above, the test results should be within normal reference ranges. If the 
results of the serum chemistry panel, hematology, or urinalysis are outside the normal 
reference ranges, the subject may be included only if the investigator judges the 
abnormalities or deviations from normal to be not clinically significant or to be 
appropriate and reasonable for the population under study. This determination must be 
recorded in the subject's source documents and initialed by the investigator.
13.
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/ 
additional 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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
49
Approved, Date: 18 April 2017
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).  
14.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction until 90 days after EOT (or longer, if dictated by local regulations).
15.
Men with a female partner of childbearing potential must agree to use adequate reliable 
contraceptive methods (see also Inclusion Criterion 13) 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.
16.
Men must agree not to donate sperm during the study until 90 days after EOT (or longer, 
if dictated by local regulations).
17.
Each subject (or their legally acceptable representative) must sign an ICF indicating that 
he or she understands the purpose of and procedures required for the study and are willing 
to participate in the study.
18.
Subject must be able to swallow tablets. 
19.
Subject must be a man or woman ≥18 years of age.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
50
Approved, Date: 18 April 2017
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
Subject has been diagnosed with a new AIDS-defining condition (see Attachment 2) within 
the 30 days prior to screening.
2.
Subject has proven or suspected acute hepatitis within 30 days prior to screening.
3.
Subject is hepatitis C antibody positive; however, spontaneously cured 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.
Subject is hepatitis B surface antigen (HBsAg) positive.
5.
Subject has a history of cirrhosis. 
6.
Subject has a 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, penile or cervical intra-epithelial neoplasia.
7.
Subject has active, severe infections (other than HIV-1 infection) requiring parenteral 
antibiotic or antifungal therapy within 30 days prior to baseline.
8.
Subject has known allergies, hypersensitivity, or intolerance to D/C/F/TAF FDC, 
DRV/COBI FDC, and TDF/FTC FDC, or their excipients.
9.
Subject is unlikely to comply with the protocol requirements, based on clinical judgment.
10.
Participation in any other clinical study without prior approval from the sponsor.
11.
Subject is a woman who is pregnant (positive serum pregnancy test), or breast-feeding, or 
planning to become pregnant while enrolled in this study or within 90 days after the last 
dose of study drug.
12.
Subject is a man who plans to father a child while enrolled in this study or within 90 days
after the last dose of study drug.
13.
Subject has a current condition (including but not limited to alcohol or substance use)
judged by the investigator to potentially compromise the subject’s safety and/or adherence 
to the study protocol.
14.
Subject has any condition for which, in the opinion of the investigator, participation would 
not be in the best interest of the subject (eg, compromise the well-being) or that could 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
51
Approved, Date: 18 April 2017
prevent, limit, or confound the protocol-specified assessments.
15.
Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as well 
as family members of the employees or the investigator. 
16.
Subject is receiving therapy with any of the disallowed drugs in Table 1 and for whom it is 
impossible to have these discontinued at least 30 days prior to baseline.
Table 1:
Exclusionary Concomitant Medications 
Drug Class
Agents Disalloweda,b
Alpha adrenergic receptor antagonist
Alfuzosin
Analeptic
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
Antigout
Colchicine (in patients with renal or hepatic impairment)
Anti-HCV drugs
Telaprevir, Boceprevir, Simeprevir, fixed dose combination 
tablet containing Ombitasvir, Paritaprevir, and Ritonavir 
copackaged with Dasabuvir
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 β-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 concomitant medication may not be exhaustive. Refer to the current local 
Prescribing Information for these medications, where available, for additional and up-to-date information.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
52
Approved, Date: 18 April 2017
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
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. Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria.
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).
3.
A woman using oral contraceptives should use an additional birth control method (see 
inclusion criterion).
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in conducting this study. Subjects will be assigned to 
1 of 2 treatment groups based on a computer-generated schedule, constructed via random 
permuted blocks implemented in the interactive web response system (IWRS) and prepared 
before the start of the study by or under the supervision of the sponsor. Stratified randomization
minimizes the imbalance in the distribution of the number of subjects across treatment groups 
within the levels of each individual stratification factor: HIV-1 RNA level (≤100,000 copies/mL 
or 100,000 copies/mL) and CD4+ cell count (<200 cells/µL or ≥200 cells/µL) at screening. The 
IWRS will assign a unique treatment code, which will dictate the treatment assignment and 
matching study drug kit for the 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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
53
Approved, Date: 18 April 2017
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, pharmacokinetic data) will be 
handled with special care to ensure that the integrity of the blind is maintained and the potential 
for bias is minimized. This can include making special provisions, such as segregating the data in 
question from view by the investigators, clinical team, or others as appropriate until the time of 
database lock and unblinding.
Under normal circumstances, the blind should not be broken until all subjects have reached 
Week 48 and the database for the Week 48 analysis is finalized. Otherwise, the blind should be 
broken only if specific emergency treatment/course of action would be dictated by knowing the 
treatment status of the subject. In such cases, the investigator may in an emergency determine the 
identity of the treatment by contacting the IWRS. It is recommended that the investigator 
contacts the sponsor or its designee if possible to discuss the particular situation, before breaking 
the blind. Telephone contact with the sponsor or its designee will be available 24 hours per day, 
7 days per week. In the event the blind is broken, the sponsor must be informed as soon as 
possible. The date, time, and reason for the unblinding must be documented by the IWRS, in the 
appropriate section of the electronic case report form (eCRF) and in the source document. The 
documentation received from the IWRS indicating the code break must be retained with the 
subject's source documents in a secure manner.
In order to distinguish samples from subjects randomized to the D/C/F/TAF treatment arm from 
those of subjects in the control group, the bioanalytical lab will be unblinded to the treatment 
groups. However, the sponsor will remain blinded from the origin of the samples that have been 
analyzed, as well as from the outcome of the analyses, until locking of the database has been 
performed for the primary analysis.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled evaluations to receive the D/C/F/TAF FDC tablet in an open-label single-arm 
treatment phase.
6.
DOSAGE AND ADMINISTRATION
Prior to the baseline visit (Day 1), eligible subjects will be randomized in a 1:1 ratio to the 
investigational treatment arm (D/C/F/TAF FDC tablet) or the active control arm (DRV/COBI 
FDC coadministered with FTC/TDF FDC) (see also Figure 1). 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
54
Approved, Date: 18 April 2017
-
D/C/F/TAF Arm (n=335):
Regimen of a single-tablet containing DRV 800 mg/ COBI 150 mg/ FTC 
200 mg/ TAF 10 mg (D/C/F/TAF FDC tablet) once daily 
+ DRV/COBI FDC-matching and FTC/TDF FDC-matching placebo 
tablets once daily;
-
Control Arm (n=335): 
Regimen of DRV 800 mg/ COBI 150 mg FDC coadministered with FTC 
200 mg/ TDF 300 mg FDC once daily 
+ D/C/F/TAF FDC-matching placebo tablet once daily.
All baseline tests and procedures must be completed prior to the administration of the first dose 
of study treatment. Initiation of study treatment must take place within 24 hours after the 
baseline visit.
The investigational medication, D/C/F/TAF FDC tablets, the control DRV/COBI FDC tablets and 
the D/C/F/TAF FDC- and DRV/COBI FDC–matching placebo tablets (identical in physical 
appearance), will be manufactured, packaged and provided by the sponsor. The control 
FTC/TDF FDC tablets and matching placebo tablets will be manufactured, packaged by GSI and 
provided to the sponsor for distribution.
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol.
All study drugs and matching placebo tablets must be administered orally, once daily in the 
morning with food, at approximately the same time each day. Study drugs should be taken on 
site with food during study site visits (except Week 8 and Week 36), after all safety assessments 
that require fasting are taken. 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 >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 
when such temporary interruption occurs.
After Week 48, subjects will continue to take their blinded study drug and attend visits every 
12 weeks until all subjects have reached Week 48 and treatment assignments have been 
unblinded. Provided the results from the primary analysis do not preclude (further) exposure of 
subjects to D/C/F/TAF, all subjects will return for an unblinding visit and will receive the 
D/C/F/TAF FDC tablet in an open-label single-arm treatment phase until Week 96. In order to 
collect long-term safety and efficacy data on D/C/F/TAF, subjects will be given the opportunity 
to continue D/C/F/TAF treatment after Week 96 during an extension phase until the D/C/F/TAF 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
55
Approved, Date: 18 April 2017
FDC tablet 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, ARV regimen in the control 
arm and matching placebo tablets) 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, ARV regimen in the 
control arm and matching placebo tablets) 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 study medication intakes. Subjects 
should be instructed to bring their log booklet, and these will be checked and discussed with the 
subject by the investigator or designated study personnel at each visit up to Week 96.
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 (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the investigational medication (D/C/F/TAF FDC tablet, 
ARVs in the control arm, or matching placebo tablets) must be recorded in the eCRF. Recorded 
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.
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
56
Approved, Date: 18 April 2017
Data on concomitant medication will be collected up to the last FU visit, even after withdrawal 
of a subject. Concomitant therapies should be recorded beyond the last FU visit only in 
conjunction with SAEs that meet the criteria outlined in the study protocol.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
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 Prescribing Information 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 study medication. Guidance on dose adjustments for these 
concomitant medications, if applicable, is provided in Table 2. 
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 
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
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
57
Approved, Date: 18 April 2017
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. 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
58
Approved, Date: 18 April 2017
Drug Class
Agents Disalloweda
Use Discouraged or 
to be Used With Cautiona
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 200 mg. 
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.
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).
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
59
Approved, Date: 18 April 2017
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 β-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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
60
Approved, Date: 18 April 2017
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
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy,
pharmacokinetic and safety measurements applicable to this study. The protocol procedures are 
described in detail in Sections 9.2 through 9.5.
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, 48, every 12 weeks thereafter until and including a Week 96 visit. All study visits 
are to be scheduled relative to the baseline/Day 1 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 96 weeks. The study visit at Week 2 is to be completed within ±2 days of the protocol-
specified visit date based on the baseline (Day 1). The other study visits through Week 96 are to 
be completed within ±7 days of the protocol-specified visit date. For further details, see Section 
9.1.3.
After Week 48, subjects will continue to take their blinded study drug and attend visits every 
12 weeks until all subjects have reached Week 48 and treatment assignments have been 
unblinded. Provided the results from the primary analysis do not preclude (further) exposure of 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
61
Approved, Date: 18 April 2017
subjects to D/C/F/TAF, all subjects will return for an unblinding visit and will receive the 
D/C/F/TAF FDC tablet in an open-label single-arm treatment phase. Subjects from the control 
arm who switch to the D/C/F/TAF regimen after the 48-week double-blind treatment will be 
required to return to the clinic for an additional visit 3 to 7 weeks after the unblinding visit. If 
this additional visit would take place within a ±4 week window of a normal planned schedule 
visit, the additional visit can take place during this planned visit. For further details, see Section 
9.1.4.
After Week 96, subjects will be given the opportunity to continue D/C/F/TAF treatment during 
an extension phase until the D/C/F/TAF FDC tablet 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. During the extension phase subjects will 
attend visits every 6 months. The visits during the extension phase are to be completed within 
±14 days of the protocol-specified visit date. For further details, see Section 9.1.5.
Subjects who prematurely discontinue treatment, either during the double-blind treatment phase 
(from Day 1 to Week 48) or during the open-label single-arm treatment phase (between Week 48
and Week 96) will be required to complete the ESTD visit assessments within 72 hours of 
stopping 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 9.1.6.2.
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.
The total blood volume to be collected from each subject from screening through the Week 96 
visit will be approximately 585 mL and 640 mL, for subjects participating only in the main study 
and for subjects also participating in the bone investigation substudy, respectively.
Repeat or unscheduled samples may be required for safety reasons, for technical issues with the 
samples, or for confirmation of virologic failure (VF) in case of unconfirmed FV (virologic 
nonresponse or virologic rebound). When an HIV-1 RNA repeat testing is required at an 
unscheduled visit, an HIV-1 genotype/phenotype plasma sample and a plasma storage sample 
should also be drawn at the same unscheduled visit. Additional serum or urine pregnancy tests 
may be performed, as determined necessary by the investigator or required by local regulation, to 
establish the absence of pregnancy at any time during the subject's participation in the study.
Findings during these unscheduled visits or assessments need to be reported in the eCRF.
Plasma samples drawn will be frozen and stored. These stored samples may be used by the 
sponsor or its research partners for HIV-1 genotype/phenotype assays, for retesting the amount 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
62
Approved, Date: 18 April 2017
of HIV-1 RNA in the blood, for additional measurement of antiviral drug levels in the blood, 
clinical laboratory testing to provide additional safety data, or future testing to learn more about 
how the investigational drug has worked against HIV-1. No human genetic testing will be 
performed. See also Section 16.2.5.
9.1.2.
Pre-treatment Phase
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 eGFRcystatin according to the CKD-EPI formula.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
63
Approved, Date: 18 April 2017

eGFRcreatinine ≥70 mL/min according to the Cockcroft-Gault formula for creatinine 
clearance; for details, see Section 9.5.4.

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.

HIV-1 PR/RT genotype.

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. 
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 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.

Review of clinical status and available data.

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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
64
Approved, Date: 18 April 2017

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.

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. 

Hematology profile (see also Section 9.1.2.1).

Cystatin C and eGFRcystatin according to the CKD-EPI formula.

eGFRcreatinine according to the Cockcroft-Gault formula and the CKD-EPI formula; for 
details, see Section 9.5.4.

Plasma HIV-1 RNA.

CD4+ cell count.

HIV-1 resistance testing. HIV-1 PR/RT genotype/phenotype testing will be requested 
by the study virologist on samples from subjects eligible for resistance testing. 

Plasma storage samples for possible additional testing.

PBMC storage sample for exploratory analysis (eg to characterize archived viral 
resistance) if deemed necessary by the study virologist.

Study drug dispensation (D/C/F/TAF FDC and DRV/COBI FDC + FTC/TDF FDC matching 
placebos or D/C/F/TAF FDC-matching placebo and DRV/COBI FDC + FTC/TDF FDC) in a 
double-blind fashion: 

All subjects must initiate dosing with study medication within 24 hours after the 
baseline visit.

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 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): CTX, P1NP, PTH, and 25-hydroxy vitamin D. If the subject has not 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
65
Approved, Date: 18 April 2017
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). A rescan for technical reasons is allowed 
within 2 weeks.
Note: For female subjects absence of pregnancy will be confirmed at screening prior to 
performing the DXA scan.
9.1.3.
Double-blind Treatment Phase
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). After Week 48, subjects will continue to 
take their blinded study drug and attend visits every 12 weeks until all subjects have reached 
Week 48 and treatment assignments have been unblinded. Provided the results from the primary 
analysis do not preclude (further) exposure of subjects to D/C/F/TAF, all subjects will return to 
the clinic for an unblinding visit, preferably at the next planned visit.
The time window for the Week 2 visit is ±2 days, and for the visits through the unblinding visit
is ±7 days of the protocol-specified visit date. 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, 48, and at the unblinding visit
(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, 36, and every 
12 weeks following Week 48 until unblinding.

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, 48, every 12 weeks following Week 48 
until and including the unblinding visit (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).
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
66
Approved, Date: 18 April 2017

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, 48, every 
12 weeks following Week 48 until and including the unblinding visit (see also 
Section 9.1.2.1).

Hematology profile (see also Section 9.1.2.1).

Cystatin C and eGFRcystatin according to the CKD-EPI formula.

eGFRcreatinine according to the Cockcroft-Gault formula, and the CKD-EPI formula (for 
details, see Section 9.5.4).

Plasma HIV-1 RNA.

CD4+ cell count.

HIV-1 resistance testing. HIV-1 PR/RT genotype/phenotype testing will be requested 
by the study virologist on samples from subjects eligible for resistance testing.

Plasma storage sample for possible additional clinical testing at Weeks 2, 4, 12, 24, 36, 
48, and the unblinding visit. 

PBMC storage sample at Weeks 24 and 48, for exploratory analysis (eg to characterize 
archived viral resistance) if deemed necessary by the study virologist.

Pharmacokinetic sample collection:

Blood samples will be collected at least 30 minutes to maximum 4 hours postdose at 
Weeks 2, 4, 12, 24, and 48.

Blood samples will be collected at 2 time points with at least 2.5 hours in between 
sampling at Weeks 8 and 36. The first pharmacokinetic sample at these visits should be 
taken between 1 and 4 hours postdose (dosing may occur prior to the study site visit).

Document study drug dispensation and accountability (except at Week 2) 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, 48, and Week 72 (if applicable) (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. Biomarkers PTH and 25-hydroxy vitamin 
D should be assessed at Weeks 24 and 48 only. If the subject has not fasted prior to the 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
67
Approved, Date: 18 April 2017
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. A time window of ±2 weeks and a 
rescan for technical reasons within 4 weeks are allowed. 
9.1.4.
Open-label Single-arm Phase 
After the unblinding visit, provided the results from the primary analysis do not preclude 
(further) exposure of subjects to D/C/F/TAF, subjects will receive the D/C/F/TAF FDC tablet in 
an open-label single-arm treatment phase of the study and will be required to attend visits every 
12 weeks. Subjects from the control arm who switch to the D/C/F/TAF treatment after the 48-
week double-blind treatment will be required to return to the clinic for an additional visit 3 to 7 
weeks after the unblinding visit. If the additional visit would take place within a ±4 week 
window of a normal planned schedule visit, the additional visit can take place during a planned 
visit. 
The time window for the visits during the open-label single-arm treatment phase is ±7 days of 
the protocol-specified visit date, except for the additional visit where no extra time window is 
applicable. The following evaluations are to be completed and documented at each 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 3 to 7 weeks following the unblinding visit (only 
for those subjects who switched to D/C/F/TAF), every 12 weeks following the unblinding 
visit until and including 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 3 to 7 weeks following the unblinding visit (only for those 
subjects who switched to D/C/F/TAF), every 12 weeks following the unblinding visit 
until and including Week 96 (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).
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
68
Approved, Date: 18 April 2017

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 (see also Section 
9.1.2.1).

Hematology profile (see also Section 9.1.2.1).

Cystatin C and eGFRcystatin according to the CKD-EPI formula at 3 to 7 weeks 
following the unblinding visit (only for those subjects who switched to D/C/F/TAF) 
(for details, see Section 9.5.4).

eGFRcreatinine according to the Cockcroft-Gault formula and the CKD-EPI formula (for 
details, see Section 9.5.4).

Plasma HIV-1 RNA.

CD4+ cell count.

HIV-1 resistance testing. HIV-1 PR/RT genotype/phenotype testing will be requested 
by the study virologist on samples from subjects eligible for resistance testing.

Plasma storage sample for possible additional clinical testing at 3 to 7 weeks following 
the unblinding visit (only for those subjects who switched to D/C/F/TAF) and at Week 
96. 

PBMC storage sample at Week 96 for exploratory analysis (eg to characterize archived 
viral resistance) if deemed necessary by the study virologist.

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 3 to 7 weeks following the unblinding visit (only for those 
subjects who switched to D/C/F/TAF) and every 24 weeks until and including 
Week 96 (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 
should be assessed at Week 96 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 Week 96. A time window of ±2 weeks and a rescan for 
technical reasons within 4 weeks is allowed.
9.1.5.
Extension Phase 
After Week 96 subjects will be given the opportunity to continue D/C/F/TAF treatment during an
extension phase until the D/C/F/TAF FDC tablet 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. During the extension phase subjects will 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
69
Approved, Date: 18 April 2017
attend visits every 6 months thereafter. The time window during the extension phase is ±14 days 
of the protocol-specified visit date. The following evaluations are to be completed and 
documented at each visit.

Review of AEs and changes in concomitant medications.

Symptom-directed physical examination (physical examination of body parts for which 
symptoms have been reported by the subject) as needed.

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 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). 

Hematology profile (see also Section 9.1.2.1).

eGFRcreatinine according to the Cockcroft-Gault formula, and the CKD-EPI formula (for 
details, see Section 9.5.4).

Plasma HIV-1 RNA. 

CD4+ cell count.

HIV-1 resistance testing. HIV-1 PR/RT genotype/phenotype testing will be requested 
by the study virologist on samples from subjects eligible for resistance testing.

Document study drug dispensation and accountability for all study drugs dispensed. 
9.1.6.
Post-treatment Phase 
9.1.6.1.
Early Study Treatment Discontinuation Visit
Subjects who prematurely discontinue, either during the double-blind treatment phase (from 
Day 1 to Week 48) or during the open-label single-arm treatment phase (between Week 48 and 
Week 96) will be required to return to the clinic within 72 hours of stopping study treatment for 
the ESTD visit.
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
70
Approved, Date: 18 April 2017
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).

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).

Hematology profile (see also Section 9.1.2.1).

eGFRcreatinine according to the Cockcroft-Gault formula, and the CKD-EPI formula (for 
details, see Section 9.5.4).

Plasma HIV-1 RNA.

CD4+ cell count.

HIV-1 resistance testing. HIV-1 PR/RT genotype/phenotype testing will be requested 
by the study virologist on samples from subjects eligible for resistance testing. 

Plasma storage sample for possible additional clinical testing. 

PBMC storage sample for exploratory analysis (eg, to characterize archived viral 
resistance) if deemed necessary by the study virologist.

Pharmacokinetic blood sample.

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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
71
Approved, Date: 18 April 2017

DXA scan of spine and hip: only to be performed at ESTD (±2 Weeks) if the last scan is 
more than 12 weeks from the date of the ESTD visit and the ESTD visit takes place before 
Week 96. A rescan for technical reasons within 4 weeks is allowed.
9.1.6.2.
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.

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). 

Hematology profile (see also Section 9.1.2.1).

eGFRcreatinine according to the Cockcroft-Gault formula, and the CKD-EPI formula (for 
details, see Section 9.5.4).

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 Event 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 %).
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
72
Approved, Date: 18 April 2017
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 genotype/phenotype resistance testing, as well as a PBMC sample will be 
taken at the time points specified in the Time and Event Schedule. PBMC samples will be taken 
for storage for exploratory analysis (eg, to characterize archived viral resistance) only if deemed 
necessary by the study virologist.
9.2.2.1.
Virologic Failure 
Subjects who are on study medication and who experience a protocol defined confirmed VF, ie, 
virologic nonresponse (NR) or virologic rebound (RB), as defined below, will be considered to 
have VF for the purpose of the resistance analysis.
Virologic Nonresponse: 

HIV-1 RNA <1 log10 reduction from baseline and ≥50 copies/mL at the Week 8 visit, 
confirmed at the following scheduled or unscheduled visit following Week 8.
Subjects (and the resistance testing on samples from these subjects), who meet the criteria for
NR will be managed according to the protocol schema provided in Figure 2.
Virologic Rebound:

At any visit, after achieving confirmed (consecutive) HIV-1 RNA <50 copies/mL, a rebound
in HIV-1 RNA to ≥50 copies/mL, which is subsequently confirmed at the following 
scheduled or unscheduled visit; or

At any visit, a >1 log10 increase in HIV-1 RNA from the nadir which is subsequently
confirmed at the following scheduled or unscheduled visit.
Subjects (and the resistance testing on samples from these subjects), meeting the criteria for RB
will be managed according to the schema provided in Figure 3.
9.2.2.2.
Subjects Eligible for Resistance Testing
To investigate the emergence of PR/RT resistance, the following subjects will be eligible for 
genotypic/phenotypic resistance testing:

Any subject who experiences a protocol defined confirmed VF, ie NR or RB, and has an 
HIV-1 RNA value ≥400 copies/mL (see Section 9.2.2.1);

Any 
subject 
who 
discontinues 
study 
treatment 
and 
has 
an 
HIV-1 
RNA 
value ≥400 copies/mL at the last viral load measurement (within 72 hours
after
discontinuation of the study treatment). 
For subjects with confirmed VF (NR or RB), the plasma sample corresponding to the confirmed 
VF time point will be analyzed if HIV-1 RNA value ≥400 copies/mL. In case of confirmed VF 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
73
Approved, Date: 18 April 2017
but with an HIV-1 RNA value <400 copies/mL at the confirmed VF point, resistance testing 
might then be done at a later time point if HIV-1 RNA value ≥400 copies/mL or at the 
unconfirmed VF point if HIV-1 RNA value ≥400 copies/mL. In case of persistent low level 
viremia between 50 and 400 HIV-1 RNA copies/mL, study drugs may be discontinued at the 
investigator’s discretion and the subject will be withdrawn from the study.
An HIV-1 PR/RT genotypic assay will be used to determine the screening genotype for all 
patients. Further PR/RT genotypic resistance testing will be performed on eligible subjects and 
phenotypic resistance testing may be done upon request of the study virologist. Baseline 
phenotyping (and genotyping) may be performed retrospectively on subjects with confirmed VF
if they showed evidence of reduced susceptibility after VF to any of the study drugs. Other time 
points may still be analyzed if deemed necessary by the protocol virologist.
In case of early discontinuation an HIV-1 genotypic resistance report will be forwarded to the 
investigator in order to assist in the selection of a new ARV regimen.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
74
Approved, Date: 18 April 2017
Figure 2:
Virologic Nonresponse Schema 
a
If virologic nonresponse is not confirmed, the subject will remain on its assigned study drug and the subject’s 
viral load will be further monitored.
b
Upon confirmation of virologic nonresponse potential causes should be documented. Assessment should 
include lack of adherence, concomitant medication, and comorbidities (eg, active substance abuse, depression, 
or other intercurrent illnesses).
c
If virologic nonresponse is confirmed, the HIV-1 genotype/phenotype (RT and PR) will be analyzed if HIV-1 
RNA ≥400 copies/mL.
d
If HIV-1 RNA <400 copies/mL, the subject’s viral load will be further monitored and resistance testing may be 
done at a later time point if HIV-1 RNA ≥400 copies/mL or at the unconfirmed virologic failure point if HIV-1 
RNA ≥400 copies/mL. In case of persistent low level viremia between 50 and 400 HIV-1 RNA copies/mL, 
Screening
Treatment Period 
ESTD
HIV-1 genotype/phenotype
(if HIV-1 RNA ≥400copies/mL)
c,d
If no resistance to study drugs is 
detected, continue on study 
drugs at the investigator’s 
discretion
f
If resistance to study drugs is 
detected, drugs may be 
discontinued at the 
investigator’s discretion
e
Confirmed virologic nonresponse
b
Blood drawn for repeat 
of HIV-1 RNA testing
and potential 
genotype/phenotype
Unconfirmed virologic 
nonresponse: 
remain on current study drugs
a
Baseline 
(Day 1)
Week 8
Scheduled or unscheduled visit 
within 2 to 4 weeks after Week 8 HIV-1 RNA result 
HIV-RNA 1 log10
reduction from baseline 
and 
50 copies/mL
Genotype/phenotype results 
available
Contact the subject as soon as results 
are known, assess potential causes and 
provide adherence counsellation as 
appropriate or take any other action as 
deemed appropriate.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
75
Approved, Date: 18 April 2017
study drugs may be discontinued at the investigator’s discretion and the subject will be withdrawn from the 
study.
e
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.
f
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
76
Approved, Date: 18 April 2017
Figure 3:
Virologic Rebound Schema
a
If virologic rebound is not confirmed, the subject will remain on its current regimen and the subject’s viral load 
will be further monitored.
b
Upon confirmation of virologic rebound potential causes should be documented. Assessment should include 
lack of adherence, concomitant medication, and comorbidities (eg, active substance abuse, depression, or other 
intercurrent illnesses).
c
If virologic rebound is confirmed, the HIV-1 genotype/phenotype (RT and PR) will be analyzed if HIV-1 RNA 
≥400 copies/mL
d
If HIV-1 RNA <400 copies/mL, the subject’s viral load will be further monitored. In this case of HIV-1 RNA 
<400 copies/mL at the confirmed virologic failure point, resistance testing may then be done at a later time 
point if HIV-1 RNA ≥400 copies/mL or at the unconfirmed virologic failure point if HIV-1 RNA 
≥400 copies/mL. In case of persistent low level viremia between 50 and 400 HIV-1 RNA copies/mL, study 
drugs may be discontinued at the investigator’s discretion and the subject will be withdrawn from the study.
e
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.
f
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.
Screening
Treatment Period 
ESTD
HIV-1 genotype/phenotype
(if HIV-1 RNA ≥400copies/mL)
c,d
If no resistance to study drugs is 
detected, continue on study 
drugs at the investigator’s 
discretion
f
If resistance to study drugs is 
detected, drugs may be 
discontinued at the 
investigator’s discretion
e
Confirmed virologic rebound
b
Within 2 to 4 weeks of HIV-1 RNA result, 
return for scheduled/unscheduled visit 
to repeat
HIV-1 RNA testing and sampling for a 
potential genotype/phenotype
At any visit, after achieving confirmed HIV-1 
RNA <50 copies/mL, a rebound in HIV-1 
RNA to ≥50 copies/mL OR
>1 log10 increase in HIV-1 RNA from the 
nadir 
Unconfirmed virologic rebound: 
remain on current study drugs
a
Baseline (Day 1)
Contact the subject as soon as 
results are known, assess 
potential causes and provide 
adherence counsellation as 
appropriate or take any other 
action as deemed appropriate. 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
77
Approved, Date: 18 April 2017
9.3.
Pharmacokinetics Evaluations 
9.3.1.
Evaluations 
Pharmacokinetic assessments (sparse sampling) will be performed for all subjects at the time 
points specified in the Time and Event Schedule.
In order to distinguish samples from subjects randomized to the D/C/F/TAF treatment arm from 
those of subjects in the control group, the bioanalytical lab will be unblinded to the treatment 
groups. However, the sponsor will remain blinded from the origin of the samples that have been 
analyzed, as well as from the outcome of the analyses, until locking of the database has been 
performed for the primary analysis.
Single sparse blood samples will be collected at least 30 minutes to maximum 4 hours post-dose
on the Weeks 2 through 48 visits, and the ESTD visit (if applicable). At the Weeks 8 and 36 
only, 2 blood samples will be collected at 2 time points at least 2.5 hours apart. The first 
pharmacokinetic sample for the Week 8 and 36 visits should be taken between 1 and 4 hours 
post-dose (dosing may occur prior to the study site 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 ARVs may also be evaluated using stored plasma samples (see 
Section 9.1.1), if deemed necessary and upon request of the study pharmacologist.
9.3.2.
Analytical Procedures
Plasma concentrations of DRV, COBI and TAF of samples from subjects in the D/C/F/TAF 
treatment arm will be analyzed under the responsibility of the sponsor, using validated high-
performance liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methods.
Plasma concentrations of FTC and/or TFV of samples from subjects in the D/C/F/TAF treatment 
arm and plasma concentrations of the ARVs in the control arm may be determined, using 
validated methods, at the sponsor’s discretion.
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.
9.3.3.
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
78
Approved, Date: 18 April 2017

Trough plasma concentration (C0h) and AUCtau for DRV and COBI;

Plasma concentrations x hours after dosing (Cxh) and AUCtau for TAF;

C0h and AUCtau for FTC, TVF and their metabolites, or other ARVs in the control arm, if 
deemed necessary, upon request of the study pharmacologist.
9.4.
Safety Evaluations
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Event 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 
procedures are described in Sections 9.4.1 through 9.4.6. 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 1).
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 be 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.
Details regarding the Independent Data Monitoring Committee are provided in Section 11.8.
9.4.1.
Adverse 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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
79
Approved, Date: 18 April 2017
will be recorded if these events are AIDS-defining illnesses (see World Health Organization 
[WHO] Clinical Staging of HIV/AIDS, Attachment 2). 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 Event 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 
record any clinically relevant changes occurring during the study in the adverse event section of 
the eCRF. 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 1) 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 3.
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
80
Approved, Date: 18 April 2017
If dipstick result is abnormal, urine flow cytometry will be used to analyze 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: 
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, and amylase (reflex lipase testing is performed in 
subjects with total amylase >1.5 x ULN), and AAG.
At baseline, Weeks 24, 48, every 12 weeks following Week 48 until and including the 
unblinding visit, and Week 96, analyses of glucose will be done as part of the fasting 
metabolic assessments and not as part of the chemistry profile.
For the calculation of eGFRcreatinine according to the Cockcroft-Gault and CKD-EPI 
formulas, and eGFRcystatin 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 locally 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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
81
Approved, Date: 18 April 2017

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 and PTH and 25-hydroxy vitamin D (collected 
fasted) (only for subjects participating in the bone investigation 
substudy). Biomarkers PTH and 25-hydroxy vitamin D should 
be assessed at Day 1, Weeks 24, 48 and 96 only.

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
An 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, 
television, 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. If blood sampling or 
vital sign measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECG(s), vital signs, blood draw.
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.3,13
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 Event 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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
82
Approved, Date: 18 April 2017
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 Event 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 at least 170 subjects (85 in each treatment 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 Event 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.
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 9.4.6.
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 Event Schedule. 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
83
Approved, Date: 18 April 2017
9.5.
Toxicity Management
The toxicity management guidelines in this section are applicable throughout the entire study, 
starting from baseline through the 96-week treatment period and the extension phase.
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. 

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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
84
Approved, Date: 18 April 2017

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.
A schematic overview of these guidelines is provided in Attachment 3 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.
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 with vesicles or limited number of bullae or superficial ulceration of mucous 
membrane limited to 1 site.
For the purpose of this study, the sponsor considers qualifying as a grade 3 rash:

Cutaneous reaction/rash with at least 1 of the following:

elevations of ALT/AST >2 x baseline but ≥5 x ULN;
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
85
Approved, Date: 18 April 2017

fever 38°C or 100°F;

serum sickness-like reaction;

eosinophil count >1,000/mm³.

The syndromes of DRESS and 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 
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
86
Approved, Date: 18 April 2017
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 with vesicles or limited 
number of bullae
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 >1,000/mm³
DRESS and 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. 
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
87
Approved, Date: 18 April 2017
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
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
88
Approved, Date: 18 April 2017
9.5.4.
Potential Renal Toxicity
Estimated glomerular filtration rate for creatinine clearance (eGFRcreatinine calculated according to 
the Cockcroft-Gault formula and the CKD-EPI formula), and eGFR for cystatin C clearance 
(eGFRcystatin C calculated according to the CKD-EPI formula) will be followed post-baseline 
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, eGFRcreatinine according to the Cockcroft-Gault formula 
for creatinine clearance will be monitored. All subjects with eGFRcreatinine <50 mL/min must have 
serum creatinine re-measured preferably within 3 calendar days of receipt of results. At the time 
of this repeat serum creatinine assessment, cystatin C will also be measured and the eGFRcystatin
will be calculated and compared with the baseline measurement.
-
eGFRcreatinine according to the Cockcroft-Gault formula:9
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)
-
eGFRcreatinine and eGFRcystatin according to the CKD-EPI formula:19
eGFRcreatinine
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
eGFRcystatin
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 eGFRcreatinine (by Cockcroft-Gault) <50 mL/min, and who also 
experience >20% reduction in eGFRcystatin (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 
eGFRcreatinine <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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
89
Approved, Date: 18 April 2017
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 contacts 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.
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 to 18mg/kg) had minimal mononuclear cell infiltration in the posterior uvea, considered 
secondary to general debilitation; this finding did not occur in animals given lower doses and it 
has not occurred in other animal studies. This preclinical finding has also not been observed in 
humans where the dose is much lower, nor have there been reports of posterior uveitis in human 
clinical studies. Nonetheless, if 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 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. 
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
90
Approved, Date: 18 April 2017
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 4). 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 1) 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.
9.6.
Sample Collection and Handling
Refer to the Time and Event Schedule for the timing and frequency of all sample collections.
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
91
Approved, Date: 18 April 2017
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual. 
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
In the period up to Week 96, a subject will be considered to have completed the 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, that for safety or tolerability reasons such as an 
AE) 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:
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
92
Approved, Date: 18 April 2017

An SAE occurs.

The subject fails to comply with the protocol or study staff requirements.

The subject starts disallowed treatment.

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree.

The subject requires new onset treatment with one of the medications reported on the list of 
disallowed medications (see Section 8.1).

The subject demonstrates VF/viral resistance to any of the ARVs in the HAART regimen; 
see also Section 9.2.2.1.
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 wait contact with the sponsor.
Subjects who prematurely discontinue, either during the double-blind active-controlled treatment 
phase (from Day 1 to Week 48) or during the open-label single-arm D/C/F/TAF treatment phase 
(from Week 48 up to Week 96), will be required to return to the clinic within 72 hours of 
stopping study treatment for the ESTD visit.
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).
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
93
Approved, Date: 18 April 2017
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: 

Formal independent DMC analyses for monitoring purposes, including a futility analysis for 
the lack of (non-inferior) efficacy and a blinded sample size re-estimation (see also Section 
11.8).

The primary analysis: once all subjects have completed the Week 48 assessments 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 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 study is provided in Section 2. The 
analysis endpoints are listed below. 
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects who have HIV-1 RNA<50 copies/mL 
at Week 48 as defined by the FDA snapshot analysis.
Secondary Endpoints
The secondary endpoints of this study are:

The proportion of subjects with HIV-1 RNA <50 copies/mL at Week 96 as defined by the 
FDA snapshot analysis;

The proportion of subjects with HIV-1 RNA <20 and <200 copies/mL at Weeks 48 and 96 
as defined by the FDA snapshot analysis;

The proportion of subjects with HIV-1 RNA <20, <50, and <200 copies/mL at Weeks 48 
and 96 as defined by the time to loss of virologic response (TLOVR) algorithm;

The change from baseline in log10 HIV-1 RNA at Weeks 48 and 96;

The change from baseline in CD4+ cell count at Weeks 48 and 96;

The change from baseline in serum creatinine, eGFRcreatinine (by Cockcroft-Gault and by 
CKD-EPI) and eGFRcystatin C (by CKPD-EPI) at Weeks 48 and 96;
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
94
Approved, Date: 18 April 2017

The proportion of subjects experiencing grade 3 and 4 AEs, SAEs, and premature 
discontinuations due to AEs through Weeks 48 and 96.

The change from baseline in renal biomarkers at Weeks 48 and 96;

The development of viral resistance through Week 48 and 96;

Pharmacokinetic parameters (by population pharmacokinetic analysis) for DRV and TAF.  
The endpoints of the bone investigation substudy are:

The percentage change from baseline in hip and spine BMD and change from baseline 
T-score in hip and spine, at Weeks 24, 48, and 96;

The change from baseline in bone biomarkers at Weeks 24, 48, and 96.
11.2.
Subject Information
For all subjects who are randomly assigned to study drug 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.
An intent-to-treat (ITT), per protocol (PP) and pharmacokinetic analysis population, will be 
defined:

The ITT population will include all the subjects who were randomized and received ≥1 dose 
treatment 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.

Since an analysis on the ITT population may not be conservative in a noninferiority setting, 
an analysis based on the 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, and (3) without any 
major protocol deviation that is considered to potentially affect efficacy outcomes (eg, 
inadequate baseline resistance profile, use of concomitant medication interfering with 
antiviral efficacy, inadequate adherence to drug intake). 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 ≥1 dose of 
investigational treatment in the study, and for whom plasma concentration data of any 
analytes of interest are available.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
95
Approved, Date: 18 April 2017
11.3.
Sample Size Determination
A sample size of 670 (335 subjects in D/C/F/TAF arm and 335 subjects in the control arm) will 
yield 90% power. It is assumed that both treatment arms have a response rate of 80% (HIV-1 
RNA <50 copies/mL at Week 48 as defined by the FDA snapshot analysis), that the 
noninferiority margin is 10%, and that the significance level of the test is at a 1-sided, 
0.025 level.
A minimum of 170 subjects (85 per treatment arm) is targeted to be included in the bone 
investigation substudy. Assuming a 4% inter-subject variability in BMD and a 1-sided alpha 
level of 2.5%, 85 subjects per treatment arm is sufficient to detect at least an absolute difference 
of 2% between the treatment arms with 90% power. Power calculations are presented in Table 5.
Table 5:
BMD at the Lumbar Spine, Power Calculations 
Mean % Change from 
Baseline
Common Standard 
Deviation (%)
Power
N=170
2
3.5
96%
4
90%
3
3.5
>99%
4
>99%
11.4.
Efficacy Analyses
11.4.1.
Primary Analysis 
The primary analysis will consist of a noninferiority evaluation of the D/C/F/TAF FDC tablet 
(investigational treatment arm) versus DRV/COBI FDC coadministered with FTC/TDF FDC 
(control arm), with respect to the proportion of subjects with HIV-1 RNA <50 copies/mL at 
Week 48 after the start of treatment in this study (as defined by the FDA snapshot analysis). It 
will be concluded that the D/C/F/TAF FDC tablet is not inferior to the control regimen if the 
lower bound of the 2-sided 95% confidence interval (CI) of the difference between treatment 
arms (D/C/F/TAF arm - control arm) in the response rate is greater than -10% (ie, a margin of 
10% is applied to noninferiority assessment). The difference (with associated 95% confidence 
interval) will be constructed using the stratum-adjusted Mantel-Haenszel difference in 
proportions, where the stratification factors (HIV-1 RNA level [≤100,000 copies/mL or 
>100,000 copies/mL] and CD4+ cell count [<200 cells/µL or ≥200 cells/µL] at screening) 
determine the strata. 
If noninferiority of the D/C/F/TAF arm to control arm is established, the lower bound of the 95% 
CI will be compared to 0; if the lower bound of the 95% CI is greater than 0, then superiority of 
D/C/F/TAF over the control arm will be established. 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
96
Approved, Date: 18 April 2017
11.4.2.
Secondary Analyses 
Antiviral Efficacy 
As secondary analyses, the proportion of subjects with HIV-1 RNA <20 and <200 copies/mL at 
Week 48 as defined by the FDA snapshot analysis will be analyzed using the same method as for 
the primary efficacy endpoint to compare treatment arms. 
In addition, confirmed virologic response defined as HIV-1 RNA <20, <50, and <200 copies/mL 
at Week48 determined by the TLOVR algorithm will be analyzed using the same method as for 
the primary efficacy endpoint to compare treatment arms.
Immunologic Change
The changes from baseline in CD4+ cell count at Week 48, and 96 will be summarized using 
descriptive statistics. The differences in changes from baseline in CD4+ cell count at Week 48 
between the 2 treatment arms and the associated 95% confidence intervals will be constructed 
using analysis of covariance (ANCOVA), including CD4+ cell count at baseline as continuous 
covariate in the model.
Resistance 
Screening HIV-1 PR/RT genotype analysis will be performed for all subjects. Post-screening
HIV-1 PR/RT genotype/phenotype testing will be available from subjects who are eligible for 
resistance testing (subjects with virologic rebound, virologic nonresponse, and discontinuations 
with last available viral load measurement ≥400 copies/mL). The number and type of amino acid 
changes, of HIV-1 PR (including IAS-USA PI RAMs and IAS-USA primary PI mutations), and 
RT (including IAS-USA NRTI RAMs and IAS-USA NNRTI RAMs), as well as specific, but not 
limited to, IAS-USA41 mutations associated with resistance to DRV, FTC, and TDF will be 
tabulated. Available fold change (FC) in 50% effective concentration (EC50) of ARVs will be 
tabulated. In subjects with paired screening or baseline and post-baseline genotypes/phenotypes, 
development of resistance will be analyzed. 
11.5.
Pharmacokinetic Analyses 
The plasma concentration data of DRV, TAF, and COBI of subjects randomized to the 
D/C/F/TAF treatment arm will be evaluated. Plasma concentration data for each analyte may be 
subjected to population pharmacokinetic modeling, if appropriate population pharmacokinetic 
models are available. Model specifications will be described in separate report(s), as applicable.
The pharmacokinetics of other ARVs in the study (eg, FTC, TFV) and their metabolites, as well 
as the ARVs in samples from subjects in the control arm, may be analyzed, if deemed necessary, 
upon request of the protocol pharmacologist.
Descriptive statistics will be calculated for the plasma concentrations of DRV, COBI, and TAF 
by visit and for the derived pharmacokinetic parameters as available, and also for any of the 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
97
Approved, Date: 18 April 2017
other ARVs in the study analyzed upon sponsor’s request, if applicable. Summary statistics 
include n, mean, SD, coefficient of variation (CV), geometric mean, median, minimum and 
maximum.
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 SOC and PT) 
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 1) 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, eGFRcreatinine (by Cockcroft-Gault and by CKD-
EPI) and eGFRcystatin (by CKPD-EPI) at Weeks 48 and 96 will be summarized by treatment arm
and using descriptive statistics. The difference in changes from baseline at Week 48 in serum 
creatinine between the 2 treatment arms will be tested using ANCOVA, including baseline serum 
creatinine in the model. 
Renal Biomarkers
Selected renal biomarkers, including retinol binding protein and beta-2-microglobulin, will be 
summarized by treatment arm and visit using descriptive statistics. The difference in change 
from baseline in these biomarkers at Week 48 between 2 treatment arms will be tested using the 
Wilcoxon rank-sum test.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
98
Approved, Date: 18 April 2017
ECG
ECG assessments were done locally, only at screening and thus not suitable to be analyzed. For 
definitions of abnormalities of ECG, refer to Attachment 5.
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 summarized. For definitions of 
abnormalities of vital signs, refer to Attachment 5.
Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
DXA Substudy – 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 the Wilcoxon signed-rank test. The comparison between the 
2 treatment arms at Weeks 24 and 48 will be performed using the Wilcoxon rank-sum test.
Percent change from baseline in spine and hip BMD at Weeks 24, 48, and 96, 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 a 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 Week 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.
Treatment Adherence
Treatment adherence based on pill count will be summarized by means of descriptive statistics 
and frequency tabulations.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
99
Approved, Date: 18 April 2017
11.8.
Data Monitoring Committee
An independent 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, the available Week 24 
data (used as predictor for the primary endpoint), and the Week 48 primary endpoint data (if any) 
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 
superiority or noninferiority 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 response rate is 
anticipated to be different than assumed, eg, due to a higher drop-out rate. 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.
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 non-investigational) 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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
100
Approved, Date: 18 April 2017
medicinal (investigational or non-investigational) product, whether or not related to that
medicinal (investigational or non-investigational) product. (Definition per ICH).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.4.1, All 
Adverse Events, 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. 
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 was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity.

Is a congenital anomaly/birth defect.

Is a suspected transmission of any infectious agent via a medicinal product.

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
101
Approved, Date: 18 April 2017
definition above. These should usually be considered serious. 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 1 (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 at the time the AE is reported.
For D/C/F/TAF FDC tablet, the expectedness of an AE will be determined by whether or not it is 
listed in the adverse reaction table provided in the IB or its relevant IB addendum.16,17 For
DRV/COBI FDC and FTC/TDF FDC 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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
102
Approved, Date: 18 April 2017
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 following general categorical descriptors
outlined in the DAIDS toxicity grading table in Attachment 1. 
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. 
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
103
Approved, Date: 18 April 2017
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 CRF. Any special reporting situation that 
meets the criteria of a 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 
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 a SAE will be reported as SAEs, regardless of whether they 
are protocol-specific assessments. Anticipated events will be recorded and reported as described 
in Attachment 6.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
104
Approved, Date: 18 April 2017
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 suspected unexpected serious adverse reactions (SUSARs). The investigator 
(or sponsor where required) must report SUSARs to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities 
unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR summary, 
unless otherwise specified.
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.

Any other information that is required to do an emergency breaking of the blind.
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 a SAE should be made by 
facsimile (fax).
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:
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
105
Approved, Date: 18 April 2017

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 (refer to Section 12.1.1).
12.4.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs
and must be reported using the Serious Adverse Event Form. Any subject who becomes pregnant 
during the study must be promptly withdrawn from the study. 
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 the pregnancy and any postnatal sequelae in the 
infant will be required, also if the outcome is post-study.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
106
Approved, Date: 18 April 2017
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 on 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 (refer to 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 on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
D/C/F/TAF FDC, DRV/COBI FDC, and the matching placebo tablets will be manufactured and 
provided under the responsibility of the sponsor. 

The D/C/F/TAF FDC tablets supplied for this study are yellow capsule-shaped, plain-faced
(double-blind treatment phase) or debossed (open-label treatment phase), film-coated tablets 
containing 800 mg of DRV (as 867 mg of darunavir ethanolate), 150 mg of COBI (288.5 mg 
total weight of COBI on silicon dioxide carrier), 200 mg of FTC, and 10 mg of TAF (as 11.2 
mg TAF fumarate). Each D/C/F/TAF FDC tablet in the open-label treatment phase is 
debossed with “8121” on one side and “JG” on the other side. The D/C/F/TAF FDC tablet 
cores contain silicon dioxide, croscarmellose sodium, microcrystalline cellulose, magnesium 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
107
Approved, Date: 18 April 2017
stearate, polyvinyl alcohol, iron oxide yellow, polyethylene glycol, talc, and titanium 
dioxide.

The D/C/F/TAF FDC-matching placebo tablets supplied for this study are identical in 
physical 
appearance 
and 
contain 
lactose
monohydrate, 
croscarmellose 
sodium, 
microcrystalline cellulose, magnesium stearate, polyvinyl alcohol, iron oxide yellow, 
polyethylene glycol, talc, and titanium dioxide.

The DRV/COBI FDC tablets supplied for this study are pink oval shaped, plain-faced, 
containing, plain faced, film coated tablets containing 800 mg of DRV (as 867 mg of 
darunavir ethanolate) and 150 mg of COBI (288.5 mg total weight of COBI on silicon 
dioxide carrier). The DRV/COBI cores contain hypromellose, silicon dioxide, silicified 
microcrystalline cellulose, crospovidone,
magnesium stearate,
polyethylene glycol, 
polyvinyl alcohol, talc, titanium dioxide, iron oxide red and iron oxide black.

The DRV/COBI FDC-matching placebo tablets supplied for this study are identical in 
physical appearance and contain silicified microcrystalline cellulose, colloidal anhydrous 
silica, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, 
iron oxide red and iron oxide black.
The control FTC/TDF FDC tablets and matching placebo tablets will be manufactured, packaged 
and provided by GSI.

FTC/TDF FDC tablets are capsule-shaped, film-coated blue tablets that are debossed with 
“GILEAD” on one side and plain-faced on the other side. The FDC/TDF FDC tablets 
contain 200 mg of emtricitabine and 300 mg of tenofovir DF. In addition to the active 
ingredients, the tablets contain microcrystalline cellulose, pregelatinized starch, 
croscarmellose sodium, lactose monohydrate, magnesium stearate, hypromellose, titanium 
dioxide, triacetin, and FD&C blue #2/indigo carmine aluminum lake. 

FTC/TDF FDC-matching placebo tablets are identical in physical appearance and contain 
denatonium benzoate, lactose monohydrate, pregelatinized starch, croscarmellose sodium, 
magnesium stearate, hypromellose, titanium dioxide, triacetin, and FD&C blue #2/Indigo 
carmine aluminum lake.
14.2.
Packaging
D/C/F/TAF FDC, DRV/COBI FDC, TDF/FTC FDC and the matching placebo tablets will be 
packaged under responsibility of the sponsor and will allow for blinded administration.
The D/C/F/TAF FDC and –matching placebo tablets are packaged in white, high-density 
polyethylene (HDPE) 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.
The DRV/COBI FDC and –matching placebo tablets are packaged in HDPE bottles with a child-
resistant closure and induction foil seal. 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
108
Approved, Date: 18 April 2017
The FTC/TDF FDC and –matching placebo tablets are packaged in white, HDPE bottles with a 
silica gel desiccant canister or sachet. Each bottle is enclosed with a white, continuous thread, 
child-resistant screw cap fitted with an induction-sealed, aluminum-faced liner.
No study medication can be repacked without prior approval from the sponsor.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
No study medication can be relabeled without prior approval from the sponsor.
14.4.
Preparation, Handling, and Storage
All study drugs must be stored according to the storage conditions printed on the label.
To ensure the stability of D/C/F/TAF FDC tablets, DRV/COBI FDC and FTC/TDF FDC tablets 
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 on 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.
Study 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 study drug, and study 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 study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
109
Approved, Date: 18 April 2017
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 and IB addendum of D/C/F/TAF;

IWRS manual;

Sample ICF;

eCRF completion guidelines;

Pharmacy manual/study site investigational product manual;

Laboratory manual;

DXA manual (if applicable);

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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
110
Approved, Date: 18 April 2017
Good Clinical Practice 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.

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
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
111
Approved, Date: 18 April 2017

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 
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
112
Approved, Date: 18 April 2017
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(s) 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(s) 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.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained.
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
113
Approved, Date: 18 April 2017
16.2.5.
Long-term Retention of Samples for Additional Future 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand D/C/F/TAF FDC, 
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.
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 (refer to Section 10.2 Withdrawal From the Use of Samples in Future 
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, Study-Specific Design Considerations.
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 
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 CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
114
Approved, Date: 18 April 2017
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.

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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
115
Approved, Date: 18 April 2017
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 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 CRF: 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. 
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.
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
116
Approved, Date: 18 April 2017
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 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 eCRF.
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 eCRF, 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.
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 CRFs 
and all source documents that support the data collected from each subject, as well as all study 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
117
Approved, Date: 18 April 2017
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 
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
118
Approved, Date: 18 April 2017
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 health 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 CRFs. 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.
17.11. Use of Information and Publication
All information, including but not limited to information regarding the D/C/F/TAF FDC tablet or 
the sponsor's operations (eg, patent application, formulas, manufacturing processes, basic 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
119
Approved, Date: 18 April 2017
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 FDC tablet, and thus 
may be disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain 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. Results of analyses performed after 
the Clinical Study Report has been issued will be reported in a separate report and will not 
require a revision of the Clinical Study Report. Study 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 GCP 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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
120
Approved, Date: 18 April 2017
Biomedical Journals, which state that the named authors must have made a significant 
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
121
Approved, Date: 18 April 2017
REFERENCES
1.
Abdallah H, Jerling M. Effect of hepatic impairment on the multiple-dose pharmacokinetics of ranolazine 
sustained-release tablets. J Clin Pharmacol. 2005;45(7):802-809.
2.
ACTG Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus 
(HIV)-Infected adults receiving antiretroviral therapy: Recommendations of the HIV Medicine Association of 
the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003;37 
(5):613-627
3.
Bazett HC. An analysis of the time-relations of electrocardiograms. Heart. 1920;7:353-370.
4.
Birkus G, Kutty N, He GX, Mulato A, Lee W, McDermott M, et al. Activation of 9-[(R)-2-[[(S)-[[(S)-1-
(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-methoxy]propyl]adenine (GS-7340) and other 
tenofovir phosphonoamidate prodrugs by human proteases. Mol Pharmacol. 2008;74(1):92-100.
5.
Capeau J. Premature Aging and Premature Age-Related Comorbidities in HIV Infected Patients: Facts and 
Hypotheses. Clin Infect Dis. 2011;53(11):1127-1129.
6.
Centers for Disease Control and Prevention (CDC). HIV/AIDS among Persons Aged 50 and Older. October 
2008. Available at: http://www.cdc.gov/hiv/pdf/library_factsheet_HIV_among_PersonsAged50andOlder.pdf .
7.
CHMP. CHMP/ICH/2/04. ICH Topic 14. The clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs. November 2005. Available at: http://www. ema.europa. 
eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002879.pdf.
8.
Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis. 2000;30(Suppl 2):S171-S6.
9.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.
10.
Dejesus E, Young B, Morales-Ramirez JO, Sloan L, Ward DJ, Flaherty JF, et al. Simplification of 
antiretroviral therapy to a single-tablet regimen consisting of efavirenz, emtricitabine, and tenofovir disoproxil 
fumarate versus unmodified antiretroviral therapy in virologically suppressed HIV-1-infected patients. J 
Acquir Immune Defic Syndr. 2009;51(2):163-174
11.
Egger M et al. ART Cohort Collaboration, Prognosis of HIV-1-infected patients starting highly active 
antiretroviral therapy: a collaborative analysis of prospective studies. Lancet, 2002 Jul 13; 360(9327): 119-29.
12.
Jayaweera D, Dejesus E, Nguyen KL, et al. Virologic suppression, treatment adherence, and improved quality 
of life on a once-daily efavirenz-based regimen in treatment naïve HIV-1 infected patients over 96 weeks. HIV 
Clin. Trials 2009;10(6):375-384.
13.
Fridericia LS. Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken. Acta 
Med Scand. 1920;53:469-486.
14.
Hodder SL, Mounzer K, Dejesus E, Ebrahimi R, Grimm K, Esker S, et al. Patient-reported outcomes in 
virologically suppressed, HIV-1-infected subjects after switching to a simplified, single-tablet regimen of 
efavirenz, emtricitabine, and tenofovir DF. AIDS Patient Care STDS. 2010;24(2):87-96.
15.
Hoetelmans R et al. The pharmacokinetic interaction between TMC114 boosted with a low dose of ritonovir 
and tenofovir in healthy volunteers. Tibotec NV, Clinical Research Report TMC114-C124, 27 June 2003.
16.
Investigator’s Brochure: Darunavir/cobicistat/emtricitabine/tenofovir alfenamide, Edition 3, 17 September 
2014.
17.
Investigator’s Brochure Addendum: Darunavir/cobicistat/emtricitabine/tenofovir alfenamide, Edition 3 
Addendum 1, 6 March 2015.
18.
Lee WA, He G-X, Eisenberg E, Cihlar T, Swaminathan S, Mulato A, et al. Selective intracellular activation of 
a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to 
preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother. 2005;49(5):
1898-1906.
19.
Levey AS, Stevens LA, et al. A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med. 
2009;150:604-612.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
122
Approved, Date: 18 April 2017
20.
Maggiolo F, Migliorino M, Maserati R, Rizzi L, Pan A, Rizzi A, et al. Once-a-day treatment for HIV infection: 
Final 48-week results. 8th Conference on Retroviruses and Opportunistic Infections; 2001 February 4-8; 
Chicago, IL. Abstract 320.
21.
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of mortality 
across Europe in patients infected with HIV-1. Lancet. 1998;352(9142):1725-1730.
22.
Palella FJ, Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and 
mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998;338 
(13):853-860.
23.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents 
in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: 
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
24.
Prejean J, Song R, Hernandez A, Ziebell R, Green T, Walker F, et al. Estimated HIV incidence in the United 
States, 2006-2009. PLoS ONE. 2011;6(8):e17502.
25.
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.
26.
1994 Revised classification system HIV infection in children less than 13 years of age. MMWR 1994;43 [RR-
12].
27.
Sax PE, Meyers J, Mugavero M, Davis KL. Adherence to Antiretroviral Treatment Regimens and Correlation 
with Risk of Hospitalization Among Commercially Insured HIV Patients in the United States [Poster O113]. 
10th International Congress on Drug Therapy in HIV Infection; 2010 November 7-11; Glasgow, UK.
28.
Sterne J, Hernán M, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-term effectiveness of potent 
antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet. 2005;366(9483):378-
384.
29.
Stone VE, Jordan J, Tolson J, Pilon T. Potential impact of once daily regimens on adherence to HAART 
[abstract]. 40th Annual Meeting of the Infectious Disease Society of America; 2002 Oct 24-27; Chicago, Ill. p. 
129. Abstract 486.
30.
Stone VE, Jordan J, Tolson J, Miller R, Pilon T. Perspectives on adherence and simplicity for HIV-infected 
patients on antiretroviral therapy: Self-report of the relative importance of multiple attributes of highly active 
antiretroviral therapy (HAART) regimens in predicting adherence. J Acquir Immune Defic Syndr Hum 
Retrovirol. 2004;36(3):808-816.
31.
Summary of Product Characteristics for Emtriva® (emtricitabine). Gilead Sciences Inc; December 2012.
32.
Summary of Product Characteristics for Truvada® (emtricitabine/tenofovir disoproxil fumarate). Gilead 
Sciences Inc; December 2010.
33.
Summary of Product Characteristics for Viread® (tenofovir disoproxil fumarate). Gilead Sciences Inc; May 
2013.
34.
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.
35.
US Prescribing Information for Emtriva® (emtricitabine). Gilead Sciences Inc; April 2013.
36.
US Prescribing Information for Truvada® (emtricitabine/tenofovir disoproxil fumarate). Gilead Sciences Inc; 
April 2013.
37.
US Prescribing Information for Viread® (tenofovir disoproxil fumarate). Gilead Sciences Inc; November 2012.
38.
Viciana P, Rubio R, Ribera E, Knobel H, Iribarren JA, Arribas JR, Pérez-Molina JA; Investigadores del 
Estudio CUVA. Longitudinal study on adherence, treatment satisfaction, and effectiveness of once-daily versus 
twice-daily antiretroviral therapy in a Spanish cohort of HIV-infected patients (CUVA study). Enferm Infecc 
Microbiol Clin 2008;26(3):127-34
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
123
Approved, Date: 18 April 2017
39.
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. 
40.
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.
41.
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.
42.
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
124
Approved, Date: 18 April 2017
ATTACHMENTS
Attachment 1: 
Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events ........................................................................................................... 125
Attachment 2: 
WHO Clinical Staging of HIV/AIDS ............................................................................. 147
Attachment 3: 
Management of Clinically Significant Laboratory Toxicities ........................................ 149
Attachment 4:
Management of Dyslipidemia...................................................................................... 150
Attachment 5:
Cardiovascular Safety: Definitions of Abnormalities ................................................... 154
Attachment 6:
Anticipated Events....................................................................................................... 155
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
125
Approved, Date: 18 April 2017
Attachment 1: 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 for Parameters Not Identified in the Grading Table 
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
Adult Activities such as bathing, dressing, toileting, transfer or 
movement, continence, and feeding.
Young Children Activities that are age and culturally appropriate, 
such as feeding one’s 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, 
such as social interactions, play activities, or learning tasks.
Intervention
Medical, surgical, or other procedures recommended or provided 
by a healthcare professional for the treatment of an adverse event.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
126
Approved, Date: 18 April 2017
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
127
Approved, Date: 18 April 2017
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.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
128
Approved, Date: 18 April 2017
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.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
129
Approved, Date: 18 April 2017
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
130
Approved, Date: 18 April 2017
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.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
131
Approved, Date: 18 April 2017
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) 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
132
Approved, Date: 18 April 2017
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) 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
133
Approved, Date: 18 April 2017
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.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
134
Approved, Date: 18 April 2017
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
135
Approved, Date: 18 April 2017
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.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
136
Approved, Date: 18 April 2017
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) 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
137
Approved, Date: 18 April 2017
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) 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
138
Approved, Date: 18 April 2017
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 accessed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants >5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤5 years of age.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
139
Approved, Date: 18 April 2017
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
140
Approved, Date: 18 April 2017
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.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
141
Approved, Date: 18 April 2017
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.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
142
Approved, Date: 18 April 2017
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 (ie, 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.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
143
Approved, Date: 18 April 2017
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
144
Approved, Date: 18 April 2017
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.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
145
Approved, Date: 18 April 2017
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
146
Approved, Date: 18 April 2017
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 Neonate21
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.  
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
147
Approved, Date: 18 April 2017
Attachment 2: 
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]). 25,39
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
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
148
Approved, Date: 18 April 2017
-
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
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
149
Approved, Date: 18 April 2017
Attachment 3: 
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
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
150
Approved, Date: 18 April 2017
Attachment 4:
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
151
Approved, Date: 18 April 2017
unclear. Hypertriglyceridemia seems to be most significant in patients with regimens that include 
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 6 and Table 7). 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 AIDS Clinical Trial Group (ACTG) Cardiovascular Disease Focus 
Group (see Table 6 and Table 7). 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 g/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 7). 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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
152
Approved, Date: 18 April 2017
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 (>1,000 mg/dL) may benefit from a 
very low-fat diet, even if they are not overweight.
Table 6:
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 
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
153
Approved, Date: 18 April 2017
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 7:
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.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
154
Approved, Date: 18 April 2017
Attachment 5:
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 1).
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.7
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
155
Approved, Date: 18 April 2017
Attachment 6:
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§

Chronic hepatitis secondary to hepatitis B infection

Chronic hepatitis secondary to hepatitis C infection

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†
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
156
Approved, Date: 18 April 2017

Pneumonia, recurrent†§

Progressive multifocal leukoencephalopathy 

Salmonella septicemia, recurrent 

Toxoplasmosis of brain, onset at age >1 month†

Tuberculosis

Wasting syndrome attributed to HIV
* Only among children aged <13 years26
† 
Condition that might be diagnosed presumptively
§ 
Only among adults and adolescents aged >13 years25
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).
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001 Amendment 2
157
Approved, Date: 18 April 2017
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 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
NCT02431247


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Magda Opsomer
19Apr2017, 14:43:12 PM, UTC
Document Approval
NCT02431247


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, double-blind study to evaluate efficacy and 
safety of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) once daily 
fixed dose combination regimen versus a regimen consisting of darunavir/cobicistat fixed 
dose combination coadministered with emtricitabine/tenofovir disoproxil fumarate fixed 
dose combination in antiretroviral treatment-naïve human immunodeficiency virus type 1 
infected subjects.
Protocol TMC114FD2HTX3001; 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: 2015-000754-38
Status:
Approved  
Date:
14 May 2020
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
EDMS number:
EDMS-RIM-47470, 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.
NCT02431247


COVID-19 Appendix
D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001
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 TMC114FD2HTX3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 14 May 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL
Drug Supply and Drug Return

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 
(±14 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 
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.


COVID-19 Appendix
D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)
Clinical Protocol TMC114FD2HTX3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 14 May 2020
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 TMC114FD2HTX3001
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.


Signature
User
Date
Reason
VAN LANDUYT ERIKA 10013110
15-May-2020
13:53:00
(GMT)
Document Approval

SAP_003.pdf: 
1
Approved, Date: 25 April 2018
Janssen Research & Development *
Statistical Analysis Plan
(Week 96 Analysis)
A Phase 3, randomized, active-controlled, double-blind study to evaluate efficacy and 
safety of darunavir/cobicistat/emtricitabine/tenofovir alafenamide once-daily single-tablet 
regimen versus a regimen consisting of darunavir/cobicistat fixed dose combination 
combined with emtricitabine/tenofovir disoproxil fumarate fixed dose combination in 
antiretroviral treatment-naïve human immunodeficiency virus type 1 infected subjects
Protocol TMC114FD2HTX3001; Phase 3
D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)  
Status:
Approved
Date:
25 April 2018
Prepared by:
Janssen Infectious Diseases - Diagnostics BVBA  
Document No.: EDMS-ERI-155952251
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT02431247


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
2
Approved, Date: 25 April 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.2.
Trial Design ...................................................................................................................................... 5
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 7
1.4.
Sample Size Justification ................................................................................................................. 7
1.5.
Randomization and Blinding ............................................................................................................ 8
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
2.1.
Treatment Arms ............................................................................................................................... 8
2.2.
Visit Windows................................................................................................................................... 8
2.2.1.
Trial Phases............................................................................................................................... 8
2.2.2.
Analysis Time points................................................................................................................ 10
2.3.
Analysis Sets.................................................................................................................................. 10
2.3.1.
Efficacy Analysis Set(s) .............................................................................................................. 10
2.3.1.1.
Intent-to-Treat Analysis Set..................................................................................................... 10
2.3.1.2.
Per Protocol Analysis Set........................................................................................................ 10
2.3.2.
Safety Analysis Set..................................................................................................................... 11
2.3.3.
Bone Investigation Sub-study Analysis Set................................................................................ 11
2.4.
Definition of Subgroups.................................................................................................................. 11
2.4.1.
Subgroups for Efficacy Analyses................................................................................................ 11
2.4.2.
Subgroups for Safety Analyses .................................................................................................. 11
2.5.
Re-classification of Stratification Factors for Purpose of Analysis................................................. 12
2.6.
Reference....................................................................................................................................... 12
3.
SUBJECT INFORMATION................................................................................................................ 12
3.1.
Demographics and Baseline Characteristics ................................................................................. 12
3.2.
Disposition Information................................................................................................................... 13
3.3.
Treatment Adherence .................................................................................................................... 13
3.4.
Extent of Exposure......................................................................................................................... 14
3.5.
Protocol Deviations ........................................................................................................................ 14
3.6.
Concomitant Medications............................................................................................................... 14
4.
EFFICACY ......................................................................................................................................... 14
4.1.
Analysis Specifications................................................................................................................... 14
4.1.1.
Level of Significance................................................................................................................... 14
4.1.2.
Data Handling Rules................................................................................................................... 14
4.1.3.
FDA Snapshot Approach and Time to Loss of Virologic Response Algorithm (TLOVR) ........... 15
4.2.
Primary Efficacy Endpoint(s).......................................................................................................... 16
4.2.1.
Definition..................................................................................................................................... 16
4.2.2.
Analysis Methods........................................................................................................................ 16
4.3.
Major Secondary Efficacy Endpoints ............................................................................................. 16
4.3.1.
Definition..................................................................................................................................... 16
4.3.2.
Analysis Methods........................................................................................................................ 17
4.3.2.1.
Antiviral Efficacy ...................................................................................................................... 17
4.3.2.2.
Immunologic Change............................................................................................................... 17
4.3.2.3.
Resistance Determinations...................................................................................................... 17
4.3.2.3.1.
Genotype.............................................................................................................................. 18
4.3.2.3.2.
Phenotype ............................................................................................................................ 19


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
3
Approved, Date: 25 April 2018
5.
SAFETY............................................................................................................................................. 20
5.1.
Adverse Events .............................................................................................................................. 20
5.1.1.
Definitions................................................................................................................................ 20
5.1.2.
Analysis Methods .................................................................................................................... 21
5.2.
Clinical Laboratory Tests................................................................................................................ 22
5.2.1.
Definitions................................................................................................................................ 22
5.2.2.
Analysis Methods .................................................................................................................... 23
5.2.3.
Creatinine and Glomerular Filtration ....................................................................................... 23
5.2.3.1.
Serum Creatinine and Cystatin C............................................................................................ 23
5.2.3.2.
Proximal Renal Tubular Function ............................................................................................ 24
5.3.
Vital Signs and Physical Examination Findings ............................................................................. 25
5.3.1.
Definitions................................................................................................................................ 25
5.3.2.
Analysis methods .................................................................................................................... 26
5.4.
Bone Investigations........................................................................................................................ 26
5.4.1.
Definitions................................................................................................................................ 26
5.4.2.
Analysis methods .................................................................................................................... 27
REFERENCES............................................................................................................................................ 28
ATTACHMENTS......................................................................................................................................... 29
ATTACHMENT 1 ........................................................................................................................................ 29
ATTACHMENT 2 ........................................................................................................................................ 32
ATTACHMENT 3 ........................................................................................................................................ 45
ATTACHMENT 4 ........................................................................................................................................ 49
ATTACHMENT 5 ........................................................................................................................................ 50


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
4
Approved, Date: 25 April 2018
AMENDMENT HISTORY
Not applicable.
ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ARV
antiretroviral
AST
aspartate aminotransferase
ATC
Anatomic and Therapeutic Class
ATV
atazanavir
AUC24h
area under the plasma concentration-time curve over the 24h dosing interval
BIS
bone investigation substudy
BMD
bone mineral density
BMI
body mass index
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
C0h
Pre-dose (trough) plasma concentration
COBI
cobicistat
DAIDS
Division of AIDS
D/C/F/TAF
darunavir/cobicistat/emtricitabine/tenofovir alafenamide 
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
DRV
darunavir
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
eGFRcr
eGFR for creatinine clearance 
eGFRcyst
eGFR for cystatin C clearance 
ESTD
early study treatment discontinuation
FDA
Food and Drug Administration
FDC
fixed-dose combination
FTC
emtricitabine
GSI
Gilead Sciences, Inc.
HIV-1
human immunodeficiency virus type 1
ITT
Intent-to-Treat
LLOQ
Lower limit of quantification
LPV
lopinavir
MedDRA
Medical Dictionary for Regulatory Activities
NCEP
National cholesterol education program
PK
pharmacokinetic(s)
RAM
resistance-associated mutation
RNA
ribonucleic acid
rtv
ritonavir
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
TAF
tenofovir alafenamide
TDF
tenofovir disoproxil fumarate
TD
target detected
TND
target not detected
WHO
World Health Organization


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
5
Approved, Date: 25 April 2018
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the Week 96 analysis that will be performed after the last 
subject enrolled in the open-label extension phase completes the Week 96 visit, or prematurely 
discontinues from the study. The final analysis will be described in a separate SAP.
1.1.
Trial Objectives
The primary objective of this study was to demonstrate non-inferiority in efficacy of a D/C/F/TAF FDC 
tablet versus DRV/COBI FDC co-administered with FTC/TDF FDC in HIV-1 infected, ARV treatment-
naïve adult subjects, as determined by the proportion of virologic responders defined as having HIV-1 
RNA <50 copies/mL at Week 48 (FDA-defined Snapshot analysis), with a maximum allowable 
difference of 10%.
The secondary objectives of this study were:
-
To evaluate superiority of a D/C/F/TAF FDC tablet versus DRV/COBI FDC co-administered 
with FTC/TDF FDC as determined by the proportion of virologic responders defined as having 
HIV-1 RNA <50 copies/mL at Week 48 (FDA-defined Snapshot analysis), in case non-inferiority
is established;
-
To evaluate the immunologic response (CD4+ cell count) of the 2 treatment arms through Week 
48;
-
To evaluate the incidence of grade 3 and 4 AEs, serious adverse events (SAEs), and premature 
discontinuations due to AEs in the 2 treatment arms through Week 48;
-
To evaluate the change from baseline in serum creatinine, eGFRcreatinine (by Cockcroft-Gault and 
by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formulas) and eGFRcystatin C
(by CKD-EPI) in the 2 treatment arms at Week 48;
-
To evaluate the change from baseline in renal biomarkers at Week 48;
-
To assess the development of viral resistance in the 2 treatment arms through Week 48;
-
To evaluate the steady-state pharmacokinetics of DRV and TAF;
Objectives of a bone investigation sub-study performed at selected study sites:
-
To evaluate the safety in the 2 treatment arms as determined by the percentage change from
baseline in hip and spine BMD and change from baseline in T-score at Week 48;
-
To evaluate the change from baseline in bone biomarker levels at Week 48.
       The secondary objectives to be assessed in the study single arm treatment phase:
-
To evaluate long-term safety, resistance, and efficacy of the D/C/F/TAF regimen (until Week 96 
and beyond);
1.2.
Trial Design
This is a randomized, double-blind active-controlled, multicenter, Phase 3 study to evaluate efficacy and 
safety of D/C/F/TAF once daily fixed dose combination regimen versus a regimen consisting of 
DRV/COBI FDC combined with FTC/TDF FDC in ARV treatment-naïve HIV-1 infected adult subjects. 
The aim of this study was to include 670 subjects that were to be randomly assigned with 335 subjects 
planned per treatment group. Subjects who met all eligibility criteria were randomized in a 1:1 ratio to 1 
of the following 2 treatment arms:


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
6
Approved, Date: 25 April 2018
-
D/C/F/TAF Arm:
Regimen of a single tablet containing DRV 800 mg/ COBI 150 mg/ 
FTC 200 mg/ TAF 10 mg (D/C/F/TAF FDC) once daily, (n=335) 
+ DRV/COBI FDC-matching and FTC/TDF FDC-matching placebo tablets 
once daily;
-
Control Arm: 
Regimen of DRV 800 mg/ COBI 150 mg FDC coadministered with FTC 
200 mg/ TDF 300 mg FDC once daily, (n=335)
+ D/C/F/TAF FDC-matching placebo tablet once daily.
Randomization was stratified by HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL) and by 
CD4+ cell count (<200 cells/µL or ≥200 cells/µL) at screening. 
Subjects will be treated for 96 weeks, and will return for study visits at Weeks 2, 4, 8, 12, 24, 36, 48, 
every 12 weeks thereafter until and including a Week 96 visit.
After Week 48, subjects will continue to take their blinded study drug and attend visits every 12 weeks 
until all subjects have reached Week 48, the database for the primary analysis has been locked, and 
treatment assignments have been unblinded. Provided the results from the primary analysis do not 
preclude (further) exposure of subjects to D/C/F/TAF, all subjects will return for an unblinding visit and 
will receive the D/C/F/TAF FDC tablet treatment during an open-label single-arm treatment phase up to 
Week 96. Subjects from the control arm who switch to the D/C/F/TAF regimen after the 48-week double-
blind treatment will be required to return to the clinic for an additional visit 3 to 7 weeks after the 
unblinding visit.
After Week 96, subjects will be given the opportunity to continue D/C/F/TAF treatment during an 
extension phase until the D/C/F/TAF FDC tablet 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. During the extension phase subjects will attend visits every 6 months.
Subjects who prematurely discontinue, either during the double-blind treatment phase (from Day 1 to 
Week 48) or during the single-arm D/C/F/TAF phase (between Week 48 and Week 96) will be required to 
return to the clinic within 72 hours of stopping study treatment for the early study treatment 
discontinuation (ESTD) visit.
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 consists of a screening period of approximately 30 days (up to maximum 6 weeks) 
starting from the signature of the informed consent form (ICF), double-blind active controlled treatment 
for at least 48 weeks, an open-label single-arm D/C/F/TAF treatment up to Week 96 and an extension 
phase. A 30-day FU visit may take place as described above.
The primary analysis of this study will be performed when all subjects have completed the Week 48 visit 
or discontinued earlier. An additional analysis will be performed when all subjects have completed the 
Week 96 visit. The final analysis will be performed once all subjects have completed the extension phase 
(and the 30-day FU visit if applicable), or discontinued earlier.
The safety and tolerability, as well as efficacy, of the enrolled subjects and treatment regimens will be 
monitored by an independent Data Monitoring Committee (DMC). Refer to Section 11.8 of the protocol 
for details. In addition to the Week 48, Week 96, and final analyses, formal DMC analyses will be 
performed for monitoring purposes, including a futility analysis for lack of (non-inferior) efficacy and a 
blinded sample size re-estimation.
A diagram of the study design is provided in Figure 1. 


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
7
Approved, Date: 25 April 2018
Figure 1:
Schematic Overview of the Study
                Baseline                          Week 24                               Week 48 c,d                    Week 96 e
                (Day 1) a                               DMC b                                             Primary analysis           Analysis
Screening
Double-Blind Treatment Phase f
Single-arm
Treatment 
Phase c,d,f
Extension 
Phase e
Follow-up
≤ 30 days
prior
to baseline
Treatment arm 1 (Test) (n=335):
   D/C/F/TAF FDC once daily g
   DRV/COBI FDC-matching and FTC/TDF 
FDC-
  matching placebo tables once daily g
D/C/F/TAF 
FDC
D/C/F/TAF 
FDC
ESTD f and 
30-day 
FU visit h
Treatment arm 2 (Control) (n=335):
   DRV/COBI FDC coadminsitered with 
FTC/TDF 
   FDC once daily g
   D/C/F/TAF FDC-matching placebo tablet once 
  daily g
a Following the baseline visit, subjects will return for study visits at Weeks 2, 4, 8, 12, 24, 36, 48, and every 12
weeks thereafter until and including a Week 96 visit.
b Formal DMC interim analyses will be performed for monitoring purposes, including a futility analysis for lack 
of non-inferior) efficacy and a blinded sample size re-estimation.
c Subjects will continue to take their blinded study drug and to attend visits every 12 weeks following Week 48
until treatment assignment is unblinded.
d After unblinding, provided the results from the primary analysis do not preclude (further) exposure of subjects 
to D/C/F/TAF, all subjects will receive D/C/F/TAF treatment during a single-arm treatment phase up to Week 
96. Subjects from the control arm who switch to the D/C/F/TAF regimen after the 48-week double blind
treatment will be required to return to the clinic for an additional visit 3 to 7 weeks after the unblinding visit.
e After Week 96, subjects will be given the opportunity to continue D/C/F/TAF treatment during an extension
phase until the D/C/F/TAF FDC tablet 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. During the extension phase subjects will attend visits every 6 months.
f Subjects who prematurely discontinue, either during the double-blind treatment phase (from Day 1 to Week 48)
or during the single-arm D/C/F/TAF treatment phase (between Week 48 and Week 96) will be required to 
complete the ESTD assessments within 72 hours of stopping study treatment.
g All study drugs and matching placebo tablets must be administered orally, once daily in the morning with food,
at approximately the same time each day.
h Any subject who has an ongoing AE or SAE at the time of his/her last study visit will be required to return to
the clinic 30 days after the completion their his/her study visit for a 30-day FU visit (unless consent is
withdrawn).
1.3.
Statistical Hypotheses for Trial Objectives
The primary efficacy endpoint of this study was the proportion of subjects who have HIV-1 RNA <50 
copies/mL at Week 48 as defined by the FDA Snapshot analysis. Thus, no formal statistical hypothesis is 
to be tested in the Week 96 SAP. 
1.4.
Sample Size Justification
A sample size of 670 (335 subjects in D/C/F/TAF arm and 335 subjects in the control arm) will yield 90% 
power. It was assumed that both treatment arms have a response rate of 80% (HIV-1 RNA <50 copies/mL 
at Week 48 as defined by the FDA snapshot analysis), that the non-inferiority margin is 10%, and that the 
significance level of the test is at a 1-sided, 0.025 level.


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
8
Approved, Date: 25 April 2018
A minimum of 170 subjects (85 per treatment arm) was targeted to be included in the bone investigation 
sub-study. Assuming a 4% inter-subject variability in BMD and a 1-sided alpha level of 2.5%, 85 subjects 
per treatment arm is sufficient to detect at least an absolute difference of 2% between the treatment arms 
with 90% power. Power calculations are presented in Table 1. 
Table 1:
BMD at the Lumbar Spine, Power Calculations
Mean % Change from 
Baseline
Common Standard 
Deviation (%)
Power
N=170
2
3.5
96%
4
90%
3
3.5
>99%
4
>99%
1.5.
Randomization and Blinding
Randomization
Central randomization was implemented in conducting this study. Subjects were assigned to 1 of 2 
treatment groups in a 1:1 ratio based on computer-generated randomization schedule implemented in the 
interactive web response system (IWRS) before the study. Randomization minimizes the imbalance in the 
distribution of the number of subjects across treatment groups within the levels of each individual 
stratification factor: HIV-1 RNA level (≤100,000 copies/mL or > 100,000 copies/mL) and CD4+ cell 
count (<200 cells/μL or ≥200 cells/μL) at screening. Based on the algorithm, the IWRS assigned a unique 
treatment code, which dictated the treatment assignment and matching study drug kit for the subject.
Blinding
Subjects continued to take their blinded study drug and to attend visits every 12 weeks following Week 
48 until treatment assignment was unblinded. After unblinding, all subjects will receive D/C/F/TAF 
treatment during a single-arm treatment phase up to Week 96. Subjects from the control arm who switch 
to the D/C/F/TAF regimen after the 48-week double blind treatment were required to return to the clinic 
for an additional visit 3 to 7 weeks after the unblinding visit.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Treatment Arms
Following notations for the treatment arms in the single arm treatment phase will be used:
-
Initial D/C/F/TAF Arm:  subjects who received D/C/F/TAF FDC treatment at baseline of the 
treatment phase
-
Late Switch to D/C/F/TAF Arm: subjects who were on DRV/COBI FDC+ FTC/TDF FDC 
treatment and switched to D/C/F/TAF treatment during the single arm treatment phase
2.2.
Visit Windows
2.2.1.
Trial Phases
Phases will be constructed for each subject as follows for adverse events, concomitant therapies, and for 
the determination of the worst-case/toxicity/change in the cross-tabulations.


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
9
Approved, Date: 25 April 2018
Trial phase
Start date
End date
Screening
Minimum of Date of signing the 
informed consent and Date of 
the screening visit
1 day before start of treatment 
Comparative
Treatment 
Phase
Date of the first intake (after 
randomization)
For ongoing subjects, in order of priority: 
-
Week 48 visit date;
if missing then;
-
Projected Week 48 visit date, where 
projected Week 48 visit date = baseline visit 
date + (7 *48)
In case of withdrawal use: 
-
Minimum(last intake date of study drug, 
study withdrawal date) +2 days
Extended 
double-blind
treatment 
phase (up to 
Switch)
Comparative treatment phase 
end date +1 day
If a subject switches prior to Week 96:
-
Minimum(Date of last double-blind intake 
+2 days, Start Date of first Open Label 
D/C/F/TAF intake)
If a subject never switches prior to Week 96:
-
Week 96 visit date;
if missing then;
-
Projected Week 96 visit date, where 
projected Week 96 visit date = baseline visit 
date + (7 *96)
In case of withdrawal prior to switching use: 
Minimum (last intake date of study drug, study 
withdrawal date) + 2 days
Single Arm 
treatment 
phase (Switch 
to Week 96) *
Extended double-blind 
treatment phase end date +1 day
-
Week 96 visit date;
if missing then;
-
Projected Week 96 visit date, where 
projected Week 96 visit date = baseline visit 
date + (7 *96)
In case of withdrawal after switch use: 
-
Minimum (last intake date of study drug, 
study withdrawal date) + 2 days
Follow-up
Maximum (end date of extended 
double-blind treatment phase, 
end date of single arm treatment 
phase) +1 day
Trial termination date for all groups (date of last 
contact)
* The 3-7 WEEKS AFTER UNBLINDING visit will be handled as follows:
     - All efficacy assessments collected at this visit will be attributed to the DRV/COBI FDC + FTC/TDF FDC regimen
    - All safety assessments collected at this visit will be attributed to the D/C/F/TAF FDC regimen
Data up to each subject’s Week 96 visit are in scope for this analysis; in addition DXA data (DP domain) 
up to Week 96 visit+28 days, and if applicable, any (confirmatory) viral load or genotype/phenotype 
results immediately subsequent to Week 96 (up to 6 weeks) will also be included in this analysis.


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
10
Approved, Date: 25 April 2018
2.2.2.
Analysis Time points
All visits/assessments will be allocated to the following time points as per the table below, based on the 
number of days in the study, calculated as “assessment date – start date of comparative treatment phase + 
1 day” for Comparative Treatment, Extended Double-blind Treatment/Single Arm Treatment and Follow-
up phase and “assessment date – start date of Comparative Treatment phase” for Screening phase.
The following time intervals will be used for reporting of efficacy as well as safety data:
Phase 
Visit
Target day
Analysis time point
Time interval (days)
Screening
1
-∞
Screening
< Day 0
Comparative 
Treatment
Phase
2
1
Baseline a
<=Day 1
3
15
Week 2
Day 2 – Day 21
4
29
Week 4
Day 22 – Day 42
5
57
Week 8
Day 43 – Day 70
6
85
Week 12
Day 71 – Day 126
7
169
Week 24
Day 127 – Day 210
8
253
Week 36
Day 211 – Day 294
9
337
Week 48
Day 295 – Day 378
Extended Double-
blind & Single Arm 
Treatment phase
10
421
Week 60
Day 379 – Day 462
11
505
Week 72
Day 463 – Day 546
12
589
Week 84
Day 547 – Day 630
13
673
Week 96
Day 631 – Day 714
Follow-up
14
31
Follow-up
Day 1 onwards
a Except for DXA, only the record closest to target day 1 will be allocated to analysis time point ‘Baseline’, all 
records prior to day 1 are assigned to ‘Screening’. For DXA, a scan up to 28 days post baseline visit can be allocated 
to the analysis time point ‘Baseline’.
Unless specified otherwise, if two visits fall within the same interval, the one closest to the target day will 
be used for the analysis displays and graphics in order to have only one evaluation per subject per analysis 
time point. However, all data will be presented in the listings. If distances of both visits to the target day 
are equal, the visit latest in time will be used. If multiple visits that fall within the same analysis window 
have the same date/time, the one with the highest sequence number will be used.
2.3.
Analysis Sets
2.3.1.
Efficacy Analysis Set(s)
2.3.1.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set is the primary analysis set for efficacy analysis. The 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. 
2.3.1.2.
Per Protocol Analysis Set
Since an analysis on the ITT population may not be conservative in a non-inferiority 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, and 
(3) without any major protocol deviation that is considered to potentially affect efficacy outcomes. 
Specific details are provided in Attachment 1. 


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
11
Approved, Date: 25 April 2018
2.3.2.
Safety Analysis Set
The safety analysis (including all data collected up to 30-day follow-up visit) is also performed on the ITT
analysis set.
2.3.3.
Bone Investigation Sub-study Analysis Set
The bone investigation sub-study (BIS) analysis set will include all subjects who are randomized and 
have received ≥1 dose of treatment in the study, and have at least one post-reference value either in 
biomarker or in BMD data. Subjects will be grouped according to the treatment arm (D/C/F/TAF or 
control) to which they were randomized.
2.4.
Definition of Subgroups
2.4.1.
Subgroups for Efficacy Analyses

Adherence based on D/C/F/TAF (i.e., worst D/C/F/TAF adherence from baseline to switch and 
switch to week 96 for the Initial D/C/F/TAF group, and from switch to week 96 for the Late 
Switch to D/C/F/TAF group) on drug accountability for both derivations (>95%: adherent, ≤95%: 
non-adherent, missing/unknown)

Re-classified (see section 2.5) viral load stratification factor (≤ 100,000, > 100,000 copies/mL)

Re-classified (see section 2.5) CD4+ count:
o
< 200, ≥ 200 cells/mm3[200≤ x<350, 350≤x≤500, >500 cells/mm3]

Combination of re-classified (see section 2.5) stratification factors:
o
Viral load ≤ 100,000 copies/mL and CD4+ < 200 cells/ mm3
o
Viral load ≤ 100,000 copies/mL and CD4+ ≥ 200 cells/ mm3
o
Viral load > 100,000 copies/mL and CD4+ < 200 cells/ mm3
o
Viral load > 100,000 copies/mL and CD4+ ≥ 200 cells/ mm3

Race (American Indian or Alaska Native, Asian, Black or African American, White, Native
Hawaiian or other Pacific Islander, Other, Non Black or African American)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Gender (Male, Female)

Age group:
o
≤50, >50 years

Region (Europe, North America)

WHO Clinical Staging of HIV/AIDS

HIV-1 subtype (B, non-B)

Any PI RAMs (primary + secondary) (0-3, 4-6, 7-9, >=10)

Presence (Yes/No) of one or more:
o
primary and/or DRV RAMs, 
o
NRTI RAMs, 
o
NNRTI RAMs, 
o
M184V/I 
Subgroup analyses will be performed on the ITT analysis set.
2.4.2.
Subgroups for Safety Analyses

Age group:
o
≤50, >50 years

Re-classified (see section 2.5) viral load stratification factor (≤ 100,000, > 100,000 copies/mL)

Re-classified (see section 2.5) CD4+ count (< 200, ≥ 200 cells/mm3)

Combination of re-classified (see section 2.5) stratification factors:
o
Viral load ≤ 100,000 copies/mL and CD4+ < 200 cells/ mm3


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
12
Approved, Date: 25 April 2018
o
Viral load ≤ 100,000 copies/mL and CD4+ ≥ 200 cells/ mm3
o
Viral load > 100,000 copies/mL and CD4+ < 200 cells/ mm3
o
Viral load > 100,000 copies/mL and CD4+ ≥ 200 cells/ mm3

Race (American Indian or Alaska Native, Asian, Black or African American, White, Native
Hawaiian or other Pacific Islander, Other, Non Black or African American)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Gender (Male, Female)

Region (Europe, North America)

WHO Clinical Staging of HIV/AIDS
Subgroups for Bone Investigation Analyses:

Race (American Indian or Alaska Native, Asian, Black or African American, White, Native 
Hawaiian or other Pacific Islander, Other, Non Black or African American)

Gender (Male, Female)

Baseline BMI:
o
Underweight (< 18.5 kg/m2)
o
Normal range (18.5 – 24.99 kg/m2)
o
Overweight (25.0 – 29.99  kg/m2)
o
Obese (≥ 30.0 kg/m2)

Age group (≤50, >50 years)

Current smoking status (Y/N)
2.5.
Re-classification of Stratification Factors for Purpose of Analysis
For the purpose of analysis the stratification factors (HIV-1 RNA [≤ 100,000, > 100,000 copies/mL] and 
CD4+ count [(< 200, ≥ 200 cells/mm3]) will be re-classified based on the baseline values from the 
laboratory data.  If the baseline data are missing, then the laboratory data at screening will be used.  If the 
laboratory data at screening are missing, then the data from the IVRS/IWRS will be used.  
The re-classified stratification factors will be used for analysis. Listings showing the discrepancies 
between the strata entered at randomization (IVRS/IWRS) and actual screening laboratory data will be 
presented. 
2.6.
Reference
For Initial D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 
analysis. For the Late Switch group, the references are as follows:
1.
Comparative treatment phase baseline (for efficacy this reference will be used for periods 
before and after the switch; for safety this reference will be used for periods before the 
switch).
2.
Last value prior to the switch will be used as a reference for periods after the switch for both 
efficacy and safety; for DXA scan, data up to (and including) 28 days after the switch to open 
label D/C/F/TAF can be used as reference.
3.
SUBJECT INFORMATION
3.1.
Demographics and Baseline Characteristics
These parameters will not be included in this analysis, because no new subjects were recruited since the 
Week 48 analysis.


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
13
Approved, Date: 25 April 2018
3.2.
Disposition Information
A tabulation of the total number (with percentages) of subjects screened, randomized and not treated and 
randomized and treated will be provided.
Tabulation per treatment arm of the number of subjects who have completed the treatment/single arm
phase, who are ongoing, and who have discontinued the trial with the reason for discontinuation will be 
provided.  For the Initial D/C/F/TAF group, the tabulation will be presented by time period as follows; 
baseline to Week 48, Week 48 to Week 96 and overall from baseline to Week 96.  For the Late Switch 
group, the tabulation will be presented by time period as follows; baseline to Week 48, Week 48 to the 
switch, from the switch to Week 96, and overall from baseline to Week 96.
A Kaplan-Meier graph for the time to Study Discontinuation (any reason) will be included.
3.3.
Treatment Adherence
Treatment adherence based on drug accountability will be summarized by means of descriptive statistics 
and frequency tabulations. Cumulative treatment adherence will be calculated from baseline to the switch, 
and again from the switch to Week 96.  Cumulative treatment adherence will be determined (derivation i).  
The following parameters are derived:
Amount to be taken through switch/Week 96 = (number of days since start of treatment/switch × 
number of tablets to be taken per day).
Number of days since start of start of treatment/switch is based on (whichever comes sooner):
-
last study medication intake (if available) or, in case subject discontinued and last study 
medication intake is missing, the last visit date prior to withdrawal will be used.
-
Switch/Week 96 visit date,
In addition (derivation ii), the cumulative treatment adherence up to time point where not more than one 
bottle is missing, or if available, up to switch/Week 96, whichever comes sooner, will be calculated.
Actual amount taken = (number of tablets dispensed – number of tablets returned), summed over time 
points up to the time point of interest.
Level of adherence = (actual amount taken / amount to be taken) × 100%
Treatment adherence is defined as:
- adherent: the level of adherence is >95%, 
- non-adherent: the level of adherence is ≤95%.
Additionally, following categories of level of adherence will be defined:
-
>95% 
-
]80%; 95%]
-
]65%; 80%]
-
]50%; 65%]
-
≤ 50%
Interruptions (for AEs) are not to be taken into account for the calculation of adherence, i.e. they will not 
be subtracted from the amount to be taken.
Within treatment group comparison using McNemar’s Exact test comparing adherence (i.e., adherent 
versus non-adherent) before and after the switch will be calculated. The statistical test will be interpreted
at the 5% two-sided significance level.


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
14
Approved, Date: 25 April 2018
3.4.
Extent of Exposure
Descriptive statistics will be tabulated for the duration of treatment of both treatment groups, in weeks, 
during the respective active treatment phases, as of reference up to the Week 96 visit or in case of early 
discontinuation, last study medication intake. In addition, subject-years of exposure will be shown, 
derived as mean of treatment duration (in weeks) x N) x 7 / 365.25. Tabulation of the distribution of 
exposure per 4 week intervals will be presented. Additionally, the number (with percentages) of subjects 
who switched by analysis time point will be provided along with the subject-years of exposure to 
D/C/F/TAF per analysis time point.
Treatment duration (in weeks) is derived as follows:
(End of phase – reference + 1) / 7
Treatment interruptions will not be taken into account for the above definition.
3.5.
Protocol Deviations
All major protocol deviations will be tabulated and listed by treatment arm and overall. The proportion of 
subjects with one or more major protocol deviation that led to exclusion from the per protocol analysis set 
(see Attachment 1) will also be tabulated.
3.6.
Concomitant Medications
Concomitant medications are defined as any therapy used on or after the same day as the first dose of 
study agent, including those that started before and continue on after the first dose of study agent.
Combination drugs are split up into their respective compounds. 
Concomitant therapies will be grouped as follows, using a list of dictionary derived terms provided as 
metadata. These groups will be tabulated (n, %) per treatment group and analysis phase:
-
lipid lowering drugs
-
antidiabetic drugs
-
antihypertensive drugs 
-
drugs for cardiovascular disease
-
antiosteoporotic drugs
4.
EFFICACY
4.1.
Analysis Specifications
4.1.1.
Level of Significance
No formal statistical tests will be performed.  All analyses will be descriptive. 
4.1.2.
Data Handling Rules
Plasma viral load levels will be measured using the ROCHE COBAS® AmpliPrep/COBAS® Taqman®
HIV-1 Test, v2.0, which will be conducted by the central laboratory.
Imputation of left censored HIV-1 RNA values: viral load results recorded as “< 20 HIV-1 RNA 
copies/mL detected” and “< 20 HIV-1 RNA copies/mL not detected” will be scored at 19.
CD4+ cell count and HIV-1 RNA data collected on treatment (up to the last dose date of study drug) will 
be used in the analysis.


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
15
Approved, Date: 25 April 2018
4.1.3.
FDA Snapshot Approach and Time to Loss of Virologic Response 
Algorithm (TLOVR)
FDA Snapshot approach (applying 20/50/200 copies/mL as threshold): The Snapshot approach will 
classify subjects into 3 outcome categories: “virologic success”, “virologic failure”, or “no viral load data 
in the Week 96 visit window”. Several subcategories of the outcome will also be presented in the analysis 
and are shown below. The categories below are mutually exclusive such that a subject will be included in 
one (sub)category. If a subject discontinues in the time window but also has an HIV-RNA value in the 
time window then the viral load value will be used to classify the subject’s category.   

Virologic success: 
o
Last available HIV RNA <20/50/200 copies/mL in the Week 96 visit window (Week 90-
102)

Virologic failure:
o
Last available HIV RNA ≥20/50/200 copies/mL in the Week 96 visit window (Week 90-
102)
o
Virologic failure leading to discontinuation
o
Discontinued due to other reason (i.e., other than AE/death or virologic failure) and last 
available HIV RNA ≥20/50/200 copies/mL

No viral load data in the Week 96 visit window:
o
Discontinued due to AE/death (subjects will be classified in this category if discontinued 
prior to Week 96 window regardless of HIV RNA level)
o
Discontinued due to other reason (i.e., other than AE/death or virologic failure) and the 
last available HIV RNA <20/50/200 copies/mL (or missing)
o
Missing data during the Week 96 visit window but on study
‘Virologic failure’ as reason for discontinuing the trial was inadvertently not included in the Study 
Termination eCRF page.  Therefore, whether a subject would be classified into the subcategory
‘Virologic failure leading to discontinuation’ will be determined by a medical assessment of the comment 
fields and other specification reasons for discontinuation to determine if anyone discontinued the trial due 
to lack of efficacy reasons. A current list of comments and other specification reasons are documented in 
Attachment 5, and will be used to programmatically identify such subjects. Upon further clinical 
evaluation additional comments or other specification reasons might need to be added, and these will be 
documented in the DPS. An identified subject will be classified to the Snapshot categories as follows:

Data within window: If an identified subject has HIV RNA value within the window, the last HIV 
RNA value will be used to classify the subject as either at or above the threshold or below the 
threshold

No data within window: If an identified subject does not have an HIV RNA value in window, 
then regardless of the last HIV RNA value the subject will be classified as “Virologic failure 
leading to discontinuation” 
Virologic response will then be categorized as follows: Yes (virologic success), or No (virologic failure 
and no viral load data in the Week 96 visit window).
The Snapshot approach will also be displayed over time by analysis time point, and will follow the same 
logic as defined above (please see Section 2.2.2 for visit intervals)
Imputations for missing values
The following imputation method is used to calculate virologic response at a given time point:


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
16
Approved, Date: 25 April 2018

observed case: subjects with a missing value are disregarded in the analysis for that time point.

TLOVR: responders/non-responders are defined according to the FDA Time To Loss Of 
Virologic Response algorithm; a subject is considered a responder at a given time point if the 
applicable HIV-RNA criterion is fulfilled at that time point and at the subsequent time point; a 
subject is considered a confirmed non-responder at a time point in the following situations in 
order of precedence:
o
the subject shows a 'rebound' HIV-RNA value (>=threshold copies/mL) at that time point 
and the subsequent time point;
o
the subject shows a confirmed rebound at an earlier time point (irrespective of re-
suppression of viral load)
o
the subject (permanently) discontinued at that time point or before
o
intermittently missing values are considered as response if the immediately preceding and 
following visits demonstrated response; in case the subject had not reached the next visit 
yet, no imputation is performed for the missing time points, unless the subject had 
discontinued the trial.
o
Remark: in case multiple virologic response observations are available within the same 
time window, all observations are used to determine TLOVR-imputed response for that 
time window. In case the subject has not reached the next visit yet, this subject is left out 
of the analysis for the missing time points.
4.2.
Primary Efficacy Endpoint(s)
4.2.1.
Definition
The primary efficacy endpoint of this study was the proportion of subjects who have HIV-1 RNA <50 
copies/mL at Week 48 as defined by the FDA Snapshot analysis. Thus, the analysis of this endpoint is not 
described in the Week 96 SAP.
4.2.2.
Analysis Methods
Not applicable.
4.3.
Major Secondary Efficacy Endpoints
4.3.1.
Definition
-
The proportion of subjects with HIV-1 RNA <20, <50, and <200 copies/mL at Week 96 as 
defined by the FDA Snapshot analysis;
-
The proportion of subjects with HIV-1 RNA <20, <50, and <200 copies/mL at Week 96 as 
defined by the time to loss of virologic response (TLOVR) algorithm;
-
The change from reference in log10 HIV-1 RNA up to Week 96;
-
The change from reference in CD4+ cell count up to Week 96;
-
The development of viral resistance through Week 96;


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
17
Approved, Date: 25 April 2018
4.3.2.
Analysis Methods
4.3.2.1.
Antiviral Efficacy
Tabulations (numbers and proportions) per time point will be provided for the Snapshot outcomes 
(success, failure, no data within window). Tabulations (numbers and proportions) will also be provided 
for Snapshot outcome at Week 96 based on observed data (i.e., subjects with a missing value are 
disregarded in the analysis for that time point), and TLOVR through Week 96. The exact 2-sided 95% CIs 
around in each treatment group will be calculated by the Clopper-Pearson method for Snapshot virologic 
success and virologic failure, and TLOVR response. Bar charts will be presented for Snapshot outcomes. 
Cross-tabulations for protocol defined virologic failure (see Section 4.3.2.3) versus the FDA snapshot 
algorithm at Week 96 (HIV-1 RNA < 50 copies/mL) will be presented.
4.3.2.2.
Immunologic Change
Change from reference is defined as: value at a given time point minus reference value.
Actual and changes from reference values in CD4+ cell count and log10 HIV-1 RNA at each time point
will be summarized using descriptive statistics (n, mean (SE), median, min, and max). 
The changes from reference in CD4+ cell count (NC=F) and log10 HIV-1 RNA (NC=F) at Week 96 will 
be constructed using analysis of covariance (ANCOVA), separately for each treatment group, including 
CD4+ cell count or log10 HIV-1 RNA at reference, respectively, as continuous covariate in the model.  
Subjects who discontinue will have their CD4 or log10 HIV-1 RNA values after discontinuation imputed 
with their reference value, thus resulting in a 0 change (NC=F). Other (intermittent) missing values will 
be imputed using last observation carried forward (LOCF). Apart from imputed, observed data will also 
be presented. For cases where no observation is available at the baseline date, the last available screening 
value will be taken. 
A supportive mixed model for repeated measures in change from reference in CD4+ cell count (observed) 
will also be performed separately for each treatment group. The model will include post-baseline change 
from reference as a response variable, terms for visit, and the corresponding reference value as a covariate 
An unstructured covariance matrix will be used to model the correlation among repeated measurements.
Cross-tabulations of Week 96 CD4 cell count versus reference will be provided using the categories: < 
200, 200≤ x<350, 350≤x≤500, >500 cells/mm3.
4.3.2.3.
Resistance Determinations
Subjects who are on study medication and who experience a protocol defined confirmed virologic failure, 
i.e., virological non-response (NR), virologic rebound (RB), or viremic at final time point, as defined 
below, will be considered to have VF for the purpose of the resistance analysis.
Virologic Nonresponse:

HIV-1 RNA <1 log10 reduction from baseline and ≥50 copies/mL at the Week 8 visit, confirmed at 
the following scheduled or unscheduled visit following Week 8.
Virologic Rebound:

At any visit, after achieving confirmed (consecutive) HIV-1 RNA <50 copies/mL, a rebound in HIV-
1 RNA to ≥50 copies/mL, which is subsequently confirmed at the following scheduled or 
unscheduled visit; 
or

At any visit, a >1 log10 increase in HIV-1 RNA from the nadir which is subsequently confirmed at the 
following scheduled or unscheduled visit.
Virologic at Final Time Point:


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
18
Approved, Date: 25 April 2018

Any subject with on-treatment HIV-1 RNA ≥400 copies/mL at the study endpoint or study 
discontinuation after Week 8 
For the management of subjects experiencing VF (and the resistance testing on samples from these 
subjects) see section 9.2.2.1 of the protocol.
Screening HIV-1 PR/RT genotype analysis will be performed for all subjects. Post-screening HIV-1 
PR/RT genotype/phenotype testing will be available from subjects who are eligible for resistance testing 
(subjects with at protocol defined VF and have HIV-1 RNA ≥400 copies/mL). Note: baseline 
genotype/phenotype may be available for subjects with confirmed VF if they showed evidence of reduced 
susceptibility after VF to any of the study drugs.
4.3.2.3.1.
Genotype
At screening HIV-1 PR/RT genotype will be assessed by the GenoSureMG™ assay. Post-screening HIV-
1 PR/RT genotype/phenotype will be assessed by the PhenoSenseGT™ assay.
Evaluation of screening and treatment-ermergent RAMs will be based on PI, N(t)RTI, and NNRTI 
mutation lists defined by IAS-USA.  RAMs were considered treatment-emergent if they were detected 
post-baseline but not at screening/baseline. Individual listings will be generated. Genotypes will be shown 
per region (PR and RT), time point and treatment phase. Mutations will be marked by lists and if they 
emerged.
At screening, a tabulation per treatment group will present the number of patients with a specific mutation 
or number of patients with at least one PR or RT mutation belonging to a specific mutation list (see 
below). Percentages and the mean/median will be calculated based on the number of subjects with 
screening genotypes. 
Post baseline, a tabulation of emerging mutations per treatment group will present the number of patients 
with a specific emerging mutation or number of patients with emerging mutations belonging to a specific
mutation list (see below). 
The analysis assumes a worst-case scenario in case of multiple post-screening sequencing results: if any 
of a patient's samples shows a mutation, the patient is assumed to have this mutation, even if other 
samples show wild-type virus. The percentage of patients with emerging mutations will be calculated on 
the number of patients with paired screening/baseline and post-baseline genotypes and on all ITT patients. 
The denominator should be shown. 
All analyses will be conducted on the Efficacy ITT population, unless specified otherwise, and will be 
presented by “all patients with available post baseline genotypes” and by “protocol defined virologic 
failure with post baseline genotypes”, taking into account either “all genotypes” or only the “genotypes 
that are on-treatment”.
Protease mutations
-
IAS-USA3 Primary PI mutations (n=23)
D30N, V32I, M46I/L, I47A/V, G48V, I50L/V, I54L/M, Q58E, T74P, L76V, V82A/F/L/S/T, N83D, 
I84V, N88S, L90M
-
IAS-USA3 Secondary PI mutations (n=52)
L10C/F/I/R/V, V11I, G16E, K20I/M/R/T/V, L24I, L33I/F/V, E34Q, M36I/L/V, K43T, F53L/Y, 
I54A/S/T/V, D60E, I62V, L63P, I64L/M/V, H69K/R, A71I/L/T/V, G73A/C/S/T, V77I, V82I, I85V, 
N88D, L89I/M/V, I93L/M
-
IAS-USA3 DRV resistance-associated mutations (n=11)
V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V
RT mutations 


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
19
Approved, Date: 25 April 2018
-
IAS-USA3 NRTI resistance-associated mutations (n=22)
M41L, A62V, K65R/E/N, D67N, 69ins, K70E/R, L74V, V75I, F77L, Y115F, F116Y, Q151M, 
M184I/V, L210W, T215F/Y, K219E/Q
-
IAS-USA3 NNRTI resistance-associated mutations (n=34)
V90I, A98G, L100I, K101E/H/P, K103N/S, V106A/I/M, V108I, E138A/G/K/Q/R, V179D/F/L/T, 
Y181C/I/V, Y188C/H/L, G190A/S, H221Y, P225H, F227C, M230I/L
-
IAS-USA3 Thymidine Analogue Mutations (TAMs) (n=8)
M41L, D67N, K70R, L210W, T215Y/F, K219Q/E
-
IAS-USA3 TFV resistance-associated mutations 
K65R/E/N, K70E
-
IAS-USA3 FTC resistance-associated mutations
K65R/E/N, M184I/V
4.3.2.3.2.
Phenotype
Predicted phenotype based GenoSureMG™, in-vitro phenotype data, and the overall resistance 
assessments based on the PhenoSenseGT™assay will be presented in individual patient listings per drug 
and time point, if available.
If available, fold change (FC) in 50% effective concentration (EC50) of ARVs versus wild-type HIV-1 
virus will be included in individual listings per drug and time point.
When one cut-off value is available, a drug is considered
-
Sensitive if the FC is below or equal to the clinical cut-off (CCO) when available or below or equal to 
the biological cut-off (BCO) otherwise;
-
Resistant if the FC is above the clinical or biological cut-off.
When two cut-off values are available, a drug is considered
-
Sensitive if the FC is below or equal to the lower cut-off;
-
Partially sensitive if the FC is above the lower cut-off and below or equal to the higher cut-off;
-
Resistant if the FC is above the higher cut-off.
If paired genotype or phenotype data are available loss of genotypic or phenotypic ARV susceptibility 
will be analyzed. Loss of susceptibility is defined as being “sensitive” at baseline (for genotype and 
phenotype) to “partially sensitive” (phenotype) or “resistance possible” (genotype) or “resistant” at post-
baseline (for genotype and phenotype).  Loss of susceptibility will be tabulated (numbers and proportions) 
per class and individual ARV. All analyses will be conducted on the Efficacy ITT population, unless 
specified otherwise, and will be presented by “all patients with available post baseline 
genotype/phenotypes” and by “protocol defined virologic failure with post baseline 
genotype/phenotypes”, taking into account either “all genotypes/phenotypes” or only the 
“genotypes/phenotypes that are on-treatment”.  
BCOs and CCOs for the PhenoSense® GT Phenotyping Assay
Cut-off
Class
Drug
Generic name
PhenoSense GTTM
(V7045/V7145)
NRTI
AZT
Zidovudine
1.9
3TC
Lamivudine
3.5
ddI
Didanosine
1.3 – 2.2
d4T
Stavudine
1.7


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
20
Approved, Date: 25 April 2018
ABC
Abacavir
4.5 – 6.5
FTC
Emtricitabine
3.5
TDF
Tenofovir
1.4 – 4.0
NNRTI
NVP
Nevirapine
4.5
DLV
Delavirdine
6.2
EFV
Efavirenz
3.0
ETR
Etravirine
2.9 – 10.0
RLP
Rilpivirine
2.0
PI
ATV
Atazanavir
2.2
ATV/rtv
Boosted Atazanavir
5.2
DRV/rtv
Boosted Darunavir
10.0 – 90.0
APV/rtv or fAPV/rtv
Boosted Amprenavir or fosamprenavir
4.0 – 11.0
IDV/rtv
Boosted Indinavir
10.0
LPV/rtv
Boosted Lopinavir (Kaletra)
9.0 – 55.0
NFV
Nelfinavir
3.6
RTV
Ritonavir
2.5
SQV/rtv
Boosted Saquinavir
2.3 – 12.0
TPV/rtv
Boosted Tipranavir
2.0 – 8.0
Clinical cut-offs are shown in bold; cutoffs are based on the PhenosenseGT algorithm version 13
5.
SAFETY
For initial D/C/F/TAF, periods ”Baseline to Week 48”, “Week 48 to Week 96” and ”Baseline to Week 96”
will be presented in the tables. For the late switchers, periods ”Baseline to Switch” and ”Switch to Week 
96” will be presented.
5.1.
Adverse Events
5.1.1.
Definitions
Reported AE parameters and grades are based on the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events ("DAIDS AE grading table"). All AEs will be coded using 
MedDRA version 19.1.
Events of interest 
The EOIs groups include a broad list of terms to identify potential cases. The list of all preferred terms 
belonging to each AEOI group is provided in Attachment 2. Upon further clinical evaluation 
additional EOIs might need to be added, and these will be documented in the DPS.
Since many of the terms used to identify potential cases are clinically non-specific, only those retrieved 
cases that upon medical review are specifically suggestive of /compatible with the AEs of special interest 
will be commented on in the CSR. 
Adverse events of interest (AEOI) groups used for the safety analyses are the following:
-
Renal AEOI (for PRT)
Subgroups: 
laboratory related events,
clinical events
-
Bone AEOI (for fractures)
Subgroups: 
Osteomalacia,


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
21
Approved, Date: 25 April 2018
Bone Loss/atrophy,
Fracture, possibly osteoporotic,
Fracture other,
Other Bone Events
-
Dyslipidaemia AEOI 
-
Liver AEOI
-
Hyperglycemia AEOI
-
Pancreas AEOI
-
Severe skin AEOI
-
Rash AEOI
-
Immune reconstitution inflammatory AEOI
-
Coronary artery AEOI
-
Ocular AEOI (for posterior uveitis)
-
Lipodystrophy AEOI
-
Cardiac conduction AEOI
Subgroups: 
Conduction defects,
Torsade de pointes/QT prolongation
-
Convulsion AEOI
Adverse Drug Reaction (ADR)
ADRs will be presented. A current list of all ADRs is in Attachment 3. In case multiple lists are 
available (US and EU definitions), ADRs will be tabulated separately per list. 
5.1.2.
Analysis Methods
A summary will be provided for the following treatment-emergent adverse events: 
-
any adverse events, 
-
serious adverse events, 
-
deaths due to AE, 
-
adverse events by toxicity grade (as well as AEs with toxicity grade at least 2 and AEs with 
toxicity grades 3 or 4), 
-
AEs at least possibly related to study medication, 
-
AEs for which the medication was temporarily/permanently stopped, 
-
serious adverse events that were at least possibly related to the medication. 


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
22
Approved, Date: 25 April 2018
Incidences of AEs for above mentioned analyses will also be presented by SOC and preferred term.  A 
listing of all AEs will be provided. There will be no formal statistical testing.
Additionally, where applicable, the exposure adjusted incidence rates (EAIR) will be provided.  EAIR is 
calculated as follows:
EAIR=n/∑ti where n is the number of subjects with events, ti is subject’s exposure time in patient-years
Summary of events and incidence tabulations for individual adverse events will be provided for AEOI 
and also for ADRs.
AIDS defining illness based on WHO clinical staging will be tabulated.
The number and percentage of subjects who experienced fracture events (subgroups Fracture, possibly 
osteoporotic and Fracture other of the Bone AEOI for fractures) will be summarized by treatment group.
Selected safety endpoints will be explored by subgroups defined in section 2.4.2. Details for subgroup 
analyses of safety endpoints will be provided in the DPS.
5.2.
Clinical Laboratory Tests
5.2.1.
Definitions
Laboratory parameters of the following lab subcategories will be investigated. The results will be 
displayed grouping the tests as follows:

General biochemistry:

blood: creatine phosphokinase, alpha-1 acid glycoprotein

urine/dipstick: blood, nitrite, leukocyte esterase

Hematology: hematocrit, hemoglobin, platelet count, red blood cell count (RBC), white blood cell 
count (WBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean 
corpuscular hemoglobin concentration (MCHC).
Hematology differential counts: basophils, eosinophils, lymphocytes, monocytes, neutrophils (counts 
and %).
Laboratory Events of Interest

Pancreatic Parameters: total amylase, lipase

Hepatic parameters: 

ALT, AST, alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), bilirubin (all 
types)

Urine/dipstick: bilirubin, urobilinogen

Lipid parameters: cholesterol, HDL cholesterol (HDL-C) (all types), LDL cholesterol (LDL-C) (all 
types), TC/HDL, triglycerides; these will be analyzed overall irrespective of fasting status as well as 
restricted to results from fasting samples separately

Glucose parameters will be analyzed overall irrespective of fasting status as well as restricted to 
results from fasting samples separately:

blood: glucose

urine/dipstick: glucose, ketones

Renal parameters: 


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
23
Approved, Date: 25 April 2018

blood: total protein, creatinine, blood urea nitrogen, uric acid, phosphorus, potassium, 
sodium, bicarbonate, chloride, albumin

urine/chemistry: creatinine, sodium, phosphate, glucose, urine albumin, urine protein

urine/dipstick: glucose, protein
Laboratory toxicities will be derived based on the DAIDS toxicity grading scale (see Protocol).
Note: Local lab results will not be used for the analyses.
5.2.2.
Analysis Methods
Descriptive statistics for the actual values and changes from reference will be provided per time point.
Cross-tabulations of the worst toxicity grades through Week 96 versus reference, and cross-tabulations of 
the worst toxicity grades at Week 96 versus reference will also be provided if applicable. Subject listings 
of abnormal laboratory values will be provided.
Additionally, the following lipid-related abnormalities according to NCEP categories will be tabulated:

Triglycerides abnormally high (≥150 mg/dL)

Total cholesterol abnormally high (≥ 200 mg/dL)

LDL abnormally high (≥ 100 mg/dL)

HDL abnormally low (< 40 mg/dL)
Hy’s Law Criteria
In addition, an analysis will be performed to identify all subjects meeting Hy’s law criteria i.e. subjects
showing 3-fold or greater elevations above the ULN of ALT or AST and a concomitant elevation of 
serum total bilirubin to >2xULN, without a concomitant elevated serum ALP (defined as serum alkaline 
phosphatase activity less than 2× the upper limit of normal).
5.2.3.
Creatinine and Glomerular Filtration
5.2.3.1.
Serum Creatinine and Cystatin C
Estimated glomerular filtration rate based on the creatinine clearance will be calculated according to the 
Cockcroft-Gault formula1 (eGFRcrCG) and the CKD-EPI formula (eGFRcrCKD-EPI) and eGFR based on
cystatin C clearance will be calculated according to the CKD-EPI formula (eGFRcystCKD-EPI).
-
eGFRcr according to the Cockcroft-Gault formula (unit: mL/min): 
Male:
(140 – age in years) x (weight in kg) eGFRcr CG(mL/min)
  72 (serum creatinine in mg/dL)
Female:
(140 – age in years) x (weight in kg) 0.85 eGFRcrCG (mL/min)
  72 (serum creatinine in mg/dL)
-
eGFRcr and eGFRcyst according to the CKD-EPI formula (unit: mL/min/1.73m2): 
eGFRcrCKD-EPI
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


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
24
Approved, Date: 25 April 2018
Scr >0.9 mg/dL
141 x (Scr/0.9)-1.209 x 0.993age
eGFRcystCKD-EPI
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)
The changes from reference in serum creatinine, eGFRcrCG and eGFRcrCKD-EPI and eGFRcystCKD-EPI at 
Week 96 will be summarized by treatment arm and using descriptive statistics. 
Within-treatment arm comparison versus reference at Week 96 will be assessed using Wilcoxon signed-
rank test.
Stages of GFR at reference versus the minimum post-reference GFR value and the last available value 
will be summarized by count and percent of subjects. Kidney disease stages are defined as follows: 1 
(Normal): GFR ≥90; 2 (Mild): GFR 60-89; 3 (Moderate): GFR 30-59; 4 (Severe): GFR 15-29; 5 (Renal 
Failure): GFR <15 mL/min).
In addition to the above, the number and proportion of subjects with a >25%, >50% and >75% decrease
from reference will be tabulated.
5.2.3.2.
Proximal Renal Tubular Function
Proteinuria by Quantitative Assessment
Total urine protein, total urine albumin, urine protein to creatinine ratio (UPCR) and urine albumin to 
creatinine ratio (UACR) will be summarized by treatment arm and visit using descriptive statistics.
The number and proportion of subjects with UACR and UPCR results in the following categories at 
Week 96 will be tabulated:

UACR: < 30, ≥ 30 to 300, >300 mg/g

UPCR: < 200 mg/g versus ≥ 200 mg/g
Median (Q1, Q3) percent change from reference over time will be plotted by treatment group.
The evolution over time of total urine protein and total urine albumin will also be presented.
Proteinuria by Urinalysis (Dipstick)
Treatment-emergent proteinuria by urinalysis (dipstick) through Week 96 will be summarized by 
treatment group. Cross-tabulation of grades at Week 96 versus reference will also be presented.
Other Renal Biomarkers
Selected renal biomarkers retinol binding protein (RBP) and beta-2-microglobulin, RBP to creatinine 
ratio and beta-2-microglobulin to creatinine ratio will be summarized by treatment arm and visit using 
descriptive statistics. The proportions of subjects with beta-2-microglobulin to creatinine ratio <=300
mg/g and >300 mg/g will be tabulated.
The number and proportion of subjects with retinal binding protein to creatinine ratio results in the 
following categories at Week 96 will be tabulated:

< 50 years of age (at the time of lab assessment): < 130 mcg/g creatinine, ≥ 130 mcg/g creatinine


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
25
Approved, Date: 25 April 2018

≥ 50 years of age (at the time of lab assessment): < 172 mcg/g creatinine, ≥ 172 mcg/g creatinine
Phosphate excretion
Other renal biomarkers include urine fractional excretion of phosphate (FEPO4) that will be summarized 
by treatment arm and visit using descriptive statistics. 
Urine fractional excretion of Phosphate (FEPO4) will be calculated as follows:

Based on unadjusted serum creatinine:
FEPO4 (%) = (SCr × UPO4) / (SPO4 × UCr) × 100 (%)
The reference, post-reference, and change from reference in FEPO4 will be summarized by treatment arm 
and visit using descriptive statistics. Median (Q1, Q3) change from baseline in FEPO4 over time will be 
plotted by treatment group. 
Subclinical renal proximal tubulopathy
Potential Markers of Renal Proximal Tubulopathy are:
1.
Increase in serum creatinine ≥ 0.40 mg/dL from reference. 
2.
Confirmed ≥ 2 grade level increase from reference in graded proteinuria
3.
Confirmed ≥ 1 grade level increase from reference in graded hypophosphatemia
4.
Confirmed ≥ 1 grade level increase from reference in graded glycosuria concurrent with serum 
glucose <=100 mg/dL (normoglycemic glycosuria)
A confirmed laboratory abnormality is defined as an abnormality observed at 2 consecutive post-
reference measurements or an abnormality observed at 1 measurement followed by study drug 
discontinuation
A subclinical renal proximal tubulopathy will be defined as confirmed abnormalities in any 2 out of the 4 
renal parameters (serum creatinine and one or more of the 3 other markers of tubular dysfunction).
5.3.
Vital Signs and Physical Examination Findings
5.3.1.
Definitions
The following vital signs parameters will be analyzed:
–
pulse (bpm)
–
systolic blood pressure, SBP (mmHg)
–
diastolic blood pressure, DBP (mmHg)
–
weight (kg)
Pulse, DBP and SBP are classified in the following abnormality codes:
Abnormality code
Pulse (bpm)
DBP (mmHg)
SBP (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


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
26
Approved, Date: 25 April 2018
Abnormality code
Pulse (bpm)
DBP (mmHg)
SBP (mmHg)
Abnormally high
120
-
-
In determining abnormalities, the following rules are applied:
-
worst grades/abnormalities are determined over the whole observational period for each trial phase 
separately, including post-reference scheduled and unscheduled measurements of that phase.
-
The abnormalities ‘abnormally low’ and ‘abnormally high’/grades are considered equally important, 
i.e. if a subject has as well an abnormally low as an abnormally high or graded value post-reference, 
both abnormalities are shown in the tables. (This means that the sum of the percentages can be more 
than 100%).
Definition treatment-emergent:
An abnormality will be considered treatment-emergent in a particular phase if it is worse than the
reference corresponding to this phase. If the reference is missing, the abnormality is always considered as 
treatment-emergent. A shift from ‘abnormally low’ at reference to ‘abnormally high’ or ‘grade …’ post 
reference (or vice versa) is also treatment-emergent.
5.3.2.
Analysis methods
Descriptive statistics for the actual values and changes from reference per time point will be presented.
For weight, comparative treatment phase and single arm treatment phase will be presented for Initial 
D/C/F/TAF group; data from baseline up to the switch, and from the switch up to Week 96 will be 
presented for the switch group.
Cross-tabulations for the worst abnormalities versus reference per vital signs test will be produced. 
Abnormal physical examination findings will be listed.
5.4.
Bone Investigations
5.4.1.
Definitions
The following bone formation markers will be analyzed:
–
Serum total alkaline phosphatase (ALP)
–
Serum type 1 procollagen N-terminal (P1NP)
Bone resorption markers:
–
Urinary or serum collagen type 1 cross-linked C-telopeptide (CTX)
Other:
–
parathyroid hormone (PTH)
–
25-hydroxy vitamin D (25-OH VitD)
DXA scan of spine and hip (data of other regions, e.g. femoral neck may also be analyzed if available):
–
BMD values
–
BMD T-scores
The BMD status will be derived based on T-scores using the following categories:


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
27
Approved, Date: 25 April 2018
Osteoporosis
Osteopenia
Normal
T-score
< -2.5
-2.5 to < -1
≥-1
5.4.2.
Analysis methods
Bone Biomarker:
Descriptive statistics for the actual values, change and percent changes from reference per time point will 
be presented for each bone biomarkers.
DXA scan:
Descriptive statistics for the actual values, change and percent changes from reference per time point will 
be presented for BMD parameters (including T- and Z-scores). Within-treatment arm comparison versus 
reference at Week 96 will be assessed using paired t-test.
The proportions of subjects with at least 3% change (decrease and increase separately) from reference in 
BMD will be presented at Week 96. Percent change from reference will also be tabulated based on 
thresholds; 5% and 7% (hip only).
BMD status will be tabulated (n, %) separately per time point, based on the T-score categories. Cross-
tabulations for the BMD status at Week 96 versus reference will be produced.


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
28
Approved, Date: 25 April 2018
REFERENCES
1.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.
2.
Guidance for Industry. Antiretroviral Drugs Using Plasma HIV RNA Measurements Clinical Considerations 
for Accelerated and Traditional Approval. October 2002.
3.
Wensing AM, Calvez V, Günthard HF, et al. 2017 update of the drug resistance mutations in HIV-1. Top 
Antivir Med Dec2016/Jan2017; 24(4):132-141


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
29
Approved, Date: 25 April 2018
ATTACHMENTS
ATTACHMENT 1
PREDEFINED MAJOR PROTOCOL DEVIATIONS-based on the current list 
The predefined major protocol deviations of this study are described in the Protocol Deviation Criteria 
document. The deviations that are considered to have an (possible) impact on efficacy are a subset of the 
predefined major protocol deviations and are indicated with ‘Yes’ below (column ‘Exclude from Per 
Protocol Analysis’) and if such deviations are reported for a subject, the subject will be excluded from the 
PP analysis.
In addition to the below table, the following subjects will also be excluded from the per-protocol analysis 
set:

Subjects with treatment adherence based on drug accountability derivation ii for the active ARVs 
(worst D/C/F/TAF adherence between baseline to switch and switch to Week 96 for the Initial 
D/C/F/TAF treatment group and worst adherence across DRV/COBI FTC/TDF, and D/C/F/TAF
for the Late Switch to D/C/F/TAF treatment group) <65%.  For the purpose of the per-protocol 
analysis set only, subjects with missing treatment adherence will be assumed to be above 65%.

Subjects with no post-baseline viral load measurement (e.g., discontinued within 2 weeks).


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
30
Approved, Date: 25 April 2018
Sequence 
No.
Description
Protocol Deviation coded term 
(DVDECOD)
Exclude from 
PP
1
Screening plasma HIV-1 RNA level < 1,000 copies/mL
Entered but did not satisfy 
criteria
Yes
2
The subject uses disallowed concomitant therapy specified in the protocol.
Entered but did not satisfy 
criteria
Yes
3
The subject has any known allergies to the excipients of the D/C/F/TAF, or 
DRV/COBI, or TDF/FTC tablets, but the subject was randomized
Entered but did not satisfy 
criteria
Yes
4
The dose of Investigational treatment arm (D/C/F/TAF tablet) or the active 
control arm was temporarily not according to protocol for more than 4 
consecutive weeks.
Received wrong treatment or 
incorrect dose (missed dose or 
extra dose) 
Based on >4 
weeks period. 
In that case 
classified as 
major and 
excluded from 
PP
5
The intake of Investigational treatment arm (D/C/F/TAF tablet) or the active 
control arm was interrupted for toxicity reasons for more than 4 consecutive 
weeks.
Received wrong treatment or 
incorrect dose (missed dose or 
extra dose) 
6
The intake of Investigational treatment arm (D/C/F/TAF tablet) or the active 
control arm was interrupted for non - toxicity reasons for more than 4 
consecutive weeks, or cumulatively for more than 8 weeks.
Received wrong treatment or 
incorrect dose (missed dose or 
extra dose 
7
The subject takes disallowed medication as defined per protocol.
Received a disallowed 
concomitant treatment 
Yes 
(adjudication 
based on 
drug/class and 
duration).
8
Subjects not showing genotypic susceptibility to DRV, FTC, TFV
Entered but did not satisfy 
criteria
Yes
9
The subject missed two or more consecutive planned visits in the trial
Other 
Yes


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
31
Approved, Date: 25 April 2018
Sequence 
No.
Description
Protocol Deviation coded term 
(DVDECOD)
Exclude from 
PP
10
Misallocation of Medkits was observed during Dosage and administration of 
study drug and subject treated differently than what they were randomized to 
for more than 4 weeks
Other 
Yes
11
After achieving confirmed (consecutive) HIV-1 RNA <50 copies/mL prior to 
Week 96 and scheduled Week 96 achieving HIV-1 RNA ≥ 50 copies/mL or 
>1log10 increase in HIV-1 RNA from the nadir at scheduled Week 96, but no 
retest in Week 96 window (90-102 weeks)
Other
Yes
12
Subject missed the Week 96 visit.
Other
Yes 


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
32
Approved, Date: 25 April 2018
ATTACHMENT 2  
Adverse Events of Interest: List of Preferred Terms
AEOI
AEDECOD (MedDRA v19.1)
Rash AEOI
Acrodynia, Drug Eruption, Generalised erythema, Lupus miliaris disseminatus 
facei, Mucocutaneous rash, Rash, Rash erythematous, Rash generalised, Rash 
macular, Rash maculo-papular, Rash maculovesicular, Rash morbilliform, 
Rash papular, Rash pruritic, Rash rubelliform, Rash scarlatiniform, Red man 
syndrome, Rash vesicular, Rash follicular, Rash papulosquamous, Dermatitis, 
Dermatitis acneiform, Dermatitis allergic , Dermatitis herpetiformis , Skin 
necrosis, Skin reaction
Liver AEOI/Cholestasis and jaundice of 
hepatic origin
Bilirubin excretion disorder, Cholaemia, Cholestasis, Cholestatic liver injury, 
Cholestatic pruritus, Drug-induced liver injury, Hepatitis cholestatic, 
Hyperbilirubinaemia, Icterus index increased, Jaundice, Jaundice cholestatic, 
Jaundice hepatocellular, Mixed liver injury, Ocular icterus, Parenteral 
nutrition associated liver disease, Deficiency of bile secretion, Yellow skin


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
33
Approved, Date: 25 April 2018
AEOI
AEDECOD (MedDRA v19.1)
Liver AEOI/Hepatic failure, fibrosis and 
cirrhosis and other liver damage
related conditions
Acute hepatic failure, Acute on chronic liver failure, Acute yellow liver 
atrophy, Ascites, Asterixis, Bacterascites, Biliary cirrhosis, Biliary cirrhosis 
primary, Biliary fibrosis, Cholestatic liver injury, Chronic hepatic failure, Coma 
hepatic, Cryptogenic cirrhosis, Diabetic hepatopathy, Drug-induced liver 
injury, Duodenal varices, Gallbladder varices, Gastric variceal injection, 
Gastric variceal ligation, Gastric varices, Gastric varices haemorrhage, 
Hepatectomy, Hepatic atrophy, Hepatic calcification, Hepatic cirrhosis, 
Hepatic encephalopathy, Hepatic encephalopathy prophylaxis, Hepatic 
failure, Hepatic fibrosis, Hepatic hydrothorax, Hepatic infiltration 
eosinophilic, Hepatic lesion, Hepatic necrosis, Hepatic steato-fibrosis, Hepatic 
steatosis, Hepatitis fulminant, Hepatobiliary disease, Hepatocellular foamy 
cell syndrome, Hepatocellular injury, Hepatopulmonary syndrome, 
Hepatorenal failure, Hepatorenal syndrome, Hepatotoxicity, Intestinal 
varices, Liver and small intestine transplant, Liver and small intestine 
transplant, Liver dialysis, Liver disorder, Liver injury, Liver operation, Liver 
transplant, Lupoid hepatic cirrhosis, Minimal hepatic encephalopathy, Mixed 
liver injury, Nodular regenerative hyperplasia, Non-alcoholic fatty liver, Non-
alcoholic steatohepatitis, Non-cirrhotic portal hypertension, Oedema due to 
hepatic disease, Oesophageal varices haemorrhage, Peripancreatic varices, 
Portal fibrosis,  Portal hypertensive enteropathy, Portal hypertensive 
gastropathy, Portal vein cavernous transformation, Portal vein dilatation, 
Portopulmonary hypertension, Renal and liver transplant, Retrograde portal 
vein flow, Reye's syndrome, Reynold's syndrome, Splenic varices, Splenic 
varices haemorrhage, Steatohepatitis, Subacute hepatic failure, Varices 
oesophageal, Varicose veins of abdominal wall, Anorectal varices, Anorectal 
varices haemorrhage, Intrahepatic portal hepatic venous fistula, 
Peritoneovenous shunt, Portal shunt, Portal shunt procedure, Small-for-size 
liver syndrome, Spider naevus, Splenorenal shunt, Splenorenal shunt 
procedure, Spontaneous intrahepatic portosystemic venous shunt, Stomal 
varices, Portal tract inflammation  


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
34
Approved, Date: 25 April 2018
Liver AEOI / Liver-related 
investigations, signs and symptoms
Alanine aminotransferase abnormal, Alanine aminotransferase increased, 
Ammonia abnormal, Ammonia increased, Ascites, Aspartate 
aminotransferase abnormal, Aspartate aminotransferase increased, 
Bacterascites, Bile output abnormal, Bile output decreased, Biliary ascites, 
Bilirubin conjugated abnormal, Bilirubin conjugated increased, Bilirubin urine 
present, Biopsy liver abnormal, Blood bilirubin abnormal, Blood bilirubin 
increased, Blood bilirubin unconjugated increased, Bromosulphthalein test 
abnormal, Child-Pugh-Turcotte score abnormal, Child-Pugh-Turcotte score 
increased, Computerised tomogram liver, Foetor hepaticus, Galactose 
elimination capacity test abnormal, Galactose elimination capacity test 
decreased, Gamma-glutamyltransferase abnormal, Gamma-
glutamyltransferase increased, Guanase increased, Hepaplastin abnormal, 
Hepaplastin decreased, Hepatic artery flow decreased, Hepatic congestion, 
Hepatic enzyme abnormal, Hepatic enzyme decreased, Hepatic enzyme 
increased, Hepatic function abnormal, Hepatic hydrothorax, Hepatic 
hypertrophy, Hepatic mass, Hepatic pain, Hepatic sequestration, Hepatic 
vascular resistance increased, Hepatobiliary scan abnormal, Hepatomegaly, 
Hepatosplenomegaly, Hyperammonaemia, Hyperbilirubinaemia, Hypercholia, 
Hypertransaminasaemia, Kayser-Fleischer ring, Liver function test abnormal, 
Liver induration, Liver palpable, Liver scan abnormal, Liver tenderness, 
Mitochondrial aspartate aminotransferase increased, Molar ratio of total 
branched-chain amino acid to tyrosine, Oedema due to hepatic disease, 
Perihepatic discomfort, Retrograde portal vein flow, Total bile acids 
increased, Transaminases abnormal, Transaminases increased, Ultrasound 
liver abnormal, Urine bilirubin increased, X-ray hepatobiliary abnormal, 
5'nucleotidase increased, Blood alkaline phosphatase abnormal, Blood 
alkaline phosphatase increased, Blood cholinesterase abnormal, Blood 
cholinesterase decreased, Deficiency of bile secretion, Glutamate 
dehydrogenase increased, Haemorrhagic ascites, Hepatic fibrosis marker 
abnormal, Hepatic fibrosis marker increased, Hypoalbuminaemia, Leucine
aminopeptidase increased, Liver function test decreased, Liver function test 
increased, Liver iron concentration abnormal, Liver iron concentration 
increased, Model for end stage liver disease score abnormal, Model for end 
stage liver disease score increased, Periportal oedema, Peritoneal fluid 
protein abnormal, Peritoneal fluid protein decreased, Peritoneal fluid protein 
increased, Pneumobilia, Portal vein flow decreased, Portal vein pressure 
increased, Retinol binding protein decreased, Urobilinogen urine decreased, 
Urobilinogen urine increased


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
35
Approved, Date: 25 April 2018
AEOI
AEDECOD (MedDRA v19.1)
Liver AEOI / Hepatitis, non infectious
Acute graft versus host disease in liver, Allergic hepatitis, Autoimmune 
hepatitis, Chronic graft versus host disease in liver, Chronic hepatitis, Graft 
versus host disease in liver, Hepatitis, Hepatitis acute, Hepatitis cholestatic, 
Hepatitis chronic active, Hepatitis chronic persistent, Hepatitis fulminant, 
Hepatitis toxic, Ischaemic hepatitis, Lupus hepatitis, Non-alcoholic 
steatohepatitis, Radiation hepatitis, Steatohepatitis, Granulomatous liver 
disease, Liver sarcoidosis, Portal tract inflammation
Hyperglycaemia AEOI
Acquired lipoatrophic diabetes, Blood 1,5-anhydroglucitol decreased, Blood 
glucose increased, Diabetes complicating pregnancy, Diabetes mellitus, 
Diabetes mellitus inadequate control, Diabetes with hyperosmolarity, 
Diabetic arteritis, Diabetic coma, Diabetic hepatopathy, Diabetic 
hyperglycaemic coma, Diabetic hyperosmolar coma, Diabetic ketoacidosis, 
Diabetic ketoacidotic hyperglycaemic coma, Diabetic metabolic 
decompensation, Fructosamine increased, Fulminant type 1 diabetes 
mellitus, Gestational diabetes, Glucose tolerance impaired, Glucose tolerance 
impaired in pregnancy, Glucose urine present, Glycosuria, Glycosuria during 
pregnancy, Glycosylated haemoglobin increased, Hyperglycaemia, 
Hyperglycaemic seizure, Hyperglycaemic unconsciousness, Impaired fasting 
glucose, Insulin resistance, Insulin resistance syndrome, Insulin resistant 
diabetes, Insulin-requiring type 2 diabetes mellitus, Ketoacidosis, Ketonuria, 
Ketosis, Latent autoimmune diabetes in adults, Metabolic syndrome, 
Monogenic diabetes, Neonatal diabetes mellitus, Pancreatogenous diabetes, 
Type 1 diabetes mellitus, Type 2 diabetes mellitus, Type 3 diabetes mellitus, 
Urine ketone body present, Hyperosmolar hyperglycaemic state


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
36
Approved, Date: 25 April 2018
AEOI
AEDECOD (MedDRA v19.1)
Dyslipidaemia AEOI
Acquired lipoatrophic diabetes, Acquired mixed hyperlipidaemia, 
Apolipoprotein B/Apolipoprotein A-1 ratio increased, Autoimmune 
hyperlipidaemia, Blood cholesterol abnormal, Blood cholesterol decreased, 
Blood cholesterol esterase increased, Blood cholesterol increased, Blood 
triglycerides abnormal, Blood triglycerides decreased, Blood triglycerides 
increased, Diabetic dyslipidaemia, Dyslipidaemia, Familial 
hypertriglyceridaemia, Fat overload syndrome, High density lipoprotein 
abnormal, High density lipoprotein decreased, High density lipoprotein 
increased, Hypercholesterolaemia, Hyperlipidaemia, Hypertriglyceridaemia, 
Hypo HDL cholesterolaemia, Hypotriglyceridaemia, Intermediate density 
lipoprotein decreased, Intermediate density lipoprotein increased, LDL/HDL 
ratio decreased, LDL/HDL ratio increased, Lecithin-cholesterol acyltransferase 
deficiency, Lipid metabolism disorder, Lipids abnormal, Lipids decreased, 
Lipids increased, Lipoprotein (a) abnormal, Lipoprotein (a) decreased, 
Lipoprotein (a) increased, Low density lipoprotein abnormal, Low density 
lipoprotein decreased, Low density lipoprotein increased, Non-high-density 
lipoprotein cholesterol decreased, Non-high-density lipoprotein cholesterol 
increased, Primary hypercholesterolaemia, Remnant hyperlipidaemia, 
Remnant-like lipoprotein particles increased, Total cholesterol/HDL ratio 
abnormal, Total cholesterol/HDL ratio decreased, Total cholesterol/HDL ratio 
increased, Type I hyperlipidaemia, Type II hyperlipidaemia, Type IIa 
hyperlipidaemia, Type IIb hyperlipidaemia, Type III hyperlipidaemia, Type IV 
hyperlipidaemia, Type V hyperlipidaemia, Very low density lipoprotein 
abnormal, Very low density lipoprotein decreased, Very low density 
lipoprotein increased
Lipodystrophy AEOI
Body fat disorder, Facial wasting, Fat redistribution, Fat tissue decreased, HIV 
lipodystrophy, Lipoatrophy, Lipodystrophy acquired, Lipohypertrophy, Partial 
lipodystrophy


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
37
Approved, Date: 25 April 2018
AEOI
AEDECOD (MedDRA v19.1)
Immune reconstitution inflammatory 
AEOI
Immune reconstitution inflammatory syndrome, Mycobacterium avium 
complex immune restoration disease, Immune Reconstitution Inflammatory 
Syndrome associated tuberculosis, Immune Reconstitution Inflammatory 
Syndrome associated Kaposi’s sarcoma,


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
38
Approved, Date: 25 April 2018
Coronary artery AEOI
Acute coronary syndrome, Acute myocardial infarction, Angina unstable, 
Blood creatine phosphokinase MB abnormal, Blood creatine phosphokinase 
MB increased, Coronary artery embolism, Coronary artery occlusion, 
Coronary artery reocclusion, Coronary artery thrombosis, Coronary bypass 
thrombosis, Coronary vascular graft occlusion, Kounis syndrome, Myocardial 
infarction, Myocardial necrosis, Myocardial reperfusion injury, Myocardial 
stunning, Papillary muscle infarction, Post procedural myocardial infarction, 
Postinfarction angina, Silent myocardial infarction, Troponin I increased, 
Troponin increased, Troponin T increased, Blood creatine phosphokinase 
abnormal, Blood creatine phosphokinase increased, Cardiac ventricular 
scarring, ECG electrically inactive area, ECG signs of myocardial infarction, 
Electrocardiogram Q wave abnormal, Electrocardiogram ST segment 
abnormal, Electrocardiogram ST segment elevation, Electrocardiogram ST-T 
segment elevation, Infarction, Myocardial necrosis marker increased, Scan 
myocardial perfusion abnormal, Vascular graft occlusion, Vascular stent 
occlusion, Vascular stent thrombosis, Angina pectoris, Angina unstable, 
Anginal equivalent, Arteriosclerosis coronary artery, Arteriospasm coronary, 
Coronary angioplasty, Coronary arterial stent insertion, Coronary artery 
bypass, Coronary artery disease, Coronary artery dissection, Coronary artery 
insufficiency, Coronary artery restenosis, Coronary artery stenosis, Coronary 
brachytherapy, Coronary bypass stenosis, Coronary endarterectomy, 
Coronary no-reflow phenomenon, Coronary ostial stenosis, Coronary 
revascularisation, Coronary vascular graft stenosis, Dissecting coronary artery 
aneurysm, ECG signs of myocardial ischaemia, External counterpulsation, 
Haemorrhage coronary artery, Ischaemic cardiomyopathy, Ischaemic mitral 
regurgitation, Microvascular coronary artery disease, Myocardial ischaemia, 
Percutaneous coronary intervention, Prinzmetal angina, Stress 
cardiomyopathy, Subclavian coronary steal syndrome, Subendocardial 
ischaemia, Arteriogram coronary abnormal, Cardiac stress test abnormal, 
Computerised tomogram coronary artery abnormal, Computerised 
tomogram coronary artery abnormal, Electrocardiogram ST segment 
depression, Electrocardiogram ST-T segment abnormal, Electrocardiogram 
ST-T segment depression, Electrocardiogram T wave abnormal, 
Electrocardiogram T wave inversion, Exercise electrocardiogram abnormal, 
Exercise test abnormal, Post angioplasty restenosis, Stress echocardiogram 
abnormal, Vascular stent restenosis, Vascular stent stenosis


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
39
Approved, Date: 25 April 2018
AEOI
AEDECOD (MedDRA v19.1)
Severe skin AEOI
Acute generalised exanthematous pustulosis, Cutaneous vasculitis, 
Dermatitis bullous, Dermatitis exfoliative, Dermatitis exfoliative generalised, 
Drug rash with eosinophilia and systemic symptoms, Epidermal necrosis, 
Erythema multiforme, Exfoliative rash, Oculomucocutaneous syndrome, Skin 
necrosis, Stevens-Johnson syndrome, Toxic epidermal necrolysis, Toxic skin 
eruption, Acquired epidermolysis bullosa, Blister, Blister rupture, Bullous 
impetigo, Conjunctivitis, Corneal exfoliation, Drug eruption, Epidermolysis, 
Epidermolysis bullosa, Fixed drug eruption, Genital ulceration, HLA-B*1502 
assay positive, HLA-B*5801 assay positive, Hypopharyngeal synechiae, Lip 
exfoliation, Mouth ulceration, Mucocutaneous ulceration, Mucosa vesicle, 
Mucosal erosion, Mucosal exfoliation, Mucosal necrosis, Mucosal ulceration, 
Nikolsky's sign, Noninfective conjunctivitis, Oral mucosal blistering, Oral 
mucosal exfoliation, Oral papule, Oropharyngeal blistering, Pemphigoid, 
Pemphigus, Penile exfoliation, Skin erosion, Skin exfoliation, Staphylococcal 
scalded skin syndrome, Stomatitis, Tongue exfoliation, Vaginal exfoliation, 
Vaginal ulceration, Vulval ulceration, Vulvovaginal rash, Vulvovaginal 
ulceration
Cardiac conduction AEOI/Conduction 
defects 
Accessory cardiac pathway, Adams-Stokes syndrome, Agonal rhythm, Atrial 
conduction time prolongation, Atrioventricular block, Atrioventricular block 
complete, Atrioventricular block first degree, Atrioventricular block second 
degree, Atrioventricular conduction time shortened, Atrioventricular 
dissociation, Bifascicular block, Brugada syndrome, Bundle branch block, 
Bundle branch block bilateral, Bundle branch block left, Bundle branch block 
right, Conduction disorder, Defect conduction intraventricular, 
Electrocardiogram delta waves abnormal, Electrocardiogram PQ interval 
prolonged, Electrocardiogram PQ interval prolonged, Electrocardiogram PR 
prolongation, Electrocardiogram PR shortened, Electrocardiogram QRS 
complex prolonged, Electrocardiogram QT prolonged, Electrocardiogram 
repolarisation abnormality, Lenegre's disease, Long QT syndrome, 
Paroxysmal atrioventricular block, Sinoatrial block, Trifascicular block, 
Ventricular dyssynchrony, Wolff-Parkinson-White syndrome


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
40
Approved, Date: 25 April 2018
AEOI
AEDECOD (MedDRA v19.1)
Cardiac conduction AEOI / Torsade de 
pointes/QT prolongation
Electrocardiogram QT interval abnormal, Electrocardiogram QT prolonged, 
Long QT syndrome, Long QT syndrome congenital, Torsade de pointes, 
Ventricular tachycardia
Pancreas AEOI
Amylase abnormal, Hyperlipasaemia, Pancreatic enzymes abnormality, 
Amylase increased, Lipase abnormal, Pancreatic enzymes abnormal, Blood 
trypsin increased, Lipase increased, Pancreatic enzymes increased, 
Hyperamylasaemia, Lipase urine increased, Cullen's sign, Grey Turner's sign, 
Haemorrhagic necrotic pancreatitis, Hereditary pancreatitis, Ischaemic 
pancreatitis, Oedematous pancreatitis, Pancreatic abscess, Pancreatic 
haemorrhage, Pancreatic necrosis, Pancreatic phlegmon, Pancreatic 
pseudocyst, Pancreatic pseudocyst drainage, Pancreatitis, Pancreatitis acute, 
Pancreatitis haemorrhagic, Pancreatitis necrotising, Pancreatitis relapsing, 
Pancreatorenal syndrome


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
41
Approved, Date: 25 April 2018
AEOI
AEDECOD (MedDRA v19.1)
Convulsions AEOI
Acquired epileptic aphasia, Acute encephalitis with refractory, repetitive 
partial seizures, Alcoholic seizure, Atonic seizures, Atypical benign partial 
epilepsy, Automatism epileptic, Autonomic seizure, Baltic myoclonic epilepsy, 
Benign familial neonatal convulsions, Benign rolandic epilepsy, Biotinidase 
deficiency, Change in seizure presentation, Clonic convulsion, Complex 
partial seizures, Convulsion in childhood, Convulsion neonatal, Convulsions 
local, Convulsive threshold lowered, Deja vu, Double cortex syndrome, 
Dreamy state, Drug withdrawal convulsions, Early infantile epileptic 
encephalopathy with burst-suppression, Eclampsia, Epilepsy, Epileptic aura, 
Epileptic psychosis, Febrile convulsion, Frontal lobe epilepsy, Generalised 
non-convulsive epilepsy, Generalised tonic-clonic seizure, Glucose 
transporter type 1 deficiency syndrome, Hemimegalencephaly, 
Hyperglycaemic seizure, Hypocalcaemic seizure, Hypoglycaemic seizure, 
Hyponatraemic seizure, Idiopathic generalised epilepsy, Infantile spasms, 
Juvenile myoclonic epilepsy, Lafora's myoclonic epilepsy, Lennox-Gastaut 
syndrome, Migraine-triggered seizure, Molybdenum cofactor deficiency, 
Myoclonic epilepsy, Myoclonic epilepsy and ragged-red fibres, Partial 
seizures, Partial seizures with secondary generalisation, Petit mal epilepsy, 
Polymicrogyria, Post stroke epilepsy, Post stroke seizure, Postictal headache, 
Postictal paralysis, Postictal psychosis, Postictal state, Post-traumatic 
epilepsy, Psychomotor seizures, Focal dyscognitive seizures, Schizencephaly,
Seizure, Seizure anoxic, Seizure cluster, Seizure like phenomena, Severe 
myoclonic epilepsy of infancy, Simple partial seizures, Status epilepticus, 
Sudden unexplained death in epilepsy, Temporal lobe epilepsy, Tonic clonic 
movements, Tonic convulsion, Tonic posturing, Topectomy, Uncinate fits


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
42
Approved, Date: 25 April 2018
AEOI
AEDECOD (MedDRA v19.1)
Ocular AEOI (for Posterior Uveitis)
Acute zonal occult outer retinopathy, Anterior chamber cell, Anterior 
chamber fibrin, Anterior chamber flare, Anterior chamber inflammation, 
Aqueous fibrin, Autoimmune retinopathy, Autoimmune uveitis, Behcet's 
syndrome, Birdshot chorioretinopathy, Blau syndrome, Blindness, Blindness 
transient, Blindness unilateral, Chemical iritis, Chorioretinitis, 
Chorioretinopathy, Choroiditis, Ciliary hyperaemia, Cystoid macular oedema, 
Cytomegalovirus chorioretinitis, Eales' disease, Endophthalmitis, 
Exudative retinopathy, Eye inflammation, Fuchs' syndrome, 
Glaucomatocyclitic crises, Iridocyclitis, Iritis, Macular oedema, Non-infectious 
endophthalmitis, Noninfective chorioretinitis, Noninfective retinitis, Ocular 
toxicity, Ocular vasculitis, Optic discs blurred, Panophthalmitis, Photophobia, 
Photopsia, Retinal exudates, Retinal oedema, Retinal pigment epitheliopathy, 
Retinal toxicity, Retinal perivascular sheathing, Retinal vasculitis, Retinitis,
Subretinal fluid, Sudden visual loss, Susac's syndrome, Sympathetic 
ophthalmia, Traumatic iritis, Tubulointerstitial nephritis and uveitis 
syndrome, Uveitis, Uveitis-glaucoma-hyphaema syndrome, Vision blurred, 
Visual acuity reduced, Visual field defect, Visual impairment, Vitreal cells, 
Vitreous floaters, Vitreous opacities, Vitritis, Vogt-Koyanagi-Harada 
syndrome
Renal AEOI (for PRT) / laboratory 
related events
Aminoaciduria, Beta-N-acetyl D glucosaminidase increased, 
Hyperphosphaturia, Renal glycosuria, Acquired aminoaciduria,
Hyperchloraemia  , Protein urine, Protein urine present, Proteinuria, Urine 
phosphorus abnormal, Beta-N-acetyl D glucosaminidase abnormal, Blood 
chloride increased, Blood phosphorus decreased, Blood potassium 
decreased, Blood uric acid abnormal, Blood uric acid decreased, Glucose 
urine present, Glycosuria, Hyperuricosuria, Hypokalaemia, 
Hypophosphataemia, Amino acid level abnormal, Amino acid level increased, 
Urine phosphorus increased, Urine uric acid abnormal, Urine uric acid 
increased
Renal AEOI (for PRT) / clinical events
Polydipsia, Polyuria, Nephropathy toxic, Renal tubular disorder, Chronic 
kidney disease, Fanconi syndrome, Fanconi syndrome acquired, Renal 
tubular acidosis


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
43
Approved, Date: 25 April 2018
AEOI
AEDECOD (MedDRA v19.1)
Bone AEOI (for fractures) /
Osteomalacia
Hypophosphataemic rickets, Osteomalacia, Chronic kidney disease-mineral 
and bone disorder, Renal rickets, Rickets
Bone AEOI (for fractures) / Bone 
Loss/atrophy
Bone atrophy, Bone decalcification, Bone density decreased, Bone formation 
decreased, Bone loss, Craniotabes, High turnover osteopathy, Hungry bone 
syndrome, Osteodystrophy, Osteolysis, Osteoporosis circumscripta cranii, 
Osteopenia, Senile osteoporosis , Osteoporosis, Cementoplasty
Bone AEOI (for fractures) / Fracture, 
possibly osteoporotic
Femoral neck fracture, Hip fracture, Lumbar vertebral fracture, Osteoporotic 
fracture, Spinal compression fracture, Spinal fracture, Thoracic vertebral 
fracture
Bone AEOI (for fractures) / Fracture 
other
Acetabulum fracture, Ankle fracture, Atypical femur fracture, Atypical 
fracture, Avulsion fracture, Cervical vertebral fracture, Chance fracture, 
Clavicle fracture, Closed fracture manipulation, Comminuted fracture, 
Complicated fracture, Compression fracture, Elevation skull fracture, 
Epiphyseal fracture, External fixation of fracture, Femur fracture, Fibula 
fracture, Foot fracture, Forearm fracture, Fracture, Fracture delayed union, 
Fracture displacement, Fracture malunion, Fracture nonunion, Fracture pain, 
Fracture reduction, Fracture treatment, Fractured ischium, Fractured sacrum, 
Fractured coccyx, Greenstick fracture, Hand fracture, Humerus fracture, Ilium 
fracture, Internal fixation of fracture, Limb fracture, Lower limb fracture, 
Multiple fractures, Open reduction of fracture, Open reduction of spinal 
fracture, Osteochondral fracture, Osteosynthesis, Patella fracture, 
Pathological fracture, Pelvic fracture, Periprosthetic fracture, Pubis fracture, 
Radius fracture, Rib fracture, Sacroiliac fracture, Scapula fracture, Skull 
fracture, Skull fractured base, Spinal fusion fracture, Sternal fracture, Stress 
fracture, Tibia fracture, Torus fracture, Traumatic fracture, Ulna fracture, 
Upper limb fracture, Wrist fracture


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
44
Approved, Date: 25 April 2018
AEOI
AEDECOD (MedDRA v19.1)
Bone AEOI (for fractures) / Other Bone 
Events
Bone density abnormal,  Bone disorder,  Bone erosion,  Bone lesion,  Bone 
formation test abnormal,  Bone fragmentation,  Bone metabolism disorder,  
Bone pain,  Bone resorption test abnormal,  Bone scan abnormal,  
Bone development abnormal,  Bone swelling,  Epiphysiolysis,  Nuclear 
magnetic resonance imaging spinal abnormal,  Osteonecrosis,  Osteonecrosis 
of jaw,  Secondary sequestrum,  Skeletal injury,  Skeletal survey abnormal,  
Skull X-ray abnormal,  Spinal X-ray abnormal,  Vertebral lesion,  Vertebral 
wedging,  X-ray limb abnormal,  X-ray of pelvis and hip abnormal,  Bone 
densitometry


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
45
Approved, Date: 25 April 2018
ATTACHMENT 3
AE preferred terms (as available in AE Clinical database) are assigned an Adverse Drug Reaction System Organ Class (ADRSOC) and Adverse Drug 
Reaction (ADRCAT) according to the table below.
Adverse Drug Reaction 
System Organ Class
Adverse Drug Reaction
Adverse Event Preferred Term
GASTROINTESTINAL 
DISORDERS
ABDOMINAL DISTENSION
ABDOMINAL DISTENSION
ABDOMINAL PAIN
ABDOMINAL PAIN
ABDOMINAL PAIN LOWER
ABDOMINAL PAIN UPPER
DIARRHOEA
DIARRHOEA
FREQUENT BOWEL MOVEMENTS
DYSPEPSIA
DYSPEPSIA
FLATULENCE
FLATULENCE
NAUSEA
NAUSEA
PANCREATITIS ACUTE
PANCREATITIS
PANCREATITIS ACUTE
VOMITING
VOMITING
GENERAL DISORDERS 
AND ADMINISTRATION 
SITE CONDITIONS
ASTHENIA
ASTHENIA
FATIGUE
FATIGUE
HEPATOBILIARY 
DISORDERS
ACUTE HEPATITIS
HEPATITIS
HEPATITIS ACUTE
HEPATOTOXICITY
IMMUNE SYSTEM 
DISORDERS
(DRUG) HYPERSENSITIVITY
DRUG HYPERSENSITIVITY
HYPERSENSITIVITY


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
46
Approved, Date: 25 April 2018
Adverse Drug Reaction 
System Organ Class
Adverse Drug Reaction
Adverse Event Preferred Term
IMMUNE RECONSTITUTION 
SYNDROME
IMMUNE RECONSTITUTION INFLAMMATORY 
SYNDROME
IMMUNE RECONSTITUTION SYNDROME
METABOLISM AND 
NUTRITION DISORDERS
ANOREXIA
DECREASED APPETITE
DIABETES MELLITUS
DIABETES MELLITUS
DIABETES MELLITUS INADEQUATE CONTROL
TYPE 2 DIABETES MELLITUS 
GLUCOSE TOLERANCE IMPAIRED
LIPODYSTROPHY
FACIAL WASTING
FAT REDISTRIBUTION
FAT TISSUE INCREASED
LIPOATROPHY
LIPODYSTROPHY ACQUIRED
LIPOHYPERTROPHY
PARTIAL LIPODYSTROPHY
MUSCULOSKELETAL AND 
CONNECTIVE TISSUE 
DISORDERS
MYALGIA
MYALGIA
OSTEONECROSIS
OSTEONECROSIS
NERVOUS SYSTEM 
DISORDERS
HEADACHE
HEADACHE
PSYCHIATRIC 
DISORDERS
ABNORMAL DREAMS
ABNORMAL DREAMS
REPRODUCTIVE SYSTEM 
AND BREAST DISORDERS
GYNAECOMASTIA
GYNAECOMASTIA
HYPERTROPHY BREAST
SKIN AND 
SUBCUTANEOUS TISSUE 
DISORDERS
ANGIOEDEMA
ALLERGIC OEDEMA
ANGIOEDEMA


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
47
Approved, Date: 25 April 2018
Adverse Drug Reaction 
System Organ Class
Adverse Drug Reaction
Adverse Event Preferred Term
CIRCUMORAL OEDEMA
CONJUNCTIVAL OEDEMA
CORNEAL OEDEMA
EPIGLOTTIC OEDEMA
EYE OEDEMA
EYE SWELLING
EYELID OEDEMA
FACE OEDEMA
GINGIVAL OEDEMA
GINGIVAL SWELLING
GLEICH'S SYNDROME
HEREDITARY ANGIOEDEMA
LARYNGEAL OEDEMA
LARYNGOTRACHEAL OEDEMA
LIP OEDEMA
LIP SWELLING
OCULORESPIRATORY SYNDROME
OEDEMA MOUTH
OROPHARYNGEAL SWELLING
PALATAL OEDEMA
PERIORBITAL OEDEMA
PHARYNGEAL OEDEMA
SCLERAL OEDEMA
SMALL BOWEL ANGIOEDEMA
SWELLING FACE
SWOLLEN TONGUE


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
48
Approved, Date: 25 April 2018
Adverse Drug Reaction 
System Organ Class
Adverse Drug Reaction
Adverse Event Preferred Term
TONGUE OEDEMA
TRACHEAL OEDEMA
PRURITUS
PRURIGO
PRURITUS
PRURITUS GENERALISED
RASH
GENERALISED ERYTHEMA
RASH
RASH ERYTHEMATOUS
RASH GENERALISED
RASH MACULAR
RASH MACULO-PAPULAR
RASH MORBILLIFORM
RASH PAPULAR
RASH PRURITIC
STEVENS-JOHNSON SYNDROME
STEVENS-JOHNSON SYNDROME
TOXIC EPIDERMAL NECROLYSIS
TOXIC EPIDERMAL NECROLYSIS
URTICARIA
URTICARIA
URTICARIA CHRONIC
URTICARIA PAPULAR
URTICARIA CHOLINERGIC
IDIOPATHIC URTICARIA
Acute generalized exanthematous
pustulosis
Acute generalized exanthematous
pustulosis
Drug reaction with eosinophilia and
systemic symptoms
Drug reaction with eosinophilia and
systemic symptoms


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
49
Approved, Date: 25 April 2018
ATTACHMENT 4
List of AE Preferred Terms (MedDRAv 19.1) for Vital Signs Blood Pressure and Heart Rate
-
Blood pressure abnormal
-
Blood pressure decreased
-
Blood pressure abnormal
-
Blood pressure diastolic abnormal
-
Blood pressure diastolic decreased
-
Blood pressure diastolic increased
-
Blood pressure increased
-
Blood pressure systolic abnormal
-
Blood pressure systolic decreased
-
Blood pressure systolic increased
-
Blood pressure abnormal
-
Labile blood pressure
-
Accelerated hypertension
-
Diastolic hypertension
-
Essential hypertension
-
Labile hypertension
-
Malignant hypertension
-
Systolic hypertension
-
Diastolic hypotension
-
Hypotension
-
Heart rate abnormal
-
Heart rate decreased
-
Heart rate increased
-
Heart rate irregular
-
Bradycardia
-
Tachycardia


D/C/F/TAF (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)    
Statistical Analysis Plan TMC114FD2HTX3001
50
Approved, Date: 25 April 2018
ATTACHMENT 5
Comment fields and other reason for discontinuation specification identified as efficacy related.
Comment (COVAL)
Other Reason for Discontinuation Specification (DSTERM)
SUBJECT HAS FAILED TO REACH VL <40 BY WEEK 36 OF 
STUDY. PI & SUB PI WANT HIM TO BE UNDETECTABLE BY 
NOW. DISCUSSED AT MDT - DECISION MADE TO CHANGE ARV 
THERAPY - THIS MEANS WE MUST WITHDRAW SUBJECT
VIROLOGICAL FAILURE AND DEVELOPMENT OF RESISTANCE 
TO STUDY DRUG. PER PI DISCRETION, SUBJECT WITHDRAWN 
FROM STUDY.
WE AGREE THE SUBJECT DID NOT MEET PROTOCOL-DEFINED 
CRITERIA FOR VIROLOGICAL FAILURE; I WAS NOT 
CONVINCED THE REGIMEN HE WAS TAKING WAS THE 
OPTIMAL FIRST-LINE REGIMEN IN HIS PARTICULAR CASE.
WE AGREE THE SUBJECT DID NOT MEET PROTOCOL-DEFINED 
CRITERIA FOR VIROLOGIC FAILURE; I WAS NOT CONVINCED 
THE REGIMEN HE WAS TAKING WAS THE OPTIMAL FIRST-
LINE REGIMEN IN HIS PARTICULAR CASE
CONSIDERED PATIENT WITHDRAWN DUE TO LACK OF 
EFFICACY - THE PATIENT WAS COMPLIANT