Conditions: HIV-1
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 109
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy of Darunavir/ Cobicistat/ Emtricitabine/ Tenofovir Alafenamide (D/C/F/TAF) fixed-dose combination (FDC) in a Test and Treat model of care in newly diagnosed human immunodeficiency virus (HIV-1)-infected, treatment-naive participants as determined by the proportion of virologic responders defined as having (HIV)-1 ribonucleic acid (RNA) lesser than 50 copies per milliliter (copies/mL) at Week 48.

Detailed description:

Arms:
arm 1: Participants will receive oral tablet containing Darunavir 800 milligram (mg)/ Cobicistat 150 mg/ Emtricitabine 200 mg/ Tenofovir Alafenamide 10 mg (D/C/F/TAF) fixed-dose combination (FDC) once daily within 24 hours of the screening/baseline visit.

Interventions: intervention 1: DRV 800 mg + COBI 150 mg + FTC 200 mg + TAF 10 mg FDC
Intervention descriptions: intervention 1: Participants will receive oral tablet containing D 800 mg /C 150 mg /F 200 mg /TAF 10 mg FDC once daily within 24 hours of the screening/ baseline visit.

Protocol document:
Prot_000.pdf: 
1
Status: Approved,  Date: 16 November 2017
Janssen Scientific Affairs, LLC
Clinical Protocol
A Phase 3, Single-arm, Open-label Study to Evaluate the Efficacy and Safety of 
Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Once Daily 
Fixed-dose Combination (FDC) Regimen in Newly Diagnosed, Antiretroviral Treatment-
naïve Human Immunodeficiency Virus Type 1 (HIV-1) Infected Subjects Receiving Care in 
a Test and Treat Model of Care
Protocol TMC114FD2HTX3002; Phase 3
Amendment 1
D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir 
alafenamide 10 mg)
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
Status:
Approved  
Date:
16 November 2017
Prepared by: Janssen Scientific Affairs, LLC
EDMS number: EDMS-ERI-137602439, 2.0
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.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
2
Approved, Date: 16 November 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES.......................................................................................................................... 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................... 7
TIME AND EVENTS SCHEDULE .............................................................................................................. 18
ABBREVIATIONS ...................................................................................................................................... 21
1.
INTRODUCTION................................................................................................................................ 24
1.1.
Study Drug ..................................................................................................................................... 24
1.2.
Background .................................................................................................................................... 24
1.2.1.
Darunavir (PREZISTA®) ............................................................................................................. 28
1.2.2.
Cobicistat (Tybost®) .................................................................................................................... 28
1.2.3.
Emtricitabine (Emtriva®).............................................................................................................. 30
1.2.4.
Tenofovir Alafenamide................................................................................................................ 30
1.3.
Overall Rationale for the Study...................................................................................................... 30
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 31
2.1.
Objectives and Endpoints .............................................................................................................. 31
2.1.1.
Objectives ................................................................................................................................... 31
2.1.2.
Endpoints.................................................................................................................................... 32
2.2.
Hypothesis ..................................................................................................................................... 33
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 33
3.1.
Overview of Study Design.............................................................................................................. 33
3.2.
Study Design Rationale.................................................................................................................. 36
4.
SUBJECT POPULATION.................................................................................................................. 38
4.1.
Inclusion Criteria ............................................................................................................................ 38
4.2.
Exclusion Criteria ........................................................................................................................... 40
4.3.
Prohibitions and Restrictions ......................................................................................................... 41
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 41
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 41
7.
TREATMENT COMPLIANCE............................................................................................................ 42
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 42
9.
STUDY EVALUATIONS .................................................................................................................... 44
9.1.
Study Procedures........................................................................................................................... 44
9.1.1.
Overview..................................................................................................................................... 44
9.1.2.
Screening Phase ........................................................................................................................ 45
9.1.3.
Open-Label Treatment Phase .................................................................................................... 45
9.1.3.1.
Main Study Period ................................................................................................................... 45
9.1.3.2.
Extension Period ..................................................................................................................... 46
9.2.
Efficacy Evaluations....................................................................................................................... 46
9.2.1.
Antiviral Efficacy and Immunologic Change ............................................................................... 46
9.2.2.
Resistance Determinations......................................................................................................... 47
9.3.
Pharmacokinetics........................................................................................................................... 47
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
3
Approved, Date: 16 November 2017
9.4.
Medical Resource Utilization and Health Economics .................................................................... 47
9.5.
Adherence...................................................................................................................................... 48
9.6.
Retention in Care ........................................................................................................................... 48
9.7.
Safety Evaluations ......................................................................................................................... 48
9.8.
Toxicity Management..................................................................................................................... 52
9.8.1.
General Guidance for the Management of Clinical Events and Laboratory Abnormalities ........ 52
9.8.2.
Cutaneous Events/Rash............................................................................................................. 53
9.8.3.
Acute Systemic Allergic Reaction............................................................................................... 55
9.8.4.
Potential Renal Toxicity .............................................................................................................. 56
9.8.5.
Potential Posterior Uveitis Cases ............................................................................................... 57
9.8.6.
Hyperglycemia............................................................................................................................ 57
9.8.7.
Hypertriglyceridemia and Hypercholesterolemia........................................................................ 58
9.8.8.
Lipodystrophy/Fat Redistribution/Body Changes ....................................................................... 58
9.9.
Sample Collection and Handling.................................................................................................... 58
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 59
10.1.
Completion ..................................................................................................................................... 59
10.2.
Withdrawal From the Study............................................................................................................ 59
10.3.
Withdrawal From the Use of Research Samples........................................................................... 61
11.
STATISTICAL METHODS................................................................................................................. 61
11.1.
Analysis Sets.................................................................................................................................. 61
11.2.
Subject Information ........................................................................................................................ 61
11.3.
Sample Size Determination ........................................................................................................... 62
11.4.
Efficacy Analyses ........................................................................................................................... 62
11.4.1.
Antiviral Efficacy and Immunologic Change ............................................................................... 62
11.4.2.
Resistance Determinations......................................................................................................... 62
11.5.
Medical Resource Utilization and Health Economics Analyses..................................................... 63
11.6.
Adherence Analyses ...................................................................................................................... 63
11.7.
Retention in Care Analyses ........................................................................................................... 63
11.8.
Safety Analyses ............................................................................................................................. 63
11.9.
Extension Period............................................................................................................................ 64
11.10.
Interim Analysis.............................................................................................................................. 64
12.
ADVERSE EVENT REPORTING ...................................................................................................... 65
12.1.
Definitions ...................................................................................................................................... 65
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 65
12.1.2.
Attribution Definitions.................................................................................................................. 67
12.1.3.
Severity Criteria .......................................................................................................................... 67
12.2.
Special Reporting Situations.......................................................................................................... 68
12.3.
Procedures..................................................................................................................................... 69
12.3.1.
All Adverse Events...................................................................................................................... 69
12.3.2.
Serious Adverse Events ............................................................................................................. 70
12.3.3.
Pregnancy................................................................................................................................... 71
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 71
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 71
13.1.
Procedures..................................................................................................................................... 71
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 72
14.
STUDY DRUG INFORMATION......................................................................................................... 72
14.1.
Physical Description of Study Drug(s) ........................................................................................... 72
14.2.
Packaging ...................................................................................................................................... 72
14.3.
Labeling.......................................................................................................................................... 72
14.4.
Preparation, Handling, and Storage............................................................................................... 72
14.5.
Drug Accountability ........................................................................................................................ 72
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 73
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
4
Approved, Date: 16 November 2017
16.
ETHICAL ASPECTS ......................................................................................................................... 73
16.1.
Study-Specific Design Considerations........................................................................................... 73
16.2.
Regulatory Ethics Compliance....................................................................................................... 74
16.2.1.
Investigator Responsibilities ....................................................................................................... 74
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 74
16.2.3.
Informed Consent ....................................................................................................................... 75
16.2.4.
Privacy of Personal Data ............................................................................................................ 76
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 77
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 77
17.1.
Protocol Amendments.................................................................................................................... 77
17.2.
Regulatory Documentation ............................................................................................................ 77
17.2.1.
Regulatory Approval/Notification ................................................................................................ 77
17.2.2.
Required Prestudy Documentation............................................................................................. 78
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 78
17.4.
Source Documentation................................................................................................................... 79
17.5.
Case Report Form Completion ...................................................................................................... 79
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 80
17.7.
Record Retention ........................................................................................................................... 80
17.8.
Monitoring ...................................................................................................................................... 81
17.9.
Study Completion/Termination....................................................................................................... 81
17.9.1.
Study Completion/End of Study.................................................................................................. 81
17.9.2.
Study Termination....................................................................................................................... 81
17.10.
On-Site Audits ................................................................................................................................ 82
17.11.
Use of Information and Publication................................................................................................ 82
REFERENCES............................................................................................................................................ 84
ATTACHMENTS......................................................................................................................................... 87
INVESTIGATOR AGREEMENT ............................................................................................................... 121
LIST OF ATTACHMENTS
Attachment 1: 
Schema for Follow-up of Subjects who Meet the Criteria for Protocol-Defined 
Virologic Failure ........................................................................................................................ 88
Attachment 2: 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events............. 90
Attachment 3: 
WHO Clinical Staging of HIV/AIDS.............................................................................. 111
Attachment 4: 
Management of Clinically Significant Laboratory Toxicities* ....................................... 113
Attachment 5:
Management of Dyslipidemia ...................................................................................... 114
Attachment 6: 
Cardiovascular Safety: Definitions of Abnormalities.................................................... 117
Attachment 7:
HIV-Treatment Satisfaction Questionnaire (HIVTSQs) ............................................... 118
Attachment 8:
Anticipated Events ....................................................................................................... 119
LIST OF IN-TEXT TABLES 
Table 1:
Summary of Cutaneous Reaction/Rash Follow-up................................................................... 55
Table 2:
Summary of Allergic Reaction Follow-up.................................................................................. 56
Table 3:
LDL and non-HDL Cholesterol Goals and Thresholds for Therapeutic Lifestyle 
Changes and Drug Therapy in Different Risk Categories ...................................................... 116
Table 4:
Choice of Drug Therapy for Dyslipidemia in HIV-infected Individuals Receiving 
HAART.................................................................................................................................... 116
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
5
Approved, Date: 16 November 2017
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
03-May-2017
Amendment 1
This document
Amendments below are listed beginning with the most recent amendment.
Amendment 1 (this document)
The overall reason for the amendment: Following FDA feedback on the clinical protocol TMC114FD2HTX3002, 
3-May-2017, the requested changes have been implemented. In addition, an extension period has been added to give 
subjects who have completed the Week 48 visit an opportunity to continue D/C/F/TAF treatment until the
D/C/F/TAF FDC tablet becomes commercially available and is reimbursed, or can be accessed through another 
source, or until the sponsor terminates clinical development. Further changes have been made to the protocol for 
clarification or correction.
Applicable Section(s)
Description of Change(s)
Rationale: To maintain continuity of treatment, subjects who have completed 48-weeks of treatment with 
D/C/F/TAF will be given the opportunity to continue D/C/F/TAF treatment during an extension period until the 
D/C/F/TAF FDC tablet becomes commercially available and is reimbursed, or can be accessed through another 
source, or until the sponsor terminates clinical development.
SYNOPSIS
Time and Events Schedule
2.1 Objectives and Endpoints
3.1 Overview of Study Design
3.2 Study Design Rationale
6 Dosage and Administration
9.1.1 Overview
9.1.3 Open-Label Treatment Phase
9.8 Toxicity Management
10 Subject Completion/Discontinuation of Study Treatment/ Withdrawal From the Study
11 Statistical Methods
Rationale: In order to minimize the chance of resistance development, HIV-1 RNA retesting in subjects with
HIV-1 RNA ≥50 copies/mL will occur 2-4 weeks after the date of confirmation of viral load ≥50 copies/mL rather
than after 3-6 weeks. 
SYNOPSIS
Time and Events Schedule
3.1 Overview of Study Design
Attachment 1
Rationale: To ensure patient safety and allow for an early analysis of this new Test and Treat model of care 
paradigm, the timing of the interim analysis has been advanced from when the last subject reaches Week 24 to when 
the last subject has been assessed for safety at Day 3, and for resistance stopping rules at Week 4.
SYNOPSIS
3.1 Overview of Study Design
11 Statistical Methods
Rationale: In order to make inclusion criterion #7 consistent with footnote w in the Time and Events Schedule and 
with the text in Section 9.7, Clinical Laboratory Tests . 
SYNOPSIS
4.1 Inclusion Criteria
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
6
Approved, Date: 16 November 2017
Applicable Section(s)
Description of Change(s)
Rationale: In order to incorporate the footnote associated with Attachment 4 into Section 9.8.1, and to specify that 
the attachment footnote and the new text in Section 9.8.1 do not apply to the retesting of abnormal screening/
baseline laboratory values.
9.7 Safety Evaluations
9.8.1 General Guidance for the Management of Clinical Events and Laboratory Abnormalities
Attachment 4
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
7
Approved, Date: 16 November 2017
SYNOPSIS
A 
Phase 
3, 
Single-arm, 
Open-label 
Study 
to 
Evaluate 
the 
Efficacy 
and 
Safety 
of 
Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Once Daily Fixed-dose 
Combination (FDC) Regimen in Newly Diagnosed, Antiretroviral Treatment-naïve Human 
Immunodeficiency Virus Type 1 (HIV-1) Infected Subjects Receiving Care in a Test and Treat Model of 
Care
STUDY DRUGS
The darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) 
tablet is a 4-agent FDC tablet in development for oral once-daily use for the treatment of human 
immunodeficiency virus (HIV)-1 infection. This tablet contains the protease inhibitor (PI) darunavir 
(DRV or D) (800 mg), the pharmacokinetic enhancer cobicistat (COBI or C) (150 mg), the nucleoside 
reverse transcriptase inhibitor (NRTI) emtricitabine (FTC or F) (200 mg), and the tenofovir (TFV) 
prodrug tenofovir alafenamide (TAF) (10 mg).
Darunavir (PREZISTA®) used with a pharmacokinetic booster is approved for treatment of HIV-1 
infection in subjects aged 3 years and above, either as a 600-mg twice-daily treatment for antiretroviral 
therapy (ART)-experienced subjects or as an 800-mg once-daily treatment for ART-naïve subjects and 
ART-experienced subjects without DRV resistance-associated mutations (RAMs). 
Cobicistat (Tybost®) 150 mg is approved as a pharmacokinetic enhancer of select antiretroviral (ARV)
agents requiring the effects of a pharmacokinetic enhancer. 
The DRV/COBI 800/150-mg FDC tablet (PREZCOBIX®) is a once-daily treatment approved for use in 
combination with other ARV agents for treatment of HIV-1 infected treatment-naïve and treatment-
experienced adults without DRV RAMs. 
Emtricitabine is approved for use in combination with other agents for the treatment of HIV-1 infection in 
adults and children (4 months of age or older) and is available as a single agent (Emtriva®) or as part of 
FDCs, including Descovy® (F/TAF).
Tenofovir alafenamide is approved as part of FDCs, including Descovy® (FTC/TAF), Genvoya®
(elvitegravir [EVG]/COBI/FTC/TAF or E/C/F/TAF), and Odefsey® (rilpivirine [RPV]/FTC/TAF). 
Descovy® is a once-daily treatment approved for use in combination with other ARV agents (including 
DRV/COBI) for treatment of HIV-1 infected adults and adolescents (aged 12 years and older).
The D/C/F/TAF FDC tablet is intended as a complete regimen for the treatment of HIV-1 infection in 
adults and adolescents (aged 12 years and older) with no mutations known to be associated with 
resistance to any of the active components. The D/C/F/TAF FDC is currently being studied in 2 ongoing 
Phase 3 clinical studies (NCT02431247 and NCT02269917).
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
The primary objective of this study is to assess the efficacy of D/C/F/TAF FDC in a Test and Treat model 
of care in newly diagnosed HIV-1-infected, treatment-naive subjects as determined by the proportion of 
virologic responders defined as having HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48 (Food 
and Drug Administration [FDA]-defined intent to treat [ITT] snapshot analysis). 
The secondary objectives of this study are:

To assess virologic and immunologic changes in the study population through 12, 24, and 48 weeks 
of treatment 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
8
Approved, Date: 16 November 2017

To evaluate the incidence of grade 3 and 4 adverse events, serious adverse events, and premature 
discontinuations due to adverse events through 24 and 48 weeks of treatment, and during the 
extension phase

To evaluate the frequency of discontinuation of D/C/F/TAF FDC due to protocol-specific stopping 
rules (refer to the section Overview of Study Design below)

To assess baseline viral resistance in the study population 

To assess the development of viral resistance in the study population through 24 and 48 weeks of 
treatment, and during the extension phase

To assess the proportion of subjects retained in care after discontinuation of study drug before
Week 48

To evaluate the influence of various intrinsic and extrinsic factors on retention in care

To assess the proportion of subjects lost to follow-up through 24 and 48 weeks of treatment

To evaluate adherence by pill count to D/C/F/TAF FDC in the study population through 24 and 
48 weeks of treatment 

To evaluate adherence by subject self-report, using a 4-day recall period through Weeks 24 and 48

To describe predictors of suboptimal adherence (<95% adherence by pill count) in the study 
population 

To assess the HIV Treatment Satisfaction Questionnaire-status version (HIVTSQs) at Weeks 4, 24, 
and 48

To evaluate healthcare resource utilization (HRU) and cost and their temporal trends in the study 
population through 48 weeks of treatment
Endpoints
The primary endpoint of this study is the proportion of subjects who have HIV-1 RNA <50 copies/mL at 
Week 48 as defined by the FDA snapshot analysis (ITT). 
The secondary endpoints of this study are:
Efficacy

Change from baseline in log10 HIV-1 RNA viral load at Weeks 2, 4, 8, 12, 24, 36, and 48 

Proportion of subjects who have HIV-1 RNA <50 copies/mL at Week 24 

The change from baseline in CD4+ cell count at Weeks 12, 24, and 48 
Safety

Proportion of subjects that required discontinuation after enrollment based on safety stopping rules 
(refer to the section Overview of Study Design below)

Proportion of subjects discontinuing therapy due to adverse events

Proportion of subjects experiencing grade 3 and 4 adverse events

Proportion of subjects experiencing grade 3 and 4 laboratory abnormalities 
Resistance

Proportion of subjects meeting resistance stopping rules (refer to the section Overview of Study 
Design below) requiring discontinuation of study drug due to baseline resistance findings
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
9
Approved, Date: 16 November 2017

Proportion of subjects with baseline protease (PR), reverse transcriptase (RT), and integrase (INI)
RAMs 

Proportion of subjects developing RAMs and loss of phenotypic susceptibility, when available, upon 
meeting protocol-defined virologic failure

Proportion of subjects with protocol-defined virologic failure at Week 24 and Week 48, and during 
the extension phase
Retention in Care

Proportion of subjects lost-to-follow-up throughout the 48 weeks of treatment 

Proportion of subjects discontinuing study drug for any reason other than withdrawal of consent 
prior to Week 48 who have a documented clinic visit with a healthcare provider within 90 days of 
discontinuing study drug
Adherence

Adherence rates by pill count at Weeks 4, 8, 12, 24, 36, and 48 

Adherence rates by subject self-report, using a 4-day recall at Weeks 4, 8, 12, 24, 36, and 48 
Tolerability/Patient-reported Outcomes 

Mean total scores for the HIVTSQs at Weeks 4, 24, and 48
Healthcare Resource Utilization/Pharmacoeconomics

The number and duration of hospitalizations, number and type of outpatient visits, number of 
emergency room visits, and number and type of medications used (both HIV-related and All-cause as 
assessed by the investigator) throughout the main study period

Direct medical costs will be calculated in United States (USA) dollars based on HRU noted above 
Hypothesis
No formal hypothesis will be tested. The findings from this study will be used to generate data on the 
efficacy and safety profile of D/C/F/TAF FDC in newly diagnosed HIV-1 infected, treatment-naïve 
subjects using a Test and Treat model of care.
OVERVIEW OF STUDY DESIGN
This is a single-arm, open-label, prospective, multicenter Phase 3 study to assess the efficacy and safety 
of D/C/F/TAF FDC in newly diagnosed (ie, within 2 weeks of the screening/baseline visit [Day 1]) HIV-1 
infected treatment-naïve subjects at least 18 years of age as part of a Test and Treat model of care in the 
USA.
After obtaining informed consent, a blood sample will be collected for central laboratory testing. 
Study drug will be dispensed before the results from the screening/baseline safety and resistance 
laboratory tests are available. Subjects must start treatment with D/C/F/TAF FDC within 24 hours of the 
screening/baseline visit. 
Following initiation of treatment, a safety assessment will be performed by the investigator at Day 3 
+1 week, or as soon as the final screening/baseline laboratory report becomes available. Subjects meeting 
any of the below safety stopping rules (based on the receipt of the screening/baseline laboratory findings) 
will be contacted to return to the study site for possible early study treatment discontinuation (ESTD) and 
for additional follow-up.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
10
Approved, Date: 16 November 2017

Estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease 
(MDRD) formula <50 mL/min. 

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5×upper limit of normal 
(ULN) 

Serum lipase ≥1.5×ULN 

Positive serum human chorionic gonadotropin pregnancy test (β-hCG) for women of childbearing 
potential

Laboratory results that the investigator believes should result in discontinuation of study medication 
(Note: It is recommended that the investigator contacts the sponsor’s medical monitor to discuss the 
discontinuation)

Subjects identified with active hepatitis C virus (HCV) infection that in the opinion of the 
investigator requires HCV treatment immediately or expected to be needed during the course of the 
study with agents not compatible with D/C/F/TAF FDC.
Retesting of abnormal screening/baseline safety laboratory values noted above will be allowed once. 
Retesting will take place during an unscheduled visit.
The investigator will review the ARV screening/baseline resistance data at Week 4 ±7 days or sooner, 
depending on the availability of the screening/baseline HIV genotypic drug resistance testing results from 
the central laboratory. Subjects who do not show full sensitivity to all drugs in the FDC study regimen 
according to the susceptibility assessment in the GenoSure Prime® report will be contacted to return to the 
study site for ESTD. Subjects with identified resistance to lamivudine/FTC, attributed to the presence of 
the M184I/V mutation alone will be permitted to remain in the study.
Subjects will be treated for 48 weeks in the main study period and will return to the site for visits at 
Weeks 2, 4, 8, 12, 24, 36, and 48. Assessment of drug accountability and reasons for non-adherence, and 
recording of concomitant therapies, adverse events, vital signs (including the subject’s body weight), and 
physical examinations (complete or symptom-directed) will be performed at each visit from baseline 
onwards. Laboratory evaluations for efficacy and safety (HIV-1 viral load, biochemistry, hematology, and 
urinalysis) will be performed at all study visits. CD4+/CD8+ cell count will be assessed at Weeks 4, 8, 12, 
24, 36, and 48. Patient-reported outcome (PRO) measures will be assessed at Weeks 4, 24, and 48 using 
the validated 10-item HIVTSQs (Version 2006). Medical resource utilization data will be collected from 
all subjects throughout the main study period. 
Subjects who are on study drug and who experience a protocol-defined virologic failure (see below) will 
undergo genotypic and phenotypic resistance testing, preferably at the time of the confirmed virologic 
failure visit if the HIV-1 RNA is ≥ 400 copies/mL. If resistance testing is not able to be performed at the 
time of confirmed virologic failure, resistance testing may be performed at the point of unconfirmed 
virologic failure or a later time point if HIV-1 RNA is ≥400 copies/mL. Subjects who have persistent 
HIV-1 RNA ≥ 400 copies/mL past Week 24 but do not meet the definition of virologic failure, should 
have their viral load monitored closely, and if appropriate undergo genotypic and phenotypic resistance 
testing. In case resistance to study drugs is observed, the subject may be discontinued from the study at 
the investigator's discretion. If the investigator makes the decision that the subject can continue in the 
study, additional resistance testing may be performed as deemed necessary. Protocol-defined virologic 
failure is not considered a stopping rule. 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
11
Approved, Date: 16 November 2017
Virologic failure will be defined in this study as follows:

Virologic Nonresponse: 
HIV-1 RNA <1 log10 reduction from baseline, AND
HIV-1 RNA ≥400 copies/mL at the Week 12 visit, subsequently confirmed at an unscheduled visit
conducted within 2 to 4 weeks after Week 12

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 a scheduled or unscheduled
visit conducted within 2 to 4 weeks of the HIV-1 RNA result; 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 conducted within 2 to 4 weeks of the HIV-1 RNA
result. 
Subjects who prematurely discontinue study treatment during the open-label treatment period will be 
required to complete ESTD assessments as soon as possible but no later than 1 week of discontinuing 
study treatment. 
In addition, a follow-up visit is required for any subject who has an ongoing adverse event or serious
adverse event at the time of his/her last study visit. These subjects are required to return to the site 
30 days (±7 days) after completion of the last study-related visit (unless consent is withdrawn).
Subjects who have completed the Week 48 visit will be given the opportunity to continue D/C/F/TAF 
treatment during an extension period until the D/C/F/TAF FDC tablet becomes commercially available 
and is reimbursed, or can be accessed through another source, or until the sponsor terminates clinical 
development. At Week 48 the investigator should dispense a sufficient supply of D/C/F/TAF to maintain 
continuity of care for the subject, however no more than 12 weeks of study medication should be 
dispensed. If a subject requires more than 12 weeks of study medication, the subject should return to the 
site for additional drug dispensation.
During the extension period, subjects will have a study visit at the site once every 6 months, if applicable, 
and complete the procedures indicated in the Time and Events Schedule, and additionally at the time of 
transition to commercial D/C/F/TAF, for final data collection.
At the end of the study (or at ESTD), subjects will resume routine clinical care with their care provider 
who will determine the future care of that subject. In anticipation of transitioning the subject to routine 
clinical care at the end of the study (or early discontinuation), the investigator should take steps to ensure 
a smooth transition (ie, secure insurance etc.) well in advance of the final study visit, so that the subjects’ 
ART is not interrupted.
For those subjects discontinuing therapy before Week 48, the investigator will be asked to monitor the 
subject’s retention in care defined as having one documented clinic visit within 90 days of discontinuing 
the study treatment (unless consent is withdrawn). 
The end of the study is defined as completion of the last data collection visit for the last subject 
participating in the study. For the purpose of the primary analysis, a subject will be considered to have 
completed the study if data collection as required per protocol through the complete course of 48 weeks 
of ART has been completed.
An interim analysis will be conducted after the last subject enrolled has been assessed for safety at Day 3,
and for resistance stopping rules at Week 4. 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
12
Approved, Date: 16 November 2017
The primary analysis of this study will be performed once all subjects have completed the Week 48 visit 
and the 30-day follow-up visit (if applicable) or discontinued earlier.
SUBJECT POPULATION
Inclusion Criteria
Sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required 
for, the study and is willing to participate in the study.
Man or woman at least 18 years of age.
Newly diagnosed with HIV-1 evidenced by any of the following within 2 weeks of the screening/baseline visit:

HIV Rapid Antibody positive*; OR

HIV Immunoassay positive; OR

Positive p24 antigen and a HIV-1 RNA viral load ≥5,000 copies/mL; OR

Non-reactive HIV-1 antibody/antigen assays and HIV-1 RNA viral load ≥5,000 copies/mL. HIV-1 RNA viral 
load must be confirmed once within 1 week of initial HIV-1 RNA viral load test.
* For those subjects testing initially positive on a 4th generation HIV Rapid Antibody Assay, results should be 
confirmed on a 3rd generation HIV Rapid Antibody Assay at a minimum, or an HIV Immunoassay, unless the 
investigator suspects acute or recent infection.
Antiretroviral treatment-naïve, except for the use of TRUVADA® for pre-exposure prophylaxis (PrEP).
Contraceptive use by men or women should be consistent with the local regulations regarding the use of 
contraceptive methods for subject participating in clinical studies. A woman must be either:

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); OR

Surgically sterile (had total hysterectomy or bilateral oophorectomy, tubal ligation/bilateral tubal clips without 
reversal operation, or otherwise incapable of becoming pregnant); OR

Not heterosexually active for the duration of the study; OR

Have a vasectomized partner; OR

If of childbearing potential and heterosexually active, practicing a highly effective method of birth control (as 
specified below) before entry, and agree to continue to use a highly effective method of contraception 
throughout the study, and for at least 90 days after receiving the last dose of study drug. Women with tubal 
ligation are required to use one additional contraceptive method.

Estrogen-based hormonal contraception may not be reliable when taking the study drug. Therefore, to be 
eligible for this study, women of childbearing potential should either use:

a double-barrier method (male condom + either diaphragm or cervical cap); OR

non-estrogen hormonal based contraceptives in combination with a barrier contraceptive (male condom, 
diaphragm or cervical cap, or female condom); OR

intrauterine device in combination with a barrier contraceptive (male condom, diaphragm or cervical cap, or 
female condom).
Note: A male condom and female condom should not be used together due to risk of breakage or damage caused 
by latex friction.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study 
and for 90 days after receiving the last dose of study drug.
A woman of childbearing potential must have a negative urine pregnancy test at screening.
Men with a female partner of childbearing potential must agree to use adequate reliable contraceptive methods (see 
above) during the study until 90 days after receiving the last dose of study drug 

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 study drug and for up to 90 days after receiving the last dose of study drug.
Men must agree not to donate sperm during the study until 90 days after receiving the last dose of study drug (or 
longer, if dictated by local regulations).
Must be able to swallow whole tablets.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
13
Approved, Date: 16 November 2017
Exclusion Criteria
Known active cryptococcal infection, active toxoplasmic encephalitis, Mycobacterium tuberculosis infection, or 
another acquired immunodeficiency syndrome (AIDS)-defining condition that in the judgement of the investigator 
would increase the risk of morbidity or mortality.
Known history of clinically relevant hepatic disease or hepatitis that in the investigator’s judgement is not 
compatible with D/C/F/TAF FDC.
Known history of cirrhosis as diagnosed based on local practices. 
Known history of chronic (≥3 months) renal insufficiency, defined as having an eGFR <50 mL/min according to 
the MDRD formula. 
Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 90 days after the 
last dose of study treatment.
Plans to father a child while enrolled in this study or within 90 days after the last dose of study treatment.
Current alcohol or substance use judged by the investigator to potentially interfere with subject study adherence.
Known history of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi’s 
sarcoma, basal cell carcinoma, or resected, noninvasive cutaneous squamous carcinoma.
Known active, severe infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy 
within 30 days prior to screening.
Any other condition or prior therapy 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 prevent, limit, or confound the protocol-
specified assessments.
Subject unlikely to comply with the protocol requirements, based on clinical judgment.
Received an investigational drug (including investigational vaccines) or used an invasive investigational medical 
device within 90 days before the planned first dose of study treatment or is currently enrolled in an investigational 
study without prior approval from the sponsor.
Subjects receiving ongoing therapy with contraindicated, not recommended, drugs that cannot be adequately dose-
adjusted, or subjects with any known allergies to the excipients of the D/C/F/TAF FDC.
Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the 
direction of that investigator or study site, as well as family members of the employees or the investigator, or 
employees of Johnson & Johnson or Gilead.
DOSAGE AND ADMINISTRATION
All subjects will receive treatment with D/C/F/TAF FDC (DRV 800 mg + COBI 150 mg + FTC 200 mg 
+ TAF 10 mg) in an open-label fashion.
Initiation of study treatment can only start after all screening/baseline tests and procedures have been 
completed and must take place within 24 hours after the baseline visit. D/C/F/TAF FDC must be taken
orally with food. All subjects will be counseled to swallow D/C/F/TAF whole once daily at 
approximately the same time each day, according to their preference. 
If subjects notice that they have 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 have missed a dose more than 12 hours after the time it 
is usually taken, they should be instructed not to take it and simply resume the usual dosing schedule. 
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 if they do not last longer than 4 consecutive weeks. The sponsor should be notified when 
such temporary interruption occurs. 
In order to maintain continuity of care, subjects will be given the opportunity to continue the D/C/F/TAF 
treatment after Week 48 during an extension period until the D/C/F/TAF FDC tablet becomes 
commercially available and is reimbursed, or can be accessed through another source, or until the sponsor 
terminates clinical development.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
14
Approved, Date: 16 November 2017
EFFICACY EVALUATIONS 
Antiviral Efficacy and Immunologic Change
Blood samples for determination of plasma HIV-1 RNA viral load and immunologic parameters will be 
taken at the time points specified in the Time and Events Schedule. 
Plasma viral load will be measured using a validated assay at a central laboratory. 
Immunologic change will be determined by changes in CD4+ cell count (absolute and %). 
Changes in viral load, changes in CD4+ cell counts (either decreases or increases), or detected resistance 
will be part of the efficacy analysis and should not be reported as adverse events or serious adverse 
events. 
Resistance Determinations
HIV-1 genotype/phenotype resistance testing will be performed at the time points specified in the Time
and Events Schedule. 
Resistance testing at the screening/baseline visit (Day 1) will be performed utilizing the GenoSure Prime®
assay. Resistance-associated mutations present at baseline will be reported and include mutations in the 
domain of PR, RT, and INI.
To investigate the emergence of resistance, the following subjects will be eligible for 
genotypic/phenotypic resistance testing (PhenoSense GT®): 

Any subject who experiences a protocol-defined virologic failure (see above); 

Any subject who discontinues study treatment after Week 12 for any reason and has an HIV-1 RNA 
value ≥400 copies/mL at the last viral load measurement;

Any subject who has persistent HIV-1 RNA ≥400 copies/mL past Week 24 but does not meet the 
definition of virologic failure. 
Baseline phenotyping may be performed retrospectively on subjects with confirmed protocol-defined 
virologic failure if after virologic failure they showed evidence of reduced phenotypic susceptibility to 
any of the study drugs. Evaluations may be performed at other time points at the sponsor’s discretion.
PHARMACOKINETIC EVALUATIONS
Plasma concentrations of DRV and COBI may be determined in subjects experiencing protocol-defined 
virologic failure, or subjects who have persistent HIV-1 RNA ≥400 copies/mL past Week 24 but do not 
meet the definition of virologic failure, using stored blood samples collected throughout the study, if 
deemed necessary.
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS
Medical resource utilization data will be collected in the electronic case report form (eCRF) by the 
investigator and study-site personnel. The following will be evaluated throughout the study as noted in 
the Time and Events Schedule: 

Number and duration of hospitalizations.

Number of outpatient visits, including type of visit (eg, general practitioner, specialist)

Number of emergency room visits.

Number and type of medications used (from the Concomitant Medication page of the eCRF). 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
15
Approved, Date: 16 November 2017
Medical resource utilization will be classified as being either HIV-related or All-cause HRU as assessed 
by the investigator. The costs will be assigned to the type of medical resource utilization to calculate a per 
subject per month cost associated with the initiation and maintenance of ART. Trends will be assessed 
over time throughout the study.
ADHERENCE
Treatment adherence will be assessed by pill count, and by subject self-report, using a 4-day recall period.
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.
RETENTION IN CARE
Retention in care will be described as the proportion of subjects who discontinue study treatment prior to 
Week 48 and remain in care after discontinuation (defined as having a documented office visit within 
90 days of discontinuing the study drug). Subjects who withdraw consent will not be followed to assess 
retention in care. 
SAFETY EVALUATIONS
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:

Adverse events;

Clinical laboratory tests (including biochemistry, hematology, urinalysis, urine chemistry);

Vital signs;

Physical examination (complete or symptom-directed);

Follow-up on specific toxicities.
PATIENT-REPORTED OUTCOMES
Patient-reported outcomes will be assessed at the time points indicated in the Time and Events Schedule
utilizing the HIVTSQs.
STATISTICAL METHODS
The following analyses will be performed:

The interim analysis: once all subjects have been assessed for safety at Day 3, and for resistance 
stopping rules at Week 4.

The primary analysis: once all subjects have completed the Week 48 assessments and the 30-day 
follow-up visit (if applicable), or discontinued earlier.
Sample Size Determination 
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 (ITT). As this is an exploratory study with no formal 
hypothesis testing on the primary endpoint, no formal sample size calculation was performed. With a 
sample size of 100 subjects and an expected virologic response rate ranging from 60-80%, the exact 
corresponding 95% confidence intervals (CIs) are: 60% (49.7%, 69.7%), 70% (60.0%, 78.8%), and 80% 
(70.8%, 87.3%). The half-width of the exact corresponding 2-sided 95% CI is 10.0%, 9.4%, and 8.3%, 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
16
Approved, Date: 16 November 2017
respectively, and is therefore less than 10% across the range of expected outcomes which is the desired 
precision. Additionally, with a sample size of 100 subjects, the probability to observe an adverse event 
with a true incidence of 1% or 4% is 63% and 98% respectively.
Efficacy Analyses
Antiviral Efficacy and Immunologic Change
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 (ITT). 
Virologic suppression (HIV-1 RNA<50 copies/mL) will also be analyzed as secondary endpoints at 
Week 24 and Week 48 according to the below analyses:

FDA Snapshot algorithm in the ITT and Per-Protocol population

Time to loss of virological response (TLOVR) algorithm in the ITT population
Virologic decay will be reported as the mean log10 change in HIV-1 viral load from baseline to Weeks 2, 
4, 8, 12, and 24 as part of the interim analysis as a secondary endpoint.
The proportion of subjects experiencing protocol defined virologic failure at Week 24 and Week 48 will 
be tabulated using descriptive statistics along with the 95% CIs. The Wilson (Score) method for the CI 
will be used. 
The changes from baseline in CD4+ cell count at Weeks 12, 24, and 48 will be summarized using 
descriptive statistics. 
Resistance Determinations
The number of PR mutations (including International AIDS Society-United States of America [IAS-USA] 
primary and secondary PI RAMs), RT mutations (including IAS-USA nucleoside/nucleotide RT inhibitor 
[N(t)RTI] RAMs and IAS-USA non-nucleoside RT inhibitor [NN(t)RTI] RAMs), and INI mutations 
(including IAS-USA primary and secondary INI-RAMs) present will be tabulated based on resistance 
tests performed at the screening/baseline visit. 
The proportion of subjects meeting resistance stopping rules, requiring discontinuation of study drug, 
based on the findings of screening/baseline resistance testing will be tabulated as part of the interim 
analysis. 
HIV-1 genotype/phenotype will be analyzed from samples of subjects with protocol-defined virologic 
failure and with HIV-1 RNA ≥400 copies/mL. 
The number of treatment-emergent PR mutations (including IAS-USA primary and secondary PI RAMs)
and RT mutations (including IAS-USA N(t)RTI RAMs and IAS-USA NNRTI RAMs), as well as specific 
mutations associated with resistance to DRV, FTC, and TAF will be tabulated based on the observed 
protocol-defined virologic failures through the study period. 
Fold change (FC) in 50% effective concentration (EC50) of ARVs will be tabulated. Loss of phenotypic 
susceptibility may be analyzed dependent on the number of virologic failures and phenotypes available 
through the study period.
Medical Resource Utilization Analyses 
All-cause and HIV-specific HRU during the study period will be summarized overall and by category as 
the counts per patient per month (PPPM). Monthly average counts per subject will also be calculated to 
show the temporal trend for each category. 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
17
Approved, Date: 16 November 2017
Costs of care will be calculated by assigning costs based on Centers for Medicare & Medicaid Services 
(CMS) fee schedule to assessed HRU on a per subject per month basis. Descriptive statistics will be 
calculated to compare the costs of care from baseline to Weeks 12, 24, and 48. 
Adherence Analyses
Treatment adherence based on pill count and on subject self-report will be summarized by means of 
descriptive statistics and frequency tabulations.
Adherence rates will be reported according to the proportion of subjects taking >95%, 80-95% and <80% 
of study drug as assessed by pill count at study visits at Weeks 4, 12, 24, and 48.
Retention in Care Analyses
Number of subject with retention of care by age, gender, race, sexual orientation, time from diagnosis to 
baseline visit, baseline CD4+ cell count, baseline HIV-1 RNA, patient satisfaction as assessed by 
HIVTSQs, and socioeconomic factors will be tabulated.
Safety Analyses
The verbatim terms used by investigators to identify adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). All reported adverse events with onset during the study 
will be included in the analysis. For each adverse event, the percentage of subjects who experience 
≥1 occurrence of the given event will be summarized.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those subjects 
who die, who discontinue treatment due to an adverse event, or who experience a severe or life-
threatening (grade 3 or 4) or a serious adverse event.
Additionally, a summary and listing of those subjects meeting predefined stopping rules due to safety or 
resistance findings will be tabulated.
Laboratory data will be summarized by 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.
Descriptive statistics of vital signs (pulse rate, systolic and diastolic blood pressure, and body weight) 
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.
Patient-reported Outcomes 
Descriptive statistics for absolutes values and changes in HIVTSQs scores will be calculated at each time
point, where applicable. 
Extension Period
For the extension period, descriptive statistics or patient data listings will be provided for adverse events, 
virologic failure, or resistance.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
18
Approved, Date: 16 November 2017
TIME AND EVENTS SCHEDULE
Phase
Open-label Treatment Phase
ESTD 
(Early 
Study 
Treatment 
Discont-
inuation) 
Visite
30-day 
Follow-
upf
90-day 
Follow-
up
Day 1
Screening/
Baselineb
Main Study 
Period
Extension 
Periodd
Weeka
Day 3 
Safety 
Assessmentc
2
4
8
12
24
36
48
Study Procedures
Screening/Administrative
Informed consent processg
X
Demographic information
X
Medical historyh
X
HIV history
X
Inclusion/exclusion criteria
X
Determine Continued Eligibility (by Investigator) 
Formal review of central screening/baseline 
safety laboratory tests by investigator (no 
scheduled clinic visit)
X
Formal review of screening/baseline HIV 
genotypic drug resistance testing by 
investigator 
Xi
Study Drug Administration
Dispense study drugj
X
X
X
X
X
X
Xk
Xk
Drug accountability (pill count)l
X
X
X
X
X
X
X
X
Adherence (subject self-report)m
X
X
X
X
X
X
X
X
Efficacy Assessments
HIV-1 RNAn
X
X
X
X
X
X
X
X
X
X
X
CD4+/CD8+
X
X
X
X
X
X
X
X
X
Combined Genotype/Phenotypeo
Xp
X
X
X
X
X
X
X
X
X
Safety Assessments
Vital signs, body weight and heightq
X
X
X
X
X
X
X
X
X
X
X
Full physical examinationr
X
X
X
X
Symptom-directed physical examinationr
X
X
X
X
X
X
X
X
Review concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Adverse events assessments
X
X
X
X
X
X
X
X
X
X
X
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
19
Approved, Date: 16 November 2017
Note: Retesting of abnormal screening/baseline safety laboratory values that may lead to exclusion will be allowed once.
Unscheduled visit(s) may be required for safety reasons, for technical issues with the samples, or for confirmation of virologic failure in case of unconfirmed virologic 
failure (virologic nonresponse or virologic rebound [see Attachment 1]). When human immunodeficiency virus (HIV)-1 ribonucleic acid (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. 
a. All study visits are to be scheduled relative to the screening/baseline visit date and are to occur at the end of Weeks 2, 4, 8, 12, 24, 36, and 48. A window of ±2 days 
is allowed for Visit 2. All other study visits through Week 48 are to be completed within ±7 days of the protocol-specified visit date.
b. Screening/baseline visit should be within 2 weeks of diagnosis. The screening and baseline assessments should preferably be completed the same day (Day 1), but if 
necessary, can be performed on different days, but must be completed within 2 business days of signing the ICF. Study drug should not be dispensed until all 
screening procedures have been completed and the investigator has determined that the subject meets the inclusion/exclusion criteria.
c. A safety assessment will be performed by the investigator at Day 3 +1 week, or as soon as the final screening/baseline laboratory report becomes available. Subjects 
meeting any of the safety stopping rules will be contacted to return to the study site for possible ESTD and additional follow-up.
d. Subjects will have a study visit at the site once every 6 months, if applicable, and additionally at the time of transition to commercial D/C/F/TAF.
e. Subjects who prematurely discontinue study treatment during the open-label treatment period (ie, including the extension period) will be required to complete ESTD 
assessments as soon as possible but no later than 1 week of discontinuing study treatment.
Phase
Open-label Treatment Phase
ESTD 
(Early 
Study 
Treatment 
Discont-
inuation) 
Visite
30-day 
Follow-
upf
90-day 
Follow-
up
Day 1
Screening/
Baselineb
Main Study 
Period
Extension 
Periodd
Weeka
Day 3 
Safety 
Assessmentc
2
4
8
12
24
36
48
Study Procedures
Health Outcome Assessments
Medical resource utilization
X
X
X
X
X
X
X
Xu
X
HIV Treatment Satisfaction Questionnaire 
(HIVTSQs)t
X
X
X
Xu
Clinical Laboratory Assessments
Hepatitis B/C serology
X
Estimated glomerular filtration rate (eGFR)
X
X
X
X
X
X
X
X
X
X
X
Genotypev
X
Pregnancy testw
X
X
X
X
X
X
X
X
X
X
X
Hematology
Xx
Xx
Xx
X
Xx
X
X
Xx
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
Serum amylase/lipasey
X
Urinalysisz
X
X
X
X
X
X
X
X
X
X
X
Other
Retention in care assessment
Xbb
Blood samples storedaa
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
20
Approved, Date: 16 November 2017
f.
Required for any subject who has an ongoing adverse event or serious adverse event at the time of his/her last study visit (unless consent is withdrawn); a ±7 days 
window may be used.
g. Signing of the informed consent form (ICF) needs to be done before the first study-related activity.
h. Including family history of premature cardiovascular disease, diabetes, hypertension, low high-density lipoprotein (HDL) cholesterol, and prior history of 
cardiovascular disease.
i.
The investigator will review the antiretroviral (ARV) screening/baseline resistance data at Week 4 ±7 days or sooner, depending on the availability of the 
screening/baseline HIV genotypic drug resistance testing results from the central laboratory.
j.
Subjects must start treatment within 24 hours of the screening/baseline visit (Day 1).
k. At Week 48 the investigator should dispense a sufficient supply of D/C/F/TAF to maintain continuity of care for the subject, however no more than 12 weeks of 
study medication should be dispensed. If a subject requires more than 12 weeks of study medication, the subject should return to the site for additional drug 
dispensation.
l.
Monitoring of treatment adherence will utilize pill counts.
m. Monitoring of treatment adherence by subject self-report, using a 4-day recall.
n. Leftover blood samples from the HIV-1 RNA determinations could be used for protocol-related testing (virology, safety, pharmacokinetic analysis) at additional 
time points.
o. Combined genotype/phenotype (PhenoSense GT®) will be assessed at the central laboratory for subjects who experience a protocol-defined virologic failure, for 
subjects who discontinue study treatment after Week 12 and have HIV-1 RNA ≥400 copies/mL, or for subjects who have persistent HIV-1 RNA ≥400 copies/mL 
past Week 24 but do not meet the definition of virologic failure. Additional samples may be analyzed upon request of the sponsor’s virologist.
p. Baseline phenotyping may be performed retrospectively on subjects with confirmed protocol-defined virologic failure if after virologic failure they showed evidence 
of reduced phenotypic susceptibility to any of the study drugs. Evaluations may be performed at other time points at the sponsor’s discretion.
q. Vital signs include systolic and diastolic blood pressure, pulse rate (supine after at least 5 minutes rest), and weight. Height will be measured at screening.
r.
A complete physical examination will be conducted at screening, Week 48, at the time of transition to commercial D/C/F/TAF, or at the ESTD visit. Symptom 
directed physical examinations may be conducted at all other scheduled and unscheduled study visits based on reported safety or tolerability issues.
s. In the setting of a suspected renal adverse event, urine chemistry (quantitative measurement) will be assessed: creatinine, sodium, phosphate, glucose, protein, 
albumin.
t.
The HIVTSQs assessment should be completed before all other study-related procedures planned during these visits to prevent influencing subject perceptions.
u. MRU and the HIVTSQ will not be collected as part of ESTD during the extension period.
v. Genotype (GenoSure Prime®) will be assessed at the time of screening.
w. At screening, pregnancy will be determined by urine pregnancy test for all female subjects of childbearing potential. A serum human chorionic gonadotropin 
(β-hCG) pregnancy test will be assessed at a central laboratory, but the results are not required for enrollment. Subsequently pregnancy will be assessed by urine 
pregnancy tests.
x. Peripheral blood mononuclear cells (PBMCs) will be isolated from whole blood at the central laboratory, and stored for future analysis if needed.
y. Serum amylase and serum lipase will be assessed at screening. If a subject is suspected of having pancreatitis during the study period serum amylase and serum 
lipase may be reassessed at scheduled or unscheduled visits.
z. Urinalysis (dipstick). If dipstick results are abnormal, the sediment will be examined microscopically.
aa. Plasma concentrations of darunavir (DRV) and cobicistat (COBI) may be assessed from stored blood samples in those subjects who experience protocol-defined 
virologic failure, or subjects who have persistent HIV-1 RNA ≥400 copies/mL past Week 24 but do not meet the definition of virologic failure.
bb. Subjects who discontinue study drug for any reason before Week 48 will be assessed for completion of a documented clinic visit within 90 days of discontinuing 
study drug (providing consent is not withdrawn).
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
21
Approved, Date: 16 November 2017
ABBREVIATIONS
3TC
lamivudine
ABC
abacavir
ADRs
adverse drug reactions
AGEP
acute generalized exanthematous pustulosis
AIDS
acquired immunodeficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ARC
Anticipated Event Review Committee
ART
antiretroviral therapy
ARV
antiretroviral 
ASMP
Anticipated Events Safety Monitoring Plan
AST
aspartate aminotransferase
ATV
atazanavir 
AV
atrioventricular
β-hCG
human chorionic gonadotropin pregnancy test
BCRP
breast cancer resistance protein
BMD
bone mineral density 
BMI
body mass index
BPAP
bilevel positive airway pressure
bpm
beats per minute
BUN
blood urea nitrogen
C
cobicistat
CAD
coronary artery disease
CFR
Code of Federal Regulations 
CHD
coronary heart disease
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMS
Centers for Medicare & Medicaid services
CNS
central nervous system
COBI
cobicistat
CPAP
continuous positive airway pressure
CYP
cytochrome P450
D
darunavir
D/C/F/TAF
darunavir/cobicistat/emtricitabine/tenofovir alafenamide
DAIDS
Division of AIDS
DBP
diastolic blood pressure 
DHHS
Department of Health and Human Services
DRESS
drug rash with eosinophilia and systemic symptoms
DRV
darunavir (formerly known as TMC114)
DTG
dolutegravir (formerly known as S/GSK1349572)
E
elvitegravir
E/C/F/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 
E/C/F/TDF
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate
EC50
50% effective concentration
ECG
electrocardiogram
eCRF
electronic case report form 
eDC
electronic data capture
eGFR
estimated glomerular filtration rate 
eGFRcreatinine
eGFR for creatinine clearance 
ESTD
early study treatment discontinuation
EU
European Union
EVG
elvitegravir
F
emtricitabine
FC
fold change
FDA
Food and Drug Administration 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
22
Approved, Date: 16 November 2017
FDC
fixed-dose combination
FTC
emtricitabine
GCP
Good Clinical Practice
GSI
Gilead Sciences, Inc
HAART
highly-active antiretroviral therapy
HBc
hepatitis B core
HBs
hepatitis B surface
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCO3
bicarbonate
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HIVTSQs
HIV Treatment Satisfaction Questionnaire-status version
HRU
healthcare resource utilization
IAS-USA
International AIDS Society-United States of America
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ID
identification
IEC
Independent Ethics Committee
IND
Investigational New Drug
INI
integrase
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent to treat
IV
intravenous
LDL
low-density lipoprotein
LLN
lower limit of normal range
MATE
multi-antimicrobial extrusion protein
MDR1
multidrug resistance protein 1
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
N(t)RTI
nucleoside/nucleotide reverse transcriptase inhibitor
N[t]RTI
nucleoside/nucleotide reverse transcriptase inhibitor
NA
not applicable
NCEP
National Cholesterol Education Program 
NN(t)RTI
non-nucleoside/nucleotide reverse transcriptase inhibitor
NRTI
nucleoside reverse transcriptase inhibitor
OATP
organic anion-transporting polypeptide
PBMCs
peripheral blood mononucleated cells
P-gp
P-glycoprotein
PI
protease inhibitor
PPPM
patient per month
PQC
Product Quality Complaint
PR
protease
PrEP
pre-exposure prophylaxis
PRO
patient-reported outcome(s) (paper or electronic as appropriate for this study)
PT
prothrombin time
PTT
partial thromboplastin time
RAM
resistance-associated mutation
RAPID
Rapid ART Program for Individuals with an HIV Diagnosis 
RBC
red blood cell
RNA
ribonucleic acid
RPV
rilpivirine
RT
reverse transcriptase
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
rtv
ritonavir when used as pharmacokinetic booster
RTV
ritonavir
SBP
systolic blood pressure 
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SJS
Stevens-Johnson syndrome
START
Strategic Timing of Antiretroviral Therapy
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
TMC114
Tibotec Medicinal Compound 114 (darunavir)
UGT1A1
uridine diphosphate glucuronosyltransferase 1A1
ULN
upper limit of normal range
USA
United States of America
WBC
white blood cell
WHO
World Health Organization
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
24
Approved, Date: 16 November 2017
1.
INTRODUCTION
1.1.
Study Drug
The 
darunavir/cobicistat/emtricitabine/tenofovir 
alafenamide 
(D/C/F/TAF) 
fixed-dose 
combination (FDC) tablet is a 4-agent FDC tablet in development for oral once-daily use for the 
treatment of human immunodeficiency virus (HIV)-1 infection. This tablet contains the protease 
inhibitor (PI) darunavir (DRV or D) (800 mg), the pharmacokinetic enhancer cobicistat (COBI or 
C) (150 mg), the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC or F) 
(200 mg), and the tenofovir (TFV) prodrug tenofovir alafenamide (TAF) (10 mg).
Darunavir (PREZISTA®) used with a pharmacokinetic booster is approved for treatment of 
HIV-1 infection in subjects aged 3 years and above, either as a 600-mg twice-daily treatment for 
antiretroviral therapy (ART)-experienced subjects or as an 800-mg once-daily treatment for 
ART-naïve subjects and ART-experienced subjects without DRV resistance-associated 
mutations (RAMs).28
Cobicistat (Tybost®) 150 mg is approved as a pharmacokinetic enhancer of select antiretroviral 
(ARV) agents requiring the effects of a pharmacokinetic enhancer.39
The DRV/COBI 800/150-mg FDC tablet (PREZCOBIX®) is a once-daily treatment approved for 
use in combination with other ARV agents for treatment of HIV-1 infected treatment-naïve and 
treatment-experienced adults without DRV RAMs.27
Emtricitabine is approved for use in combination with other agents for the treatment of HIV-1 
infection in adults and children (4 months of age or older) and is available as a single agent 
(Emtriva®) or as part of FDCs, including Descovy® (F/TAF).8,10
Tenofovir alafenamide is approved as part of FDCs, including Descovy® (FTC/TAF), Genvoya®
(elvitegravir 
[EVG]/COBI/FTC/TAF 
or 
E/C/F/TAF), 
and 
Odefsey®
(rilpivirine 
[RPV]/FTC/TAF). Descovy® is a once-daily treatment approved for use in combination with 
other ARV agents (including DRV/COBI) for treatment of HIV-1 infected adults and adolescents 
(aged 12 years and older).8,11,23
The D/C/F/TAF FDC tablet is intended as a complete regimen for the treatment of HIV-1 
infection in adults and adolescents (aged 12 years and older) with no mutations known to be 
associated with resistance to any of the active components. The D/C/F/TAF FDC is currently 
being studied in 2 ongoing Phase 3 clinical studies (NCT02431247 and NCT02269917).2
For the most comprehensive nonclinical and clinical information regarding the study drug, refer
to the Investigator’s Brochure (IB) for D/C/F/TAF and its addendum.14,15
1.2.
Background
Human immunodeficiency virus infection is a life-threatening and serious disease that is of 
major public health interest around the world. In 2015, approximately 36.7 million people were 
living with HIV-1 worldwide, an estimated 2.1 million people became newly infected with 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
25
Approved, Date: 16 November 2017
HIV-1 and 1.1 million died from acquired immunodeficiency syndrome (AIDS)-related causes.40
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.9,21,25
The primary goal of ART is to prevent HIV-associated morbidity and mortality. This goal is best 
accomplished by using effective ART to maximally inhibit HIV replication to sustain plasma 
HIV-1 ribonucleic acid (RNA) (viral load) below limits of quantification. Durable viral 
suppression improves immune function and overall quality of life, lowers the risk of both AIDS-
defining and non-AIDS-defining complications, and prolongs life.9 Furthermore, high plasma 
HIV-1 RNA is a major risk factor for HIV transmission, and effective ART can reduce viremia 
and transmission of HIV to sexual partners by more than 96%.7,29 Thus, a secondary goal of ART 
is to reduce the risk of HIV transmission.
Since 2012, the United States (USA) Department of Health and Human Services (DHHS) Panel 
on Antiretroviral Guidelines for Adults and Adolescents (the Panel) has recommended initiating 
ART in all HIV-infected subjects, regardless of CD4+ cell count.9 More recently, based on 
findings from 2 large, randomized controlled studies that addressed the optimal time to initiate 
ART (ie, START [Strategic Timing of Antiretroviral Therapy]13 and TEMPRANO37), the Panel 
increased the strength and evidence rating of this recommendation. 
While increased HIV screening efforts have helped identify nearly 85% of 1.2 million people 
living with HIV in the USA, a significant gap exists in the percentage of subjects who are 
actively engaged in care (40%), prescribed ART (37%), and those who achieve virologic 
suppression (30%).3 Many factors may influence a subject’s ability or desire to be engaged in 
care, and efforts to improve engagement in care are currently being explored as part of the 
National HIV/AIDS Strategy. One potential intervention to improve engagement in care and 
potentially the receipt of suppressive ART is the initiation of ART through a Test and Treat 
model of care. 
In traditional care models, before starting ART, it is recommended that healthcare providers 
assess various patient specific factors, including but not limited to pretreatment HIV RNA level, 
CD4+ cell count, results of baseline HIV genotypic drug resistance testing, baseline renal and 
hepatic function, pre-existing medical conditions that could affect or be affected by ART, and 
regimen-specific considerations such as potential adverse effect profile, a regimen’s genetic 
barrier to resistance, and dosing requirements. While some of these assessments can be made 
relatively quickly, several require advanced laboratory testing, which can take 2 to 3 weeks for 
results to become available (particularly HIV genotypic drug resistance testing). Traditional care 
models often require multiple clinic visits to identify a feasible regimen for subjects, potentially 
increasing the percentage of subjects who do not return to initiate ART after diagnosis.9
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
26
Approved, Date: 16 November 2017
Ongoing studies are examining a Test and Treat model of care involving the immediate provision 
of ART in those subjects newly diagnosed and willing to commit to treatment, typically at the 
same clinic visit as diagnosis. A recent study randomizing nearly 750 newly diagnosed subjects 
in Haiti to immediate ART or delayed ART for up to 3 weeks was halted early after a data safety 
monitoring board detected a 76% increase in rates of virologic suppression and a 65% decrease 
in the risk of mortality in the group who started ART immediately compared those who delayed 
ART initation.17 A similar study (RapIT) is currently ongoing in South Africa.30 Test and Treat 
models have also been explored in the developed world, but in smaller patient populations. 
Pilcher et al, recently compared outcomes of subjects who initiated ART between 2013 and 2014 
as parted of a Test and Treat model (n=39), or a traditional model of care (n=47). In this cohort, 
the median time to suppression was reduced from 4.2 months in the traditional ART group to 
56 days, or 1.9 months in subjects managed according to the “Rapid ART Program for 
Individuals with an HIV Diagnosis (RAPID)” care initiation protocol.26
As healthcare providers have less clinical information available to them in a Test and Treat
model of care, it is important to consider a regimen’s ability to work in the setting of possible
resistance, the safety of that regimen, and the subject’s ability to adhere to such a regimen. 
Currently, the DHHS treatment guidelines recommend baseline genotypic resistance testing for 
all newly diagnosed subjects before starting ART as 10% to 17% of ART-naïve subjects may 
have evidence of transmitted drug-resistant HIV strains.9,46 However, recognizing a potential 
benefit in initiating treatment sooner in certain populations such as those with acute HIV 
infection, pregnancy, and opportunistic infections, the DHHS treatment guidelines have provided 
guidance on ART initiation while awaiting the results of HIV genotypic drug resistance testing, 
or when resistance testing is not available. In those individuals in whom treatment needs to begin 
before resistance testing results are available, boosted-DRV may have an important role given 
the low rate of transmitted PI resistance, its high genetic barrier to resistance, and low rate of 
treatment-emergent resistance during many years of clinical experience.9 While genotypic 
resistance testing is recommended for all newly diagnosed subjects before starting ART, once-
daily boosted-DRV may be used in treatment-naïve subjects without conducting baseline 
genotypic and or phenotypic resistance testing due to its unique resistance profile and due to the 
very low prevalence of DRV RAMs in treatment-naïve subjects.27,28 Eleven HIV-1 protease (PR) 
mutations associated with DRV resistance were previously identified, based on analysis of a 
pooled dataset of studies in highly treatment-experienced subjects (ie, V11I, V32I, L33F, I47V, 
I50V, I54L/M, T74P, L76V, I84V, and L89V); the virologic efficacy of DRV (with ritonavir 
used as pharmacokinetic booster [rtv]) is compromised in the presence of ≥3 DRV RAMs and 
each of the 11 DRV RAMs is found in association with a median number of 13 to 
15 International AIDS Society-United States of America (IAS-USA) PI RAMs.28 In a recent 
analysis of nearly 78,000 isolates obtained and submitted in the USA for routine genotypic 
resistance testing, the prevalence of isolates without DRV RAMs increased consistently from 
77.7% in 2006 to 92.8% in 2012, indicating a low prevalence of DRV RAMs.18 In the same 
analysis a very low proportion of isolates (2.6%) were identified as having ≥3 DRV RAMs. 
Additionally, once-daily boosted-darunavir has been extensively studied in treatment-naïve and 
treatment-experienced subjects with no DRV RAMs.4,24,36
In treatment-naïve subjects 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
27
Approved, Date: 16 November 2017
experiencing virologic failure, boosted-darunavir (either with rtv or COBI) demonstrated a high 
genetic barrier to resistance, with almost no treatment-emergent primary or DRV RAMs and no 
loss of DRV susceptibility detected.24,36
Another major challenge to effective treatment of subjects with HIV is medication adherence.5
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.25 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 ART, total pill burden, dosing frequency, and safety 
concerns are among the greatest obstacles to achieving adherence.5,34,35 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.16,20,41
Co-formulated products help to decrease tablet burden and may increase a subject’s ability to 
adhere to a regimen. Currently, there are only 3 highly effective, once-daily single-tablet 
regimens approved for the treatment of HIV-1 infection and recommended by the DHHS for 
treatment-naïve subjects: Genvoya® (or E/C/F/TAF); Stribild® (EVG/COBI/FTC/tenofovir 
disoproxil fumarate (TDF) or E/C/F/TDF); and Triumeq® (abacavir [ABC]/lamivudine 
[3TC]/dolutegravir [DTG]).9 These single-tablet regimens have characteristics that limit their 
ability to be used in a Test and Treat model of care. Elvitegravir has been noted to have a low 
genetic barrier to resistance, evidenced by treatment-emergent primary integrase (INI) mutations 
developing in treatment-naïve subjects who experience virologic failure.11 Triumeq® contains 
ABC, which requires human leukocyte antigen (HLA)-B*5701 testing before initiation.38 Given 
these limitations, there are no currently available single-tablet regimens that provide a high 
genetic barrier to resistance and a clinical profile compatible with starting ART in a Test and 
Treat model of care.
Finally, the safety and tolerability of ARV regimens are critical factors that affect adherence 
levels. Once-daily boosted-darunavir has been extensively studied in Phase 3 clinical studies. 
ARTEMIS (AntiRetroviral Therapy with Tibotec Medicinal Compound 114
(TMC114)
Examined In naïve Subjects; NCT00258557), a randomized, open-label, Phase 3, 192-week 
study evaluating the safety and efficacy of once daily DRV/ritonavir (RTV), showed a 
discontinuation rate due to adverse drug reactions (ADRs) of only 2.3% at 192 weeks. The most 
common clinical ADRs to DRV/RTV greater than or equal to grade 2 were diarrhea, nausea, 
rash, headache, abdominal pain, and vomiting.24 Additionally, in Study 0130, a Phase 3b open-
label, single-arm study
designed to evaluate the safety, tolerability, efficacy,
and 
pharmacokinetics of COBI-boosted DRV in HIV-1 infected adults (as single agents) in 
combination with 2 fully active, investigator-selected nucleoside/nucleotide reverse transcriptase 
inhibitors (N[t]RTIs), ADRs associated with DRV + COBI evaluated through Week 24 or 48 did 
not differ substantially from those reported in clinical studies with DRV/RTV.36 Ongoing 
Phase 3 studies are evaluating the efficacy and safety profile of D/C/F/TAF.2 The combination of 
D/C/F/TAF is not anticipated to exacerbate known toxicities or lead to new toxicities compared 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
28
Approved, Date: 16 November 2017
with DRV/COBI FDC coadministered with FTC/TDF FDC. TAF and FTC have established 
clinical safety profiles with no significant toxicities observed.
Given these factors, the single-tablet regimen of D/C/F/TAF may serve as an ideal regimen for a 
Test and Treat model of care, combining potency, sustained efficacy, a high genetic barrier to 
resistance, with a well described safety profile of the individual components, and practical, 
convenient dosing.
1.2.1.
Darunavir (PREZISTA®)
Darunavir (formerly known as TMC114) is an inhibitor of the catalytic activity of HIV-1 
protease with potent in vitro antiviral activity against both wild-type and PI-resistant HIV-1 
strains. Darunavir 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. 
Darunavir has been developed by the sponsor as tablets at different strengths and as an oral 
suspension. In combination with low-dose rtv as a pharmacokinetic booster and other ARVs, it 
has shown significant efficacy in treatment-naïve and treatment-experienced patients. Darunavir, 
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 RAMs. 
COBI-boosted DRV is only approved for use in adults.
Darunavir was first registered in the USA (June 2006) and has obtained marketing authorization 
in the European Union (EU) in February 2007. As of 23 December 2014, DRV was registered in 
more than 99 countries around the world. Adverse drug reactions 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 
ART-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.
1.2.2.
Cobicistat (Tybost®)
Cobicistat (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. Cobicistat has been shown to be a more 
specific, mechanism-based CYP3A inhibitor than rtv. Cobicistat displays weak to minimal 
inhibition of other CYP enzymes; it is a less potent inducer of other metabolizing enzymes in 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
29
Approved, Date: 16 November 2017
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.
Cobicistat, as a single 150-mg tablet, has been developed by Gilead Sciences, Inc (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. Cobicistat 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, ART-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 ART-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, ART-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 
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. 
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1.2.3.
Emtricitabine (Emtriva®)
Emtricitabine 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. Emtricitabine 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 EU, 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. Emtricitabine 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). 
1.2.4.
Tenofovir Alafenamide 
Tenofovir alafenamide (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 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) 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, 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.
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.
1.3.
Overall Rationale for the Study
The goals of this study are to assess the efficacy and safety of D/C/F/TAF in newly diagnosed 
HIV-1 infected subjects starting ART in a Test and Treat model.
Thus far, only a few studies have examined Test and Treat models of HIV care. Most studies that 
have been completed or are ongoing are limited to the developing world, and conducted with 
regimens that are not recommended by the DHHS Treatment Guidelines.9 Differences in 
screening, healthcare system administration, treatment guidelines, and treatment regimens may 
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affect the applicability of these studies to newly diagnosed HIV-1 infected subjects in the United 
States and other developed nations. As the D/C/F/TAF FDC is still being examined in Phase 3 
clinical studies, no evidence currently exists using D/C/F/TAF FDC in a Test and Treat model. 
Given these factors, findings from this study will be used to generate data on the efficacy and 
safety profile of D/C/F/TAF FDC in newly diagnosed HIV-1 infected, treatment-naïve subjects 
using a Test and Treat model of care.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective of this study is to assess the efficacy of D/C/F/TAF FDC in a Test and 
Treat model of care in newly diagnosed HIV-1-infected, treatment-naive subjects as determined 
by the proportion of virologic responders defined as having HIV-1 RNA <50 copies/mL at 
Week 48 (Food and Drug Administration [FDA]-defined intent to treat [ITT] snapshot analysis).
Secondary Objectives
The secondary objectives of this study are:

To assess virologic and immunologic changes in the study population through 12, 24, and 
48 weeks of treatment 

To evaluate the incidence of grade 3 and 4 adverse events, serious adverse events, and 
premature discontinuations due to adverse events through 24 and 48 weeks of treatment, and 
during the extension phase

To evaluate the frequency of discontinuation of D/C/F/TAF FDC due to protocol-specific 
stopping rules (refer to Section 3.1)

To assess baseline viral resistance in the study population 

To assess the development of viral resistance in the study population through 24 and 
48 weeks of treatment, and during the extension phase

To assess the proportion of subjects retained in care after discontinuation of study drug 
before Week 48

To evaluate the influence of various intrinsic and extrinsic factors on retention in care

To assess the proportion of subjects lost to follow-up through 24 and 48 weeks of treatment

To evaluate adherence by pill count to D/C/F/TAF FDC in the study population through 
24 and 48 weeks of treatment 

To evaluate adherence by subject self-report, using a 4-day recall period through Weeks 24 
and 48

To describe predictors of suboptimal adherence (<95% adherence by pill count) in the study 
population 
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Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017

To assess the HIV Treatment Satisfaction Questionnaire-status version (HIVTSQs) at 
Weeks 4, 24, and 48

To evaluate healthcare resource utilization (HRU) and cost and their temporal trends in the 
study population through 48 weeks of treatment
2.1.2.
Endpoints
Primary Endpoint
The primary endpoint of this study is the proportion of subjects who have HIV-1 RNA 
<50 copies/mL at Week 48 as defined by the FDA snapshot analysis (ITT).
Secondary Endpoints
The secondary endpoints of this study are:
Efficacy

Change from baseline in log10 HIV-1 RNA viral load at Weeks 2, 4, 8, 12, 24, 36, and 48

Proportion of subjects who have HIV-1 RNA <50 copies/mL at Week 24

The change from baseline in CD4+ cell count at Weeks 12, 24, and 48 
Safety

Proportion of subjects that required discontinuation after enrollment based on safety 
stopping rules (refer to Section 3.1)

Proportion of subjects discontinuing therapy due to adverse events

Proportion of subjects experiencing grade 3 and 4 adverse events

Proportion of subjects experiencing grade 3 and 4 laboratory abnormalities 
Resistance

Proportion of subjects meeting resistance stopping rules (refer to Section 3.1), requiring 
discontinuation of study drug due to baseline resistance findings

Proportion of subjects with baseline PR, RT, and INI RAMs

Proportion of subjects developing RAMs and loss of phenotypic susceptibility, when 
available, upon meeting protocol-defined virologic failure

Proportion of subjects with protocol-defined virologic failure at Week 24 and Week 48, and 
during the extension phase
Retention in Care

Proportion of subjects lost-to-follow-up throughout the 48 weeks of treatment

Proportion of subjects discontinuing study drug for any reason other than withdrawal of 
consent prior to Week 48 who have a documented clinic visit with a healthcare provider 
within 90 days of discontinuing study drug
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
33
Approved, Date: 16 November 2017
Adherence

Adherence rates by pill count at Weeks 4, 8, 12, 24, 36, and 48

Adherence rates by subject self-report, using a 4-day recall at Weeks 4, 8, 12, 24, 36, and 48
Tolerability/Patient-reported Outcomes 

Mean total scores for the HIVTSQs at Weeks 4, 24, and 4812
Healthcare Resource Utilization/Pharmacoeconomics

The number and duration of hospitalizations, number and type of outpatient visits, number 
of emergency room visits, and number and type of medications used (both HIV-related and
All-cause as assessed by the investigator) throughout the main study period

Direct medical costs will be calculated in USA dollars based on HRU noted above 
Refer to Section 9, Study Evaluation, for evaluations related to endpoints.
2.2.
Hypothesis
No formal hypothesis will be tested. The findings from this study will be used to generate data 
on the efficacy and safety profile of D/C/F/TAF FDC in newly diagnosed HIV-1 infected, 
treatment-naïve subjects using a Test and Treat model of care.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a single-arm, open-label, prospective, multicenter Phase 3 study to assess the efficacy and 
safety of D/C/F/TAF FDC in newly diagnosed (ie, within 2 weeks of the screening/baseline visit
[Day 1]) HIV-1 infected treatment-naïve subjects at least 18 years of age as part of a Test and 
Treat model of care in the USA.
A target of approximately 100 subjects will participate in this study. 
After obtaining informed consent, a blood sample will be collected for central laboratory testing. 
The in- and exclusion criteria will be reviewed to confirm the subject’s eligibility. The 
screening/baseline visit (Day 1) should take place no later than 2 weeks following evidence of 
newly documented HIV-1 infection.
Study drug will be dispensed before the results from the screening/baseline safety and resistance 
laboratory tests are available. Subjects will receive treatment in a single-arm open-label fashion 
as follows:
D/C/F/TAF: DRV 800 mg + COBI 150 mg + FTC 200 mg + TAF 10 mg FDC
Subjects must start treatment within 24 hours of the screening/baseline visit. 
Following initiation of treatment, a safety assessment will be performed by the investigator at 
Day 3 +1 week, or as soon as the final screening/baseline laboratory report becomes available.
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
Subjects meeting any of the below safety stopping rules (based on the receipt of the 
screening/baseline laboratory findings) will be contacted to return to the study site for possible 
early study treatment discontinuation (ESTD) and for additional follow-up.

Estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal 
Disease (MDRD19,22,33) formula <50 mL/min.

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5×upper limit of 
normal (ULN)

Serum lipase ≥1.5×ULN 

Positive serum human chorionic gonadotropin pregnancy test (β-hCG) for women of 
childbearing potential

Laboratory results that the investigator believes should result in discontinuation of study 
medication (Note: It is recommended that the investigator contacts the sponsor’s medical 
monitor to discuss the discontinuation)

Subjects identified with active hepatitis C virus (HCV) infection that in the opinion of the 
investigator requires HCV treatment immediately or expected to be needed during the 
course of the study with agents not compatible with D/C/F/TAF FDC.
Retesting of abnormal screening/baseline safety laboratory values noted above will be allowed 
once. Retesting will take place during an unscheduled visit.
The investigator will review the ARV screening/baseline resistance data at Week 4 ±7 days or 
sooner, depending on the availability of the screening/baseline HIV genotypic drug resistance 
testing results from the central laboratory. Subjects who do not show full sensitivity to all drugs 
in the FDC study regimen according to the susceptibility assessment in the GenoSure Prime®
report will be contacted to return to the study site for ESTD. Subjects with identified resistance 
to lamivudine/FTC, attributed to the presence of the M184I/V mutation alone will be permitted 
to remain in the study.
Subjects will be treated for 48 weeks in the main study period and will return to the site for visits 
at Weeks 2, 4, 8, 12, 24, 36, and 48. Assessment of drug accountability and reasons for non-
adherence, and recording of concomitant therapies, adverse events, vital signs (including the 
subject’s body weight), and physical examinations (complete or symptom-directed) will be 
performed at each visit from baseline onwards. Laboratory evaluations for efficacy and safety 
(HIV-1 viral load, biochemistry, hematology, and urinalysis) will be performed at all study visits. 
CD4+/CD8+ cell count will be assessed at Weeks 4, 8, 12, 24, 36, and 48. Patient-reported 
outcome (PRO) measures will be assessed at Weeks 4, 24, and 48 using the validated 10-item 
HIVTSQs (Version 2006)12 (Attachment 7). Medical resource utilization data will be collected 
from all subjects throughout the main study period.
Subjects who are on study drug and who experience a protocol-defined virologic failure (see 
below) will undergo genotypic and phenotypic resistance testing, preferably at the time of the 
confirmed virologic failure visit if the HIV-1 RNA is ≥400 copies/mL. If resistance testing is not 
able to be performed at the time of confirmed virologic failure, resistance testing may be 
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Clinical Protocol TMC114FD2HTX3002 Amendment 1
35
Approved, Date: 16 November 2017
performed at the point of unconfirmed virologic failure or a later time point if HIV-1 RNA is 
≥400 copies/mL. Subjects who have persistent HIV-1 RNA ≥400 copies/mL past Week 24 but do 
not meet the definition of virologic failure, should have their viral load monitored closely, and if 
appropriate undergo genotypic and phenotypic resistance testing. In case resistance to study 
drugs is observed, the subject may be discontinued from the study at the investigator's discretion.
If the investigator makes the decision that the subject can continue in the study, additional 
resistance testing may be performed as deemed necessary. Protocol defined virologic failure is 
not considered a stopping rule.
Virologic failure will be defined in this study as follows:
Virologic Nonresponse: 

HIV-1 RNA <1 log10 reduction from baseline, AND
HIV-1 RNA ≥400 copies/mL at the Week 12 visit, subsequently confirmed at an
unscheduled visit conducted within 2 to 4 weeks after Week 12
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 a
scheduled or unscheduled visit conducted within 2 to 4 weeks of the HIV-1 RNA result; 
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 conducted within 2 to 
4 weeks of the HIV-1 RNA result. 
Subjects who meet the criteria for protocol-defined virologic failure will be managed according 
to the schema provided in Attachment 1.
Unscheduled visits can be conducted as needed based on individual tolerability issues, or 
virologic reasons (ie, suspected virologic failure) that occur between scheduled visits.
Subjects who prematurely discontinue study treatment during the open-label treatment period 
will be required to complete ESTD assessments as soon as possible but no later than 1 week of 
discontinuing study treatment. 
In addition, a follow-up visit is required for any subject who has an ongoing adverse event or 
serious adverse event at the time of his/her last study visit. These subjects are required to return 
to the site 30 days (±7 days) after completion of the last study-related visit (unless consent is 
withdrawn).
Subjects who have completed the Week 48 visit will be given the opportunity to continue 
D/C/F/TAF treatment during an extension period until the D/C/F/TAF FDC tablet becomes 
commercially available and is reimbursed, or can be accessed through another source, or until the 
sponsor terminates clinical development. At Week 48 the investigator should dispense a 
sufficient supply of D/C/F/TAF to maintain continuity of care for the subject, however no more 
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
than 12 weeks of study medication should be dispensed. If a subject requires more than 12 weeks 
of study medication, the subject should return to the site for additional drug dispensation.
During the extension period, subjects will have a study visit at the site once every 6 months, if 
applicable, and complete the procedures indicated in the Time and Events Schedule, and 
additionally at the time of transition to commercial D/C/F/TAF, for final data collection.
At the end of the study (or at ESTD), subjects will resume routine clinical care with their care 
provider who will determine the future care of that subject. In anticipation of transitioning the 
subject to routine clinical care at the end of the study (or early discontinuation), the investigator 
should take steps to ensure a smooth transition (ie, secure insurance etc.) well in advance of the 
final study visit, so that the subjects’ ART is not interrupted.
For those subjects discontinuing therapy before Week 48, the investigator will be asked to 
monitor the subject’s retention in care defined as having one documented clinic visit within 
90 days of discontinuing the study treatment (unless consent is withdrawn).
The end of the study is defined as completion of the last data collection visit for the last subject 
participating in the study. For the purpose of the primary analysis, a subject will be considered to 
have completed the study if data collection as required per protocol through the complete course 
of 48 weeks of ART has been completed.
An interim analysis will be conducted after the last subject enrolled has been assessed for safety 
at Day 3, and for resistance stopping rules at Week 4.
The primary analysis of this study will be performed once all subjects have completed the 
Week 48 visit and the 30-day follow-up visit (if applicable), or discontinued earlier.
3.2.
Study Design Rationale
Study Period
A treatment duration of 48 weeks is chosen to align with the traditional efficacy endpoint of 
previous clinical studies in treatment-naïve subjects. This is the minimal duration of time 
required to provide clinically relevant results regarding the efficacy and safety of this regimen in 
this patient population. To assure continued follow-up of the study participants and gain further 
safety information, subjects who prematurely discontinue study treatment will be asked to attend 
the ESTD (and an additional follow-up visit, if applicable). In order to maintain continuity of 
care, subjects will be given the opportunity to continue D/C/F/TAF treatment after Week 48 
during an extension period, until the D/C/F/TAF FDC tablet becomes commercially available 
and is reimbursed, or can be accessed through another source, or until the sponsor terminates 
clinical development.
Dose Selection
Darunavir 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 
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
37
Approved, Date: 16 November 2017
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).15 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).15 GS-US-299-0101 
was a Phase 1, healthy-volunteer, adaptive-design, multiple-dose study that evaluated the 
bioavailability of 3 formulations of a D/C/F/TAF FDC tablet. The results indicated that the 
D/C/F/TAF 25 mg tablet formulations provided TAF exposures in a range associated with 
antiviral activity (GS-US-120-0104) and consistent with the findings from study GS-US-311-
0101 (Cohorts 2 and 3), where DRV/COBI was coadministered with FTC/TAF 25 mg. The 
pharmacokinetic data also demonstrated achievement of TAF exposures that were associated 
with potent antiviral activity with the D/C/F/TAF 10 mg (monolayer formulation) tablet, and 
moreover TFV exposures with this formulation were in the range of historical data with TAF 
25 mg dosed alone or with the E/C/F/TAF 10 mg tablet. In addition, administration of the 
D/C/F/TAF 10 mg tablet resulted in ~90% lower steady-state TFV exposure versus COBI-
boosted DRV plus FTC/TDF. Exposures of COBI-boosted DRV and FTC were comparable 
when administered as a single D/C/F/TAF 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.
Toxicity Management
The combination of D/C/F/TAF is not anticipated to exacerbate known toxicities or lead to new 
toxicities. Measures and guidelines for the monitoring and management of specific toxicities 
with DRV, COBI, FTC, or TAF are included in Section 9.8 of this protocol. The presented 
toxicity management guidelines are applicable throughout the entire study starting from baseline 
through the 48-week main study period and through the extension period (or ESTD and an 
additional follow-up visit, if applicable).
Medical Resource Utilization and Health Economics Data Collection
Treatment of HIV-1 infection with D/C/F/TAF may result in a change in medical resource 
utilization from baseline over the duration of the study. 
Medical resource utilization data as defined in Section 9.4 will be collected throughout the main 
study period. Additionally, costs will be assigned to type of HRU to calculate a per subject per 
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Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
month cost associated with the initiation and maintenance of ART. These outcome measures are 
being examined as part of this study to ensure they are captured as accurately as possible, in a 
prospective fashion. Previous retrospective data have demonstrated a decrease in overall medical 
resource utilization with the initiation of a boosted-darunavir based regimen.45 While there is no 
comparator arm in this study, the inclusion of these endpoints as part of this study will help 
describe if similar observations are seen in a prospective cohort starting treatment on 
D/C/F/TAF. The data can also provide input for future economic modeling analysis.
Similarly, this study aims to describe changes in PRO assessed by the 10-item HIVTSQs
throughout the main study period (ie, Weeks 4, 24, and 48). Satisfaction with HIV therapy is 
being evaluated more frequently in HIV clinical studies. The HIVTSQ was designed specifically 
to measure satisfaction with medication for people infected with HIV. 43,44 In FLAMINGO, an 
open-label comparative study of DRV and DTG in combination with NRTIs, improvements in 
HIVTSQ score from baseline was observed over a 48-week period.6 While this study itself is 
non-comparative, the aim is to describe changes in patient satisfaction as a result of starting 
treatment with D/C/F/TAF. 
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 2 weeks following evidence of newly 
documented HIV-1 infection. The screening and baseline assessments should preferably be 
completed the same day (Day 1), but if necessary, can be performed on different days, but must 
be completed within 2 business days of signing the ICF. Study drug should not be dispensed 
until all screening procedures have been completed and the investigator has determined that the 
subject meets the inclusion/exclusion criteria.
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 must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed. 
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Sign an informed consent form (ICF) indicating that he or she understands the purpose 
of, and procedures required for, the study and is willing to participate in the study.
2.
Man or woman at least 18 years of age.
3.
Newly diagnosed with HIV-1 evidenced by any of the following within 2 weeks of the 
screening/baseline visit:
HIV Rapid Antibody positive*; OR
HIV Immunoassay positive; OR
Positive p24 antigen and a HIV-1 RNA viral load ≥5,000 copies/mL; OR
Non-reactive HIV-1 antibody/antigen assays and HIV-1 RNA viral load 
≥5,000 copies/mL. HIV-1 RNA viral load must be confirmed once within 1 week 
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
39
Approved, Date: 16 November 2017
of initial HIV-1 RNA viral load test.
* For those subjects testing initially positive on a 4th generation HIV Rapid Antibody 
Assay, results should be confirmed on a 3rd generation HIV Rapid Antibody Assay at a 
minimum, or an HIV Immunoassay, unless the investigator suspects acute or recent 
infection.
4.
Antiretroviral treatment-naïve, except for the use of TRUVADA® for pre-exposure 
prophylaxis (PrEP).
5.
Contraceptive use by men or women should be consistent with the local regulations 
regarding the use of contraceptive methods for subject participating in clinical studies.
A woman must be either:
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); OR
Surgically sterile (had total hysterectomy or bilateral oophorectomy, tubal 
ligation/bilateral tubal clips without reversal operation, or otherwise incapable of 
becoming pregnant); OR
Not heterosexually active for the duration of the study; OR
Have a vasectomized partner; OR
If of childbearing potential and heterosexually active, practicing a highly effective 
method of birth control (as specified below) before entry, and agree to continue to 
use a highly effective method of contraception throughout the study, and for at 
least 90 days after receiving the last dose of study drug. Women with tubal 
ligation are required to use one additional contraceptive method.
Estrogen-based hormonal contraception may not be reliable when taking the study 
drug. Therefore, to be eligible for this study, women of childbearing potential 
should either use:

a double-barrier method (male condom + either diaphragm or cervical cap); OR

non-estrogen hormonal based contraceptives in combination with a barrier 
contraceptive (male condom, diaphragm or cervical cap, or female condom); 
OR

intrauterine device in combination with a barrier contraceptive (male condom, 
diaphragm or cervical cap, or female condom).
Note: A male condom and female condom should not be used together due to risk of 
breakage or damage caused by latex friction.
6.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for 90 days after receiving the last dose of study drug.
7.
A woman of childbearing potential must have a negative urine pregnancy test at 
screening.
8.
Men with a female partner of childbearing potential must agree to use adequate reliable 
contraceptive methods (see also Inclusion Criterion 5) during the study until 90 days 
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
40
Approved, Date: 16 November 2017
after receiving the last dose of study drug

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 study drug and for 
up to 90 days after receiving the last dose of study drug.
9.
Men must agree not to donate sperm during the study until 90 days after receiving the 
last dose of study drug (or longer, if dictated by local regulations).
10.
Must be able to swallow whole tablets.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Known active cryptococcal infection, active toxoplasmic encephalitis, Mycobacterium 
tuberculosis infection, or another AIDS-defining condition that in the judgement of the 
investigator would increase the risk of morbidity or mortality.
2.
Known history of clinically relevant hepatic disease or hepatitis that in the 
investigator’s judgement is not compatible with D/C/F/TAF FDC.
3.
Known history of cirrhosis as diagnosed based on local practices. 
4.
Known history of chronic (≥3 months) renal insufficiency, defined as having an eGFR 
<50 mL/min according to the MDRD formula.
5.
Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this 
study or within 90 days after the last dose of study treatment.
6.
Plans to father a child while enrolled in this study or within 90 days after the last dose 
of study treatment.
7.
Current alcohol or substance use judged by the investigator to potentially interfere 
with subject study adherence.
8.
Known history of malignancy within the past 5 years or ongoing malignancy other 
than cutaneous Kaposi’s sarcoma, basal cell carcinoma, or resected, noninvasive 
cutaneous squamous carcinoma.
9.
Known active, severe infections (other than HIV-1 infection) requiring parenteral 
antibiotic or antifungal therapy within 30 days prior to screening.
10.
Any other condition or prior therapy 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 prevent, limit, or confound the protocol-specified assessments.
11.
Subject unlikely to comply with the protocol requirements, based on clinical judgment.
12.
Received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 90 days before the planned first dose of 
study treatment or is currently enrolled in an investigational study without prior 
approval from the sponsor.
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Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
13.
Subjects receiving ongoing therapy with contraindicated, not recommended, drugs that 
cannot be adequately dose-adjusted, or subjects with any known allergies to the 
excipients of the D/C/F/TAF FDC.14,15
14.
Employee of the investigator or study site, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study site, as well as 
family members of the employees or the investigator, or employees of Johnson & 
Johnson or Gilead.
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.
Refer to Section 8, Prestudy and Concomitant Therapy, for details regarding prohibited 
and restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements) in Sections 4.1 and 
4.2.
3.
All HIV-infected subjects should be advised to take the necessary precautions to 
reduce the risk of transmitting HIV.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
As this is single-arm study, randomization is not applicable. All subjects will receive the same 
treatment.
Blinding
As this is an open-label study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
At the screening/baseline visit (Day 1), eligible subjects will start treatment with D/C/F/TAF 
FDC in a single-arm open-label fashion. All subjects will receive treatment as follows:

D/C/F/TAF FDC: DRV 800 mg + COBI 150 mg + FTC 200 mg + TAF 10 mg FDC
Initiation of study treatment can only start after all screening/baseline tests and procedures have 
been completed and must take place within 24 hours after the baseline visit. D/C/F/TAF FDC 
must be taken orally with food. All subjects will be counseled to swallow D/C/F/TAF whole 
once daily at approximately the same time each day, according to their preference. 
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol.
If subjects notice that they have 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 
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
continue their usual dosing schedule. If subjects notice that they have missed a dose more than 
12 hours after the time it is usually taken, they should be instructed not to take it and simply 
resume the usual dosing schedule. Subjects should not take a double dose to make up for a 
missed dose.
Instructions regarding how to take the study drug, what to do if a dose is missed and how to store 
the medication will be provided on the wallet (study) card (refer to Section 12.3.1).
The last time of study drug administration will be recorded at each visit.
Prolonged temporary study treatment interruptions are only deemed acceptable if motivated by 
safety reasons and if they do not last longer than 4 consecutive weeks. The sponsor should be 
notified when such temporary interruption occurs.
In order to maintain continuity of care, subjects will be given the opportunity to continue the 
D/C/F/TAF treatment after Week 48 during an extension period until the D/C/F/TAF FDC tablet 
becomes commercially available and is reimbursed, or can be accessed through another source, 
or until the sponsor terminates clinical development.
7.
TREATMENT COMPLIANCE
Adherence to study treatment will be assessed by pill counts and by subject self-report, using a 
4-day recall period. 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, and taking into account the period elapsed since the previous visit.
The investigator/designated study-site personnel will maintain a log of all study drug dispensed 
and returned. Drug supplies for each subject will be inventoried and accounted for throughout 
the study (see also Section 14.5, Drug Accountability). If a subject’s medication intake is not 
according to the study protocol, it will be the investigator’s responsibility to take the necessary 
measures to ensure future compliance to the protocol.
If non-adherence is identified during drug accountability the reasons for non-adherence will be 
captured in the electronic case report form (eCRF).
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapies administered up to 30 days before the 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 study drug must be recorded in the eCRF. Recorded 
information will include a description of the type of drug, treatment period, dosing regimen, 
route of administration, and its indication. Modification of an effective pre-existing therapy 
should not be made for the explicit purpose of entering a subject into the study if such 
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
modification of treatment is not clinically acceptable. Any change in dosage of the medication 
must be reported in the eCRF.
For any concomitant therapy given as a treatment for a new condition or for a worsening of an 
existing condition occurring after signing of the ICF, the condition must be documented in the 
Adverse Event/HIV-related event section of the eCRF.
Data on concomitant therapies will be collected up to the last study visit. Concomitant therapies 
should be recorded beyond the last study visit only in conjunction with the treatment of serious 
adverse events that meet the criteria outlined in this protocol.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
Contraindicated and Disallowed Concomitant Agents
Darunavir coadministered with COBI is an inhibitor of CYP3A, CYP2D6, and P-glycoprotein 
(P-gp). Cobicistat also inhibits the transporters breast cancer resistance protein (BCRP), multi-
antimicrobial extrusion protein (MATE)-1, organic anion-transporting polypeptide (OATP)1B1 
and OATP1B3. Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or 
CYP2C19. Cobicistat is not expected to induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, 
uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), or multidrug resistance protein 1 
(MDR1).
D/C/F/TAF FDC should not be coadministered with medicinal products that are highly 
dependent on CYP3A for clearance and for which increased plasma concentrations are 
associated with serious and/or life-threatening events (narrow therapeutic index). These 
medicinal products include alfuzosin, astemizole, carbamazepine, cisapride, colchicine (in 
subjects with renal and/or hepatic impairment), dronedarone, elbasvir/grazoprevir, ergot 
alkaloids (eg, dihydroergotamine, ergotamine, ergonovine and methylergonovine), lovastatin, 
lurasidone, oral midazolam, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, sildenafil 
(when used for treatment of pulmonary arterial hypertension), simvastatin, St John's Wort, 
terfenadine, and triazolam.
Emtricitabine is not an inhibitor of human CYP450 enzymes. In vitro and clinical drug 
interaction studies have shown that the potential for CYP-mediated interactions involving FTC 
with other medicinal products is low. FTC is primarily excreted by the kidneys by a combination 
of glomerular filtration and active tubular secretion. No drug interactions due to competition for 
renal excretion have been observed; however, coadministration of FTC with drugs that are 
eliminated by active tubular secretion may increase concentrations of FTC and/or the 
coadministered drug. Drugs that decrease renal function may increase concentrations of FTC.
Tenofovir alafenamide is a substrate of the efflux transporter P-gp. Drugs that induce P-gp 
activity are expected to decrease the absorption of TAF, resulting in decreased plasma 
concentrations of TAF, which may lead to loss of therapeutic effect of D/C/F/TAF FDC and 
development of resistance. These medicinal products include antimycobacterials (rifabutin, 
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
44
Approved, Date: 16 November 2017
rifampin, rifapentine) and anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, 
phenytoin). Coadministration of D/C/F/TAF FDC with drugs that inhibit P-gp may increase the 
absorption and plasma concentration of TAF. 
Given the possibility for pharmacokinetic interactions, investigators should refer to the IB for the 
D/C/F/TAF FDC and individual Prescribing Information for the components of the D/C/F/TAF 
FDC for potential contraindications and management of drug interactions to preserve subject
safety during the study. 
Administration of any of the contraindicated or disallowed concomitant medication must have 
been discontinued at least 30 days before the screening/baseline visit (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. 
ART beyond study drug is also prohibited during the study.
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 
before discussion with the medical monitor, the investigator must notify the sponsor as soon as 
becoming aware.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, medical 
resource utilization, health economic, safety, and other measurements applicable to this study.
The protocol procedures are described in detail in Sections 9.2 through 9.8.
Additional visits may be required if, in the investigator’s opinion, further clinical or laboratory 
evaluation is needed. Repeat or unscheduled samples may be required for safety reasons, for 
technical issues with the samples, or for confirmation of protocol-defined virologic failure. 
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. Findings during these unscheduled visits or assessments need to be 
reported in the eCRF.
Some flexibility in the planning of the visits is allowed, however, the total treatment duration at 
the end of the main study period should be 48 weeks. A window of ±2 days is allowed for 
Visit 2. All other study visits through Week 48 are to be completed within ±7 days of the 
protocol-specified visit date.
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 
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
during the subject’s participation in the study. If a serum or urine pregnancy test is positive, the 
subject will be withdrawn from the study.
The HIVTSQs assessment should be completed at scheduled visits (see the Time and Events
Schedule) before all other study-related procedures planned during these visits to prevent 
influencing subject perceptions. 
9.1.2.
Screening Phase
The screening assessments indicated in the Time and Events Schedule will occur within 2 weeks 
following evidence of newly documented HIV-1 infection.
The ICF must be signed before any study-specific procedures at the start of the screening period.
Only subjects complying with the selection criteria as specified in Section 4, Subject Population, 
will be included in the study. The investigator will provide detailed information about the study 
to the subject and will obtain written informed consent before each subject’s study participation. 
Procedures indicated in the Time and Events Schedule will only be performed after the subject’s 
written informed consent has been obtained. Relevant historical data obtained from the subject’s 
medical records and/or subject interview will be captured.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will enter the 
open-label treatment phase.
9.1.3.
Open-Label Treatment Phase
9.1.3.1.
Main Study Period
All subjects must start dosing within 24 hours of the screening/baseline visit (Day 1).
Following initiation of treatment, a safety assessment will be made by the investigator at Day 3 
+1 week (or as soon as the final screening/baseline laboratory report becomes available), and the 
ARV screening/baseline resistance data will be reviewed by the investigator at Week 4±7 days or 
sooner, depending on the availability of screening/baseline HIV genotypic drug resistance testing 
results from the central laboratory. The investigator will determine as to whether treatment 
should be discontinued, based on the stopping rules provided in Section 3.1.
Subjects will be treated for 48 weeks in the main study period and will return to the site for visits 
at Weeks 2, 4, 8, 12, 24, 36, and 48 (scheduled relative to the date of the baseline visit) and 
complete the procedures indicated in the Time and Events Schedule. 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.
Subjects experiencing protocol-defined virologic failure (as defined in Section 3.1) will undergo 
genotypic and phenotypic resistance testing. In case resistance to study drugs is observed, the 
subject may be discontinued from the study at the investigator's discretion. Protocol-defined 
virologic failure is not considered a stopping rule.
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
9.1.3.2.
Extension Period
Subjects who have completed the Week 48 visit will be given the opportunity to continue 
D/C/F/TAF treatment during an extension period until the D/C/F/TAF FDC tablet becomes 
commercially available and is reimbursed, or can be accessed through another source, or until the 
sponsor terminates clinical development. At Week 48 the investigator should dispense a 
sufficient supply of D/C/F/TAF to maintain continuity of care for the subject, however no more 
than 12 weeks of study medication should be dispensed. If a subject requires more than 12 weeks 
of study medication, the subject should return to the site for additional drug dispensation. During 
the extension period, subjects will have a study visit at the site once every 6 months, if 
applicable, and complete the procedures indicated in the Time and Events Schedule, and 
additionally at the time of transition to commercial D/C/F/TAF, for final data collection.
Early Study Treatment Discontinuation (ESTD)
Subjects who prematurely discontinue study treatment during the open-label treatment period (ie, 
including the extension period) will be required to complete ESTD assessments as soon as 
possible but no later than 1 week of discontinuing study treatment. 
For subjects who discontinue study treatment after Week 12 for any reason and have HIV-1 
RNA ≥400 copies/mL at the last viral load measurement, the ESTD assessments will also 
include genotypic and phenotypic resistance testing. In case of early discontinuation, an HIV-1 
resistance report will be forwarded to the subject’s primary care provider to assist in the selection 
of a new ARV regimen.
30-Day Follow-up
In addition, a follow-up visit is required for any subject who has an ongoing adverse event or 
serious adverse event at the time of his/her last study visit. These subjects are required to return 
to the site 30 days (±7 days) after completion of the last study-related visit (unless consent is 
withdrawn) and complete all procedures indicated in the Time and Events Schedule.
End of Study
At the end of the study (or at ESTD), subjects will resume routine clinical care with their care 
provider who will transition them to an appropriate treatment regimen. 
9.2.
Efficacy Evaluations
9.2.1.
Antiviral Efficacy and Immunologic Change
Blood samples for determination of plasma HIV-1 RNA viral load and immunologic parameters 
will be taken at the time points specified in the Time and Events Schedule. 
Plasma viral load will be measured using a validated assay at a central laboratory. 
Immunologic change will be determined by changes in CD4+ cell count (absolute and %). 
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 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 adverse events or 
serious adverse events. 
9.2.2.
Resistance Determinations 
HIV-1 genotype/phenotype resistance testing will be performed at the time points specified in 
the Time and Events Schedule. 
Resistance testing at the screening/baseline visit (Day 1) will be performed utilizing the 
GenoSure Prime® assay. Resistance-associated mutations present at baseline will be reported and 
include mutations in the domain of PR, RT, and INI.
To investigate the emergence of resistance, the following subjects will be eligible for 
genotypic/phenotypic resistance testing (PhenoSense GT®):

Any subject who experiences a protocol-defined virologic failure;

Any subject who discontinues study treatment after Week 12 for any reason and has an 
HIV-1 RNA value ≥400 copies/mL at the last viral load measurement;

Any subject who has persistent HIV-1 RNA ≥400 copies/mL past Week 24 but does not 
meet the definition of virologic failure.
Baseline phenotyping may be performed retrospectively on subjects with confirmed protocol-
defined virologic failure if after virologic failure they showed evidence of reduced phenotypic 
susceptibility to any of the study drugs. Evaluations may be performed at other time points at the 
sponsor’s discretion.
9.3.
Pharmacokinetics
Plasma concentrations of DRV and COBI may be determined in subjects experiencing protocol-
defined virologic failure, or subjects who have persistent HIV-1 RNA ≥400 copies/mL past 
Week 24 but do not meet the definition of virologic failure, using stored blood samples collected 
throughout the study, if deemed necessary.
9.4.
Medical Resource Utilization and Health Economics
Medical resource utilization data will be collected in the eCRF by the investigator and study-site 
personnel. The following will be evaluated throughout the study as noted in the Time and Events
Schedule:
Number and duration of hospitalizations.
Number of outpatient visits, including type of visit (eg, general practitioner, specialist)
Number of emergency room visits.
Number and type of medications used (from the Concomitant Medication page of the eCRF).
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
Medical resource utilization will be classified as being either HIV-related or All-cause HRU as 
assessed by the investigator. The costs will be assigned to the type of medical resource utilization 
to calculate a per subject per month cost associated with the initiation and maintenance of ART.
Trends will be assessed over time throughout the study.
9.5.
Adherence
Treatment adherence will be assessed by pill count and by subject self-report at the time points 
specified in the Time and Events Schedule. 
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.
If non-adherence is identified during drug accountability the reasons for non-adherence will be 
captured in the eCRF.
9.6.
Retention in Care
Retention in care will be described as the proportion of subjects who discontinue study treatment 
prior to Week 48 and remain in care after discontinuation (defined as having a documented 
office visit within 90 days of discontinuing the study drug). Subjects who withdraw consent will 
not be followed to assess retention in care. 
9.7.
Safety Evaluations
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule: adverse event reporting, clinical laboratory 
tests (including biochemistry, hematology, urinalysis, and urine chemistry), vital signs, and 
physical examinations (complete or symptom-directed). These protocol procedures are described 
below. In addition to these measurements, guidelines for the management of toxicities are 
described in Section 9.8.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the eCRF.
Clinical events and clinically significant laboratory abnormalities will be graded according to the 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events located in Attachment 2.
Any evaluations showing abnormal results at any time during the study will be followed until 
satisfactory clinical resolution or stabilization. All grade 3 and grade 4 laboratory abnormalities 
and all laboratory abnormalities resulting in an increase of 2 DAIDS grades from baseline will be 
followed until return to baseline or within 1 grade from baseline (ie, ≤grade 2) (see Section 9.8.1, 
General Guidance for the Management of Clinical Events and Laboratory Abnormalities).
Evaluations at the ESTD visit showing abnormal results indicating a possible causal relationship 
with the study treatment must be followed by the investigator (as often as deemed prudent) until 
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
satisfactory clinical resolution or stabilization. Certain long-term adverse events of ART cannot 
be followed to resolution within the setting of this protocol; in these cases, follow-up will be the 
responsibility of the treating physician, which will be agreed upon with the sponsor’s medical 
monitor.
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver or surrogate) 
for the duration of the study. Adverse events will be followed by the investigator as specified in 
Section 12, Adverse Event Reporting.
Special attention will be paid to those subjects who discontinue the study for an adverse event, or 
who experience severe (grade 3) or potentially life-threatening (grade 4) adverse events, or a 
serious adverse events. For reported HIV events, further details will be recorded if these events 
are AIDS-defining illnesses (World Health Organization Clinical Staging of HIV/AIDS, located 
in Attachment 3). For subjects with specific adverse events, toxicity management should be done 
as described in Section 9.8, Toxicity Management.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be 
collected at predefined time points (see Time and Events Schedule). 
All clinical laboratory testing will be performed by the central laboratory and results will be sent 
to the investigator. The investigator must review the laboratory results, document this review, 
and record any clinically relevant changes occurring during the study in the adverse event section 
of the eCRF. The laboratory reports must be filed with the source documents.
The central laboratory will send the investigator and sponsor an alert form whenever a grade 3 or 
grade 4 laboratory abnormality (see Attachment 2) is observed. In case a grade 3 or grade 4 
laboratory abnormality occurs, a confirmatory test should be performed preferably within 
72 hours after the results have become available, before study treatment interruption or 
discontinuation, unless such delay is not consistent with good medical practice. 
If a grade 3 or grade 4 laboratory abnormality is well documented before the start of the study 
and not considered a safety concern by the investigator, a confirmatory retest is not mandatory. 
The following laboratory abnormalities do not warrant mandatory confirmation:

Asymptomatic grade 3 or grade 4 glucose elevations in subjects with pre-existing diabetes.

Asymptomatic grade 3 or grade 4 triglyceride or cholesterol elevations.
For more details on the management of grade 3 and 4 laboratory toxicities that occur during the 
open-label treatment phase, see Section 9.8.1, General Guidance for the Management of Clinical 
Events and Laboratory Abnormalities, and Attachment 4. Please note that this attachment does 
not apply to screening/baseline eGFR, AST, ALT, and lipase, and does also not apply to the 
allowed retesting of abnormal screening/baseline eGFR, AST, ALT, and lipase values (see 
Section 3.1).
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
The following tests will be performed by the central laboratory:

Hematology Panel*
-hemoglobin
-platelet count
-hematocrit
-CD4+ cell count
-absolute neutrophil count
-CD8+ cell count
-white blood cell count (WBC) with differential
-CD4+CD8+ ratio
-red blood cell count (RBC)
* Peripheral blood mononuclear cells (PBMCs) will be isolated from whole blood at the central 
laboratory at predefined time points (see Time and Events Schedule), and stored for future analysis if 
needed.

Serum Chemistry Panel
-glucose
-chloride
-calcium
-phosphate
-calcium corrected for albumin
-blood urea nitrogen (BUN)
-albumin
-serum creatinine, including calculated eGFR
-total protein
-alkaline phosphatase (ALP)
-sodium
-AST
-potassium
-ALT
-bicarbonate (HCO3)
-bilirubin (total, direct, indirect)

Urinalysis (dipstick)
-specific gravity
-ketones
-pH
-bilirubin
-glucose
-urobilinogen
-protein
-nitrite
-blood
-leukocyte esterase
If dipstick results are abnormal, the sediment will be examined microscopically. 
In the microscopic examination, observations other than the presence of WBCs, RBCs, and casts 
may also be reported by the laboratory.

Urine chemistry panel (only in the setting of a suspected renal adverse event; quantitative)
-creatinine
-glucose
-sodium
-protein
-phosphate
-albumin
Additional clinical laboratory assessments to be performed are as follows:
Hepatitis C virus (HCV) testing (HCV antibodies [Ab] and HCV RNA level [only if HCV 
Ab+]) and hepatitis B virus (HBV) testing (anti-hepatitis B core [HBc], anti-hepatitis B 
surface [HBs], hepatitis B surface antigen [HBsAg]) (at screening only). Whenever clinically 
relevant, the investigator can request additional tests at other visits.
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D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
A urine pregnancy test will be performed at screening for all female subjects of childbearing 
potential. A serum human chorionic gonadotropin pregnancy test will be assessed at a central 
laboratory, but the results are not required for enrollment. A urine pregnancy test will be
performed at subsequent study visits as outlined in the Time and Events Schedule. Positive 
urine pregnancy tests will be confirmed with a serum pregnancy test. The results of the serum 
and urine pregnancy tests should be recorded in the eCRF and in the subject’s medical 
records.
Amylase (pancreatic) (only at screening and in case of suspected pancreatitis during the study 
period)
Lipase (only at screening and reflex if amylase elevated) 
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 9.8.2, Cutaneous Events/Rash.
Vital Signs (Including Height and Weight)
Blood pressure (systolic and diastolic) and pulse/heart rate measurements (supine after at least 
5 minutes rest) should be preceded by at least 5 minutes of rest in a quiet setting without 
distractions (eg, television, cell phones). Blood pressure and pulse/heart rate measurements will 
be assessed with a completely automated device. 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.
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 Adverse Event section of the eCRF.
Physical Examination
Complete physical examinations, or symptom-directed examinations (physical examinations for 
which symptoms have been reported by the subject) as needed, will take place at the time points 
in the Time and Events Schedule. 
Complete physical examinations include skin, eyes, ears, nose, and throat, head, neck, and 
thyroid, heart, lung, chest (incl. breasts), abdomen, genitalia, anorectal, lymph nodes, 
musculoskeletal, and neurological. Urogenital/anorectal examination will be performed at the 
discretion of the investigator if clinically relevant. Subjects should be undressed during the 
complete physical examinations, which should be performed by a licensed medical doctor, 
physician’s assistant or nurse practitioner in accordance with local guidelines.
Any clinically relevant findings at screening and changes occurring during the study must be 
recorded in the Adverse Event section of the eCRF.
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Patient-reported Outcomes
Patient-reported outcomes will be assessed at the time points indicated in the Time and Events
Schedule utilizing the HIVTSQs. The HIVTSQs should be completed before all other study-
related procedures planned during these visits to prevent influencing subject perceptions.
9.8.
Toxicity Management
The toxicity management guidelines in this section are applicable throughout the entire study
starting from when the subject starts study medication through the 48-week main study period 
and the extension period. 
General guidance for the management of toxicities is provided in Section 9.8.1. Guidance for 
specific toxicities is provided in Sections 9.8.2 through 9.8.8. In addition, see Section 9.7, Safety 
Evaluations, and Section 12, Adverse Event Reporting, for details on procedures concerning the 
measurement and reporting of clinically relevant abnormalities and toxicities. 
Questions regarding toxicity management should be directed to the sponsor’s medical monitor.
9.8.1.
General Guidance for the Management of Clinical Events and 
Laboratory Abnormalities
Grade 1 and 2
Continue study treatment at the discretion of the investigator.
Grade 3 
For a grade 3 clinical event or clinically relevant laboratory abnormality, study treatment may 
be continued if the event is considered to be unrelated to study treatment.
For a grade 3 clinical event, or clinically relevant laboratory abnormality confirmed by repeat 
testing (see Section 9.7), that is considered related to study treatment, study treatment 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 for asymptomatic grade 3 triglyceride or cholesterol 
elevations.
If a laboratory abnormality recurs to grade 3 following rechallenge with study treatment and 
is considered to be related to study treatment, study treatment should be permanently 
discontinued and the subject managed according to local practice. Recurrence of laboratory 
abnormalities considered unrelated may not require permanent discontinuation. 
Grade 4 
For a grade 4 clinical event or clinically relevant laboratory abnormality confirmed by repeat 
testing (see Section 9.7), that is considered related to study treatment, study treatment 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 
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abnormality that is not confirmed upon repeat testing should be managed according to the 
algorithm for the new toxicity grade. 
Mandatory confirmation is not warranted for asymptomatic grade 4 glucose elevations in 
subjects with pre-existing diabetes, and for asymptomatic grade 4 triglyceride or cholesterol 
elevations.
Study treatment may be continued without dose interruption for a clinically nonrelevant 
grade 4 laboratory abnormalities (eg, grade 4 creatine phosphokinase after strenuous exercise, 
or triglyceride elevation that is nonfasting or that can be medically managed), or a clinical 
event considered unrelated to study treatment.
A schematic overview of these guidelines is provided in Attachment 4 for clinically relevant 
laboratory toxicities that occur while on treatment. Please note that this attachment does not 
apply to screening/baseline eGFR, AST, ALT, and lipase, and does also not apply to the allowed 
retesting of abnormal screening/baseline eGFR, AST, ALT, and lipase values (see Section 3.1).
9.8.2.
Cutaneous Events/Rash
Darunavir is a sulfonamide. Subjects who previously experienced sulfonamide allergy will be 
allowed to enter the study. To date, no potential for cross-sensitivity between drugs in the 
sulfonamide class and DRV has been identified.
Cutaneous events/rash should be captured in the Adverse Event section of the eCRF.
Management of cutaneous events/rash will be at the discretion of the investigator, taking into 
account the following protocol procedures (see also Table 1), and should follow generally 
accepted medical standards. Cetirizine, levocetirizine, topical corticosteroids, and antipruritic 
agents will be allowed at the investigator’s discretion for treatment of all grades of rashes.
Grade 1 and 2 Cutaneous Reaction/Rash
A grade 1 cutaneous reaction/rash is defined as localized rash.
A grade 2 cutaneous reaction/rash is defined as diffuse rash or target lesions.
Subjects experiencing a grade 1 or 2 rash or cutaneous event may continue treatment, or have 
their study treatment interrupted at the investigator’s discretion. Safety sampling (processed by 
the central laboratory) at the time of the rash and clinical follow-up for these adverse events will 
be at the discretion of the investigator; however, close clinical follow-up is recommended to 
monitor for any progression of the adverse event.
Grade 3 and 4 Cutaneous Reaction/Rash
A grade 3 cutaneous reaction/rash is defined as:
Diffuse rash with vesicles or limited number of bullae or superficial ulceration of mucous 
membrane limited to 1 site.
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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× baseline but ≥5×ULN
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
Toxic epidermal necrolysis (TEN)
Subjects experiencing a grade 3 or 4 rash or cutaneous event must have their study treatment 
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.
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Table 1:
Summary of Cutaneous Reaction/Rash Follow-up
DAIDS Toxicity Grade
Definitions
Investigator Action
Grade 1
Localized rash
Subject may continue study 
treatment 
Grade 2
Diffuse rash
Target lesions
Subject may continue study 
treatment 
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× baseline but ≥5× ULN)
- Fever 38°C or 100 F
- Serum sickness-like reaction
- Eosinophils >1,000/mm3
DRESS and AGEP
Permanently discontinue study 
treatment 
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 
treatment
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
9.8.3.
Acute Systemic Allergic Reaction
Management of acute systemic allergic reactions will be at the discretion of the investigator, 
taking into account the following protocol procedures (see also Table 2), and should follow 
generally accepted medical standards.
Grade 1
A grade 1 acute systemic allergic reaction is defined as localized urticaria (wheals) with no 
medical intervention indicated.
Subjects may continue study treatment or have their study treatment 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, Prestudy and Concomitant 
Therapy, or in the local Prescribing Information of the ARV agents.
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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 treatment or have their study treatment 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 treatment. 
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, 
Prestudy and Concomitant Therapy, or in the local Prescribing Information of the ARV agents.
Grade 3
A grade 3 acute systemic allergic reaction is defined as generalized urticaria, or angioedema with 
intervention indicated or symptoms of mild bronchospasm.
Subjects will permanently discontinue study treatment. 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 treatment. Subjects will be treated as clinically 
appropriate. Standard management should be undertaken.
Table 2:
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 
treatment 
Grade 2
Localized urticaria with intervention 
indicated, or
mild angioedema with no intervention 
indicated
Subject may continue study 
treatment 
Grade 3
Generalized urticaria, or
angioedema with intervention indicated, or
symptoms of mild bronchospasm
Permanently discontinue study 
treatment
Grade 4
Acute anaphylaxis, or 
life-threatening bronchospasm, or
laryngeal edema
Permanently discontinue study 
treatment
9.8.4.
Potential Renal Toxicity
Estimated glomerular filtration rate for creatinine clearance (eGFRcreatinine calculated according to 
the MDRD formula will be followed postbaseline during the treatment phase. 
Any subjects who have an eGFRcreatinine of <50 and a decrease of 20% in eGFRcreatinine 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 treatment. 
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The eGFR calculations will be performed and provided to the investigator by the central 
laboratory.
Subjects with negative or trace proteinuria at baseline who develop >1+ proteinuria on urinalysis 
must have 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 site for a 
scheduled or unscheduled follow-up visit. It is recommended that the investigator contacts the 
sponsor’s medical monitor to discuss if further consultation with a nephrologist is clinically 
warranted. 
Once an individual 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.
9.8.5.
Potential Posterior Uveitis Cases
In a 9-month toxicology study conducted in dogs, some animals administered the highest dose of 
TAF (12 to 18 mg/kg) had minimal mononuclear cell infiltration in the posterior uvea, 
considered secondary to general debilitation; this finding did not occur in animals given lower 
doses and it has not occurred in other animal studies. This preclinical finding has also not been 
observed in humans where the dose is much lower, nor have there been reports of posterior 
uveitis in human clinical studies. Nonetheless, if 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.
9.8.6.
Hyperglycemia
Grade 3: 13.89 to 27.75 mmol/L (250-500 mg/dL)
Grade 4: >27.75 mmol/L (>500 mg/dL)
Toxicity management decisions should be based on fasted results. If elevated glucose levels are 
from a nonfasted blood draw, the draw must be repeated after an 8-hour fast. 
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 treatment unless clinical assessment foresees an immediate health risk to the subject. 
Appropriate clinical management of hyperglycemia must be started in a timely fashion if 
applicable. Subjects with persistent grade 3 or 4 glucose elevations despite appropriate anti-
hyperglycemic treatment should permanently discontinue study treatment.
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9.8.7.
Hypertriglyceridemia and Hypercholesterolemia
Hypertriglyceridemia:
Grade 3:
5.7 to 11.4 mmol/L (>500-1,000 mg/dL)
Grade 4:
>11.4 mmol/L (>1,000 mg/dL)
Hypercholesterolemia:
Grade 3:
≥7.77 mmol/L (>300 mg/L)
Grade 4:
Not applicable
Toxicity management decisions should be based on fasted results. If elevated lipid levels are 
from a nonfasted blood draw, the draw must be repeated after an 8-hour fast. 
Subjects who experienced asymptomatic triglyceride or cholesterol elevations of grade 3 or 4 
may continue study treatment unless clinical assessment foresees an immediate health risk to the 
subject.
Hypertriglyceridemia and hypercholesterolemia should be treated according to the specific 
guidelines for treating HIV-positive subjects (see Attachment 5). Current treatment guidelines 
specify different lipid thresholds for intervention for different degrees of cardiovascular risk. The 
presence or absence of other significant cardiovascular risk factors, which include smoking, age, 
family history of premature cardiovascular disease, diabetes, hypertension, low high-density 
lipoprotein (HDL), and prior history of cardiovascular disease should be taken into account. 
Appropriate clinical management of hyperlipidemia in the setting of HIV should be started in a 
timely fashion if applicable, and taking into account the disallowed medications (refer to 
Section 8, Prestudy and Concomitant Therapy).
9.8.8.
Lipodystrophy/Fat Redistribution/Body Changes
Investigators are requested to avoid using the term ‘lipodystrophy acquired’ or ‘fat 
redistribution’ to describe and report body fat abnormalities, as these terms are not descriptive 
nor fully accurate. The different symptoms and gradings are listed in the DAIDS grading table 
(Attachment 2) under Endocrine/Metabolic. The following terms are included: lipohypertrophy, 
lipoatrophy, and gynecomastia.
Although metabolic abnormalities such as hyperlipidemia or hyperglycemia are often associated 
with body changes, these events should be recorded separately at adverse event reporting.
9.9.
Sample Collection and Handling
Blood 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 
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. Additionally, pharmacokinetic analyses 
for DRV and COBI may be performed for those subjects experiencing virologic failure at the 
request of the sponsor. No human genetic testing will be performed on these samples. See also 
Section 16.2.5.
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In addition, PBMCs will be isolated from whole blood at the central laboratory and stored for 
future analysis if needed.
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. See the Time and Events Schedule for the timing and frequency of all sample 
collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
In the period up to Week 48, a subject will be considered to have completed the main study 
period if he or she has continued study medication intake up to Week 48 and has completed 
assessments at Week 48. Subjects who prematurely discontinue study treatment for any reason 
before completion of the 48-week treatment period will not be considered to have completed the 
main study period.
In the period after Week 48, subjects will be considered to have completed the extension period
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, 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 extension period.
10.2.
Withdrawal From the Study
A subject will be automatically withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Discontinuation of study treatment for any reason

Subject request to stop study treatment for any reason.
A subject's study treatment must be discontinued if:

The investigator or sponsor believes (eg, that for safety or tolerability reasons 
(eg, adverse event) it is in the best interest of the subject to discontinue treatment

The subject becomes pregnant 

The subject meets any of the safety stopping rules (see Section 3.1, Overview of Study 
Design)
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
The subject meets any of the resistance stopping rules (see Section 3.1, Overview of 
Study Design)

The subject experiences unacceptable toxicity (as defined in Section 9.8, Toxicity 
Management) 

The subject develops clinical hepatitis

Prolonged temporary study treatment discontinuation >4 consecutive weeks

The study is discontinued at the request of the sponsor, concerned regulatory agency, or 
Independent Ethics Committee/Institutional Review Board (IEC/IRB)
A subject’s study treatment may be discontinued if:

A serious adverse event occurs

The subject fails to comply with the protocol or study staff requirements

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

The subject starts disallowed treatment, or requires new onset treatment with one of the 
disallowed medications (please refer to Section 8, Prestudy and Concomitant Therapy)

The subject experiences protocol-defined virologic failure, shows resistance to study 
drug(s) upon genotypic and phenotypic resistance testing, and the investigator makes 
the decision to discontinue study treatment

The subject experiences persistent HIV-1 RNA ≥400 copies/mL after Week 24, that 
does not meet the protocol-defined virologic failure criteria, but shows resistance to 
study drug(s) upon genotypic and phenotypic resistance testing, and the investigator 
makes the decision to discontinue study treatment
Protocol-defined virologic failure is not considered a stopping rule.
If the investigator considers withdrawing a subject from study treatment for one 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 study treatment during the open-label treatment period
will be required to complete ESTD assessments as soon as possible but no later than 1 week of 
discontinuing study treatment. 
In addition, a follow-up visit is required for any subject who has an ongoing adverse event or 
serious adverse event at the time of his/her last study visit. These subjects are required to return 
to the site 30 days (±7 days) after completion of the last study-related visit (unless consent is 
withdrawn). 
Investigators will refer subjects discontinuing therapy for any reason before Week 48 for follow-
up care, either at a clinic associated with the investigator or an external care facility according to 
subject preference. To assess whether subjects have been retained in care, investigators will be 
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asked to monitor subject’s engagement with the referral site. Retention in care will be defined as 
having a documented office visit within 90 days of discontinuing the study drug before Week 48. 
Subjects who complete the study through Week 48 will not be monitored for retention in care.
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. Study drug dispensed to the withdrawn 
subject may not be dispensed to another subject (unless the bottles are unopened). Subjects who 
withdraw will not be replaced. 
10.3.
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, Long-
Term Retention of Samples for Additional Future Research). In such a case, samples will be 
destroyed after they are no longer needed for the clinical study. Details of the sample retention
for research are presented in the main ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
The following analyses will be performed:

The interim analysis: once all subjects have been assessed for safety at Day 3, and for 
resistance stopping rules at Week 4.

The primary analysis: once all subjects have completed the Week 48 assessments and the 
30-day follow-up visit (if applicable), or discontinued earlier.
11.1.
Analysis Sets
The following analysis sets will be used and are defined:

Intent-to-treat (ITT) population: all subjects who have received at least one dose of study 
drug.

Per-protocol population: ITT population without major protocol deviation that is considered 
to have an impact on the safety or efficacy assessments.
11.2.
Subject Information
Subject information will be analyzed based on the ITT population, unless otherwise specified.
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For all subjects who receive at least 1 dose of study drug descriptive statistics will be provided.
11.3.
Sample Size Determination
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 (ITT). As this is an 
exploratory study with no formal hypothesis testing on the primary endpoint, no formal sample 
size calculation was performed. With a sample size of 100 subjects and an expected virologic 
response rate ranging from 60-80%, the exact corresponding 95% confidence intervals (CIs) are: 
60% (49.7%, 69.7%), 70% (60.0%, 78.8%), and 80% (70.8%, 87.3%). The half-width of the 
exact corresponding 2-sided 95% CI is 10.0%, 9.4%, and 8.3%, respectively, and is therefore 
less than 10% across the range of expected outcomes which is the desired precision. 
Additionally, with a sample size of 100 subjects, the probability to observe an adverse event with 
a true incidence of 1% or 4% is 63% and 98% respectively.
11.4.
Efficacy Analyses
11.4.1.
Antiviral Efficacy and Immunologic Change
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 (ITT). 
Virologic suppression (HIV-1 RNA<50 copies/mL) will also be analyzed as secondary endpoints 
at Week 24 and Week 48 according to the below analyses:

FDA Snapshot algorithm in the ITT and Per-Protocol population

Time to loss of virological response (TLOVR) algorithm in the ITT population
Virologic decay will be reported as the mean log10 change in HIV-1 viral load from baseline to 
Weeks 2, 4, 8, 12, and 24 as part of the interim analysis as a secondary endpoint.
The proportion of subjects experiencing protocol defined virologic failure at Week 24 and 
Week 48 will be tabulated using descriptive statistics along with the 95% CIs. The Wilson 
(Score) method for the CI will be used. 
The changes from baseline in CD4+ cell count at Weeks 12, 24, and 48 will be summarized using 
descriptive statistics. 
11.4.2.
Resistance Determinations 
The number of PR mutations (including IAS-USA primary and secondary PI RAMs), RT 
mutations (including IAS-USA N[t]RTI RAMs and IAS-USA non-nucleoside RT inhibitor 
[NN(t)RTI] RAMs), and INI mutations (including IAS-USA primary and secondary INI-RAMS) 
present will be tabulated based on resistance tests performed at the screening/baseline visit. 
The proportion of subjects meeting resistance stopping rules, requiring discontinuation of study 
drug, based on the findings of screening/baseline resistance testing will be tabulated as part of 
the interim analysis. 
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HIV-1 genotype/phenotype will be analyzed from samples of subjects with protocol-defined 
virologic failure and with HIV-1 RNA ≥400 copies/mL. 
The number of treatment-emergent PR mutations (including IAS-USA primary and secondary PI 
RAMs) and RT mutations (including IAS-USA N(t)RTI RAMs and IAS-USA NNRTI RAMs), 
as well as specific mutations associated with resistance to DRV, FTC, and TAF will be tabulated 
based on the observed virologic failures through the study period. 
Fold change (FC) in 50% effective concentration (EC50) of ARVs will be tabulated. Loss of 
phenotypic susceptibility may be analyzed dependent on the number of virologic failures and 
phenotypes available through the study period.
11.5.
Medical Resource Utilization and Health Economics Analyses 
All-cause and HIV-specific HRU during the study period will be summarized overall and by 
category as the counts per patient per month (PPPM). Monthly average counts per subject will 
also be calculated to show the temporal trend for each category. 
Costs of care will be calculated by assigning costs based on Centers for Medicare & Medicaid 
Services (CMS) fee schedule to assessed HRU on a per subject per month basis. Descriptive 
statistics will be calculated to compare the costs of care from baseline to Weeks 12, 24, and 48.
11.6.
Adherence Analyses
Treatment adherence based on pill count and on subject self-report will be summarized by means 
of descriptive statistics and frequency tabulations.
Adherence rates will be reported according to the proportion of subjects taking >95%, 80-95% 
and <80% of study drug as assessed by pill count at study visits at Weeks 4, 8, 12, 24, 36, and 
48.
11.7.
Retention in Care Analyses
Number of subject with retention of care by age, gender, race, sexual orientation, time from 
diagnosis to baseline visit, baseline CD4+ cell count, baseline HIV-1 RNA, patient satisfaction 
as assessed by HIVTSQs, and socioeconomic factors will be tabulated. 
11.8.
Safety Analyses
For all safety endpoints listed in Section 2.1.2, descriptive statistics will be used to summarize 
the endpoints. 
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse 
events are adverse events with onset during the treatment phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported adverse events will be 
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included in the analysis. For each adverse event, the percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or life-threatening (grade 3 or 4) or a serious adverse event.
Additionally, a summary and listing of those subjects meeting predefined stopping rules due to 
safety or resistance findings will be tabulated.
Clinical Laboratory Tests
Abnormalities will be analyzed according to the DAIDS grading table (see Attachment 2) and in 
accordance with the normal ranges of the clinical laboratory. Maximum toxicity grades after 
baseline will be tabulated, and special attention will be given to subjects who develop grade 3 or 
grade 4 toxicities.
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline 
and for observed values and changes from baseline at each scheduled time point. Changes from 
baseline results will be presented in pre- versus posttreatment cross-tabulations (with classes for 
below, within, and above normal ranges).
Vital Signs
Descriptive statistics of blood pressure (systolic and diastolic), pulse/heart rate, and body weight
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. See Attachment 6
for the definitions of vital signs abnormalities.
Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
Patient-reported Outcomes 
Descriptive statistics for absolutes values and changes in HIVTSQs scores will be calculated at 
each timepoint, where applicable.
11.9.
Extension Period
For the extension period, descriptive statistics or patient data listings will be provided for adverse 
events, virologic failure, or resistance.
11.10. Interim Analysis 
An interim analysis is planned once all subjects have been assessed for safety at Day 3, and for 
resistance stopping rules at Week 4.
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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 adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
An adverse event does not include the following:
Medical or surgical procedures if the condition that leads to the procedure is an adverse event.
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 adverse event. 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.
See also Section 12.2, Special Reporting Situations and Section 12.3.3, Pregnancy.
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Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The 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 definition above. 
These should usually be considered serious. Examples of such events are:
Intensive treatment in an emergency room or at home for allergic bronchospasm.
Blood dyscrasias or convulsions that do not result in hospitalization.
Development of drug dependency or drug abuse.
If a serious and unexpected adverse event 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 adverse events/serious adverse events:
Complications occurring during hospitalizations are adverse events. If a complication 
prolongs the hospitalization, it is a serious adverse event.
In-patient hospitalization means that 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 the diagnosis of an event on the basis of signs, 
symptoms, and/or other clinical information; in such cases, the diagnosis must be documented 
as the adverse event and/or serious adverse event and not the individual signs or symptoms.
A distinction should be made between seriousness and severity of adverse events. An adverse 
event that is assessed as grade 4 (potentially life-threatening) should not be confused with a 
serious adverse event. Severity is a category utilized for rating the intensity of an event, and 
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both adverse events and serious adverse events can be assessed as grade 4. An adverse event 
is defined as ‘severe’ when it meets the predefined criteria as described the DAIDS toxicity 
grading table in Attachment 2 (see also Section 12.1.3, Severity Criteria).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information at the time the adverse event is reported. For
D/C/F/TAF FDC tablet, the expectedness of an adverse event will be determined by whether or 
not it is listed in the applicable full Prescribing Information current at the time the event is 
reported.
Adverse Event Associated With the Use of the Drug
An adverse event 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, Attribution Definitions.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event 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 adverse event 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 adverse event 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 adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the general categorical descriptors outlined 
in the DAIDS toxicity grading table in Attachment 2.
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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 adverse events. An adverse 
event assessed as grade 4 (potentially life-threatening) should not be confused with a serious 
adverse event. Severity is a category utilized for rating the intensity of an event, and both adverse 
events and serious adverse events can be assessed as grade 4. An event is defined as ‘serious’ 
when it meets one of the predefined outcomes listed in Section 12.1.1, Adverse Event 
Definitions and Classifications. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events
Laboratory abnormalities are usually not recorded as adverse events or serious adverse events. 
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 adverse event as well as a serious adverse event, if applicable. Laboratory or other 
abnormal assessments (eg, vital signs) that are associated with signs and/or symptoms must be 
recorded as an adverse event or serious adverse event if they meet the definitions as described in 
Section 12.1.1, Adverse Event Definitions and Classifications. If the laboratory abnormality is 
part of a syndrome, the syndrome/diagnosis (ie, anemia) must be recorded and not the laboratory 
result (ie, decreased hemoglobin).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational 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)

Exposure to a sponsor study drug from breastfeeding

Lack of effect reports

Pregnancy reports, whether or not maternal exposure to the product occurred (see also 
Section 12.3.3, Pregnancy)

Reports of adverse reactions in infants following exposure from breastfeeding.
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Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events 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. Serious adverse 
events, 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 serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. Anticipated events will be 
recorded and reported as described in Attachment 8. 
All adverse events, 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 adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events 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). For 
anticipated events reported as individual serious adverse events the sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 
and the sponsor has determined there is a reasonable possibility that the drug caused a serious 
anticipated event, they will submit a safety report in narrative format to the investigators (and the 
head of the investigational institute where required). The investigator (or sponsor where 
required) must report SUSARs to the appropriate IEC/IRB that approved the protocol unless 
otherwise required and documented by the IEC/IRB. 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:
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
Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, 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 serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. 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 a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
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 serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.
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Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to 
Section 12.1.1, Adverse Event Definitions and Classifications).
12.3.3.
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 serious 
adverse events 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 as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of subjects, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
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13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
D/C/F/TAF FDC 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, film-
coated tablets containing 800 mg of DRV (as 867 mg of DRV ethanolate), 150 mg of COBI 
(288 mg total weight of COBI on silicon dioxide carrier), 200 mg of FTC, and 10 mg of TAF (as 
11.2 mg TAF fumarate). The D/C/F/TAF tablet cores contain silicon dioxide, croscarmellose 
sodium, microcrystalline cellulose, magnesium stearate polyvinyl alcohol, iron oxide yellow,
polyethylene glycol, talc, and titanium dioxide. 
14.2.
Packaging
D/C/F/TAF FDC tablets will be packaged under responsibility of the sponsor
The D/C/F/TAF FDC 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.
No study drug 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 drug can be relabeled without prior approval from the sponsor.
14.4.
Preparation, Handling, and Storage
All study drug must be stored according to the storage conditions printed on the label.
To ensure the stability of D/C/F/TAF FDC tablets, the study drug should not be dispensed into a 
container other than the container in which it is supplied.
Refer to the pharmacy manual/study site investigational product and procedures 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 
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return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects must be instructed to return all original containers, whether empty 
or containing study drug. All study drug will be stored and disposed of according to the sponsor's 
instructions. Study-site personnel must not combine contents of the study drug containers.
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. 
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, unless the bottles are unopened. 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.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator's Brochure and Addendum14,15

Pharmacy manual/study site investigational product and procedures manual

Laboratory manual

HIVTSQs questionnaire 

electronic Data Capture (eDC) Manual

Sample ICF

Interactive Web Response System manual
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 
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they would otherwise be entitled. Only subjects who are fully able to understand the risks, 
benefits, and potential adverse events 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.
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

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (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, unless required locally), 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:
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
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events 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, where 
required.
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, 
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and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Subjects will be 
told that alternative treatments are available if they refuse to take part and that such refusal will 
not prejudice future treatment. Finally, they will be told that the investigator will maintain a 
subject identification register for the purposes of long-term follow up if needed and that their 
records may be accessed by health authorities and authorized sponsor personnel without 
violating the confidentiality of the subject, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF the subject is authorizing such access, which includes permission 
to obtain information about his or her survival status. It also denotes that the subject agrees to 
allow his or her study physician to recontact the subject for the purpose of obtaining consent for 
additional safety evaluations, and subsequent disease-related treatments, if needed. The 
physician may also recontact the subject for the purpose of obtaining consent to collect 
information about his or her survival status.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the subject.
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 
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will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
16.2.5.
Long-Term Retention of Samples for Additional Future Research 
Blood samples collected in this study (including PBMCs isolated from whole blood) may be 
stored for up to 15 years (or according to local regulations) for additional research. Samples will 
only be used to understand D/C/F/TAF FDC tablet, to understand HIV-1 infection, and to 
understand differential drug responders. The research may begin at any time during the study or 
the post-study storage period. 
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 10.3, Withdrawal From the Use of Samples in Future 
Research.
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 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
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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
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 
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reports and communications relating to the study will identify subjects by subject identification 
and date of birth. In cases where the subject is not enrolled into the study, the date seen and date 
of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of signed informed consent; dates of visits; results of safety and efficacy 
parameters as required by the protocol; record of all AEs and follow-up of AEs; concomitant 
medication; drug receipt/dispensing/return records; study drug administration information; and 
date of study completion and reason for early discontinuation of study drug or withdrawal from 
the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
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.
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 prepared and provided by the sponsor for each subject in electronic format.
Electronic Data Capture will be used for this study. The study data will be transcribed by study-
site personnel from the source documents onto an electronic eCRF, if applicable. Study-specific 
data will be 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 the eCRF in 
English. The eCRF must be completed as soon as possible after a subject visit and the forms 
should be available for review at the next scheduled monitoring visit. 
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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.
All eCRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the eCRF are accurate 
and correct.
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 a eCRF are needed after the initial entry into the eCRF, this can be done in 
either of the following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
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 eCRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
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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 
postinitiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRFs with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and study-site personnel and are accessible for verification by 
the sponsor study-site contact. If electronic records are maintained at the study site, the method 
of verification must be discussed with the study-site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
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 
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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. 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 D/C/F/TAF FDC tablet or the 
sponsor's operations (eg, patent application, formulas, manufacturing processes, basic scientific 
data, prior clinical data, formulation information) supplied by the sponsor to the investigator and 
not previously published, and any data generated as a result of this study, are considered 
confidential and remain the sole property of the sponsor. The investigator agrees to maintain this 
information in confidence and use this information only to accomplish this study, and will not 
use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of 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.
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The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. 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 Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
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 disclose the existence of and the results of clinical studies as 
required by law.
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Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
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Infecc Microbiol Clin 2008;26(3):127-134.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
86
Approved, Date: 16 November 2017
42.
WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification 
of HIV-related disease in adults and children, 2007. Available at 
http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf?ua=1. Accessed 13 October 2016.
43.
Woodcock A, Bradley C. Validation of the HIV treatment satisfaction questionnaire (HIVTSQ). Qual Life 
Res. 2001;10(6):517-531.
44.
Woodcock A, Bradley C. Validation of the revised 10-item HIV Treatment Satisfaction Questionnaire status 
version and new change version. Value Health. 2006;9(5):320-333.
45.
Woodruff, K, Mao J, Brown K et al. Evaluation of healthcare resource use among HIV patients in a large 
insured U.S. population. Poster presented at IDWeekTM 2016; October 26-30, 2016; New Orleans, LA.
46.
World Health Organization. WHO HIV Drug Resistance Report 2012. Geneva, Switzerland. Available at 
http://www.who.int/hiv/pub/drugresistance/report2012. Accessed December 14, 2016.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
87
Approved, Date: 16 November 2017
ATTACHMENTS
Attachment 1: 
Schema for Follow-up of Subjects who Meet the Criteria for Protocol-Defined 
Virologic Failure ........................................................................................................................ 88
Attachment 2: 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events............. 90
Attachment 3: 
WHO Clinical Staging of HIV/AIDS.............................................................................. 111
Attachment 4: 
Management of Clinically Significant Laboratory Toxicities* ....................................... 113
Attachment 5:
Management of Dyslipidemia ...................................................................................... 114
Attachment 6: 
Cardiovascular Safety: Definitions of Abnormalities.................................................... 117
Attachment 7:
HIV-Treatment Satisfaction Questionnaire (HIVTSQs) ............................................... 118
Attachment 8:
Anticipated Events ....................................................................................................... 119
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
88
Approved, Date: 16 November 2017
Attachment 1: Schema for Follow-up of Subjects who Meet the Criteria for Protocol-Defined 
Virologic Failure 
Virologic Nonresponse Schema
Screening/
Baseline
Treatment Phase
ESTD
Week 12
Unscheduled visit, 
within 2 to 4 weeks after 
Week 12 HIV-1 RNA result
HIV-RNA 
1 log10 reduction 
from baseline 
AND
400 copies/mL 
Blood drawn for repeat of HIV-1 
RNA testing
and potential genotype/phenotype
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.
Unconfirmed virologic 
nonresponse: remain on 
study druga
Confirmed virologic 
nonresponseb
HIV-1 
genotype/phenotypec,d
If no resistance to study 
drug is detected, continue 
on study drug at the 
investigator’s discretion
If resistance to study drug 
is detected, study drug may 
be discontinued at the 
investigator’s discretione
a
If virologic nonresponse is not confirmed, the subject will continue 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 (PhenoSense GT®) will be analyzed.
d
In case of early discontinuation, an HIV-1 resistance report, if available, will be forwarded to the treating 
physician to assist in the selection of a new ARV regimen.
e
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 
drug for an individual subject must inform the sponsor’s medical monitor before study drug discontinuation. 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
89
Approved, Date: 16 November 2017
Virologic Rebound Schema 
Screening/
Baseline
Treatment Phase
ESTD
At any visit, after achieving confirmed consecutive HIV-1 RNA 
<50 copies/mL, a rebound in HIV-1 RNA to ≥50 copies/mL, 
OR
At any visit, a >1 log10 increase in HIV-1 RNA from the nadir
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.
Within 2 to 4 weeks of HIV-1 RNA result, return for 
scheduled/unscheduled visit for repeat of HIV-1 RNA testing
and potential genotype/phenotype
Unconfirmed virologic rebound: 
remain on study druga
Confirmed virologic reboundb
HIV-1 genotype/phenotypec,d
If no resistance to study drug is 
detected, continue on study drug at 
the investigator’s discretion
If resistance to study drug is detected, 
study drug may be discontinued at the 
investigator’s discretione
a
If virologic rebound is not confirmed, the subject will continue study drug 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 (PhenoSense GT®) will be analyzed.
d
In case of early discontinuation, an HIV-1 resistance report, if available, will be forwarded to the treating 
physician to assist in the selection of a new ARV regimen.
e
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 
drug for an individual subject must inform the sponsor’s medical monitor before study drug discontinuation. 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
90
Approved, Date: 16 November 2017
Attachment 2: DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (v 2.0, 
November 2014), or ‘DAIDS grading table’, is a descriptive terminology to be utilized for adverse event 
reporting in this study. A grading (severity) scale is provided for each adverse event term.
General Instructions
Estimating Severity Grade for Parameters Not Identified in the Grading Table
If the need arises to grade a clinical adverse event 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 adverse event 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 adverse events. When 
a single set of parameters is not appropriate for grading specific types of adverse events 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 adverse event, 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 adverse event could fall under either 1 of 2 grades (eg, the severity of an adverse 
event could be either grade 2 or grade 3), select the higher of the 2 grades for the adverse event.
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.
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 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
91
Approved, Date: 16 November 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.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
92
Approved, Date: 16 November 2017
CARDIOVASCULAR
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 Per Bazett’s formula.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
93
Approved, Date: 16 November 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 9.8.2.
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.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
94
Approved, Date: 16 November 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.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
95
Approved, Date: 16 November 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) 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
96
Approved, Date: 16 November 2017
GASTROINTESTINAL
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) 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
97
Approved, Date: 16 November 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 Bone mineral density (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, United Kingdom. 2007: Printed by the University of 
Sheffield.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
98
Approved, Date: 16 November 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 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
99
Approved, Date: 16 November 2017
NEUROLOGIC
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.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
100
Approved, Date: 16 November 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) 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
101
Approved, Date: 16 November 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) 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
102
Approved, Date: 16 November 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. BMI: Body mass index.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
103
Approved, Date: 16 November 2017
SYSTEMIC
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 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
104
Approved, Date: 16 November 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.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
105
Approved, Date: 16 November 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 <LLN14
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×ULN 
2.5 to <5.0×ULN 
5.0 to <10.0×ULN 
≥10.0×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×ULN 
2.5 to <5.0×ULN 
5.0 to <10.0×ULN 
≥10.0×ULN 
Amylase (Pancreatic) 
or Amylase (Total), 
High 
Report only one 
1.1 to <1.5×ULN 
1.5 to <3.0×ULN 
3.0 to <5.0×ULN 
≥5.0×ULN 
AST or SGOT, High 
Report only one 
1.25 to <2.5×ULN 
2.5 to <5.0×ULN 
5.0 to <10.0×ULN 
≥10.0×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 Bilirubin15, 
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×ULN 
1.6 to <2.6×ULN 
2.6 to <5.0×ULN 
≥5.0×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 Lower limit of normal range.
15 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.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
106
Approved, Date: 16 November 2017
CHEMISTRIES
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Creatine Kinase, 
High 
3 to <6×ULN 
6 to <10×ULN 
10 to <20×ULN 
≥20×ULN 
Creatinine, High 
1.1 to 1.3×ULN 
>1.3 to 1.8×ULN OR 
Increase of >0.3 mg/dL 
above baseline 
>1.8 to <3.5×ULN OR 
Increase of 1.5 to 
<2.0×above baseline 
≥3.5×ULN OR 
Increase of 
≥2.0×above baseline 
Creatinine 
Clearance16 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×ULN 
without acidosis 
≥2.0×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×ULN 
1.5 to <3.0×ULN 
3.0 to <5.0×ULN 
≥5.0×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 
LDL17, 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 
Magnesium18, 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 
16 Use the applicable formula (Modification of Diet in Renal Disease [MDRD]).
17 Low-density lipoprotein
18 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
107
Approved, Date: 16 November 2017
CHEMISTRIES
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 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
108
Approved, Date: 16 November 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 
0.600×109 to 
<0.650×109
500 to <600 
0.500×109 to 
<0.600×109
350 to <500 
0.350 x109 to 
<0.500×109
<350 
<0.350×109 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
>7 days of age 
800 to 1,000 
0.800×109 to 
1.000×109
600 to 799 
0.600×109 to 
0.799×109
400 to 599 
0.400×109 to 
0.599×109
<400 
<0.400×109
2 to 7 days of age 
1,250 to 1,500 
1.250×109 to 
1.500×109
1,000 to 1,249 
1.000×109 to 
1.249×109
750 to 999 
0.750×109 to 
0.999×109
<750 
<0.750×109
≤1 day of age 
4,000 to 5,000 
4.000×109 to 
5.000×109
3,000 to 3,999 
3.000×109 to 
3.999×109
1,500 to 2,999 
1.500×109 to 
2.999×109
<1,500 
<1.500×109
Fibrinogen, 
Decreased (mg/dL; 
g/L) 
100 to <200 
1.00 to <2.00 
OR 
0.75 to <1.00×LLN 
75 to <100 
0.75 to <1.00 
OR 
≥0.50 to <0.75×LLN 
50 to <75 
0.50 to <0.75 
OR 
0.25 to <0.50×LLN 
<50 
<0.50 
OR 
<0.25×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 
INR19, High 
(not on anticoagulation 
therapy) 
1.1 to <1.5×ULN 
1.5 to <2.0×ULN 
2.0 to <3.0×ULN 
≥3.0×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.
19 International normalized ratio.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
109
Approved, Date: 16 November 2017
HEMATOLOGY
PARAMETER 
GRADE 1
MILD
GRADE 2 
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
PTT20, High 
(not on anticoagulation 
therapy) 
1.1 to <1.66×ULN 
1.66 to <2.33×ULN 
2.33 to <3.00×ULN 
≥3.00×ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000 to <124,999
100.000×109 to 
<124.999×109
50,000 to <100,000 
50.000×109 to 
<100.000×109
25,000 to <50,000 
25.000×109 to 
<50.000×109
<25,000 
<25.000×109
PT21, High 
(not on anticoagulation 
therapy 
1.1 to <1.25×ULN 
1.25 to <1.50×ULN 
1.50 to <3.00×ULN 
≥3.00×ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
>7 days of age 
2,000 to 2,499 
2.000×109 to 
2.499×109
1,500 to 1,999 
1.500×109 to 
1.999×109
1,000 to 1,499 
1.000×109 to 
1.499×109
<1,000 
<1.000×109
≤7 days of age 
5,500 to 6,999 
5.500×109 to 
6.999×109
4,000 to 5,499 
4.000×109 to 
5.499×109
2,500 to 3,999 
2.500×109 to 
3.999×109
<2,500 
<2.500×109
20 Partial thromboplastin time.
21 Prothrombin time
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 
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
110
Approved, Date: 16 November 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×ULN 
1.6 to <2.6×ULN 
2.6 to <5.0×ULN 
≥5.0×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×ULN 
1.6 to <2.6×ULN 
2.6 to <5.0×ULN 
≥5.0×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.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
111
Approved, Date: 16 November 2017
Attachment 3: WHO Clinical Staging of HIV/AIDS
The clinical stages of HIV infection for adults and adolescents are defined as follows. (Adapted from: 
1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS 
among adolescents and adults. MMWR 1992;41(RR-17):1-19; and WHO 2007 Case definitions of HIV 
for surveillance and revised clinical staging and immunological classification of HIV-related disease in 
adults and children [Table 3]).31,42
Clinical Stage 1
Clinical Stage 1 consists of one or more of the conditions listed below in adolescents or adults (13 years) 
with documented HIV infection. Conditions listed in Clinical Stages 2, 3 or 4 must not have occurred.
-
Asymptomatic HIV infection
-
Persistent generalized lymphadenopathy
Clinical Stage 2
Clinical Stage 2 consists of symptomatic conditions in an HIV-infected adolescents or adults that are not 
included among conditions listed in Clinical Stage 3, and that meet one or more 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
-
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 (<0.5x109/L) or chronic thrombocytopenia (<50x109/L)
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
112
Approved, Date: 16 November 2017
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
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
113
Approved, Date: 16 November 2017
Attachment 4: Management of Clinically Significant Laboratory Toxicities*
a Mandatory confirmation is not warranted for asymptomatic grade 3 or grade 4 glucose elevations in subjects with pre-existing diabetes, and asymptomatic 
grade 3 or grade 4 triglyceride or cholesterol elevations.
* Please note that this Attachment does not apply to screening/baseline eGFR, AST, ALT, and lipase, and does also not apply to the allowed retesting of 
abnormal screening/baseline eGFR, AST, ALT, and lipase values (see Section 3.1).
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 study medication
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
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
114
Approved, Date: 16 November 2017
Attachment 5: Management of Dyslipidemia
RECOMMENDATIONS 
(Adapted from: 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.)1
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 highly active antiretroviral therapy (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. Non-nucleoside reverse transcriptase 
inhibitor (NNRTI) use has been associated with hypercholesterolemia. The mechanism by which PIs 
cause dyslipidemia is unclear. Hypertriglyceridemia seems to be most significant in patients with 
regimens that include 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.
NCT03227861


D/C/F/TAF (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Clinical Protocol TMC114FD2HTX3002 Amendment 1
115
Approved, Date: 16 November 2017
A fasting lipid profile (total, LDL and HDL cholesterol, triglycerides) should be obtained before 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 3 and Table 4). 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 3 and Table 4). 
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 4). 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.
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.
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Table 3:
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 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 4:
Choice of Drug Therapy for Dyslipidemia in HIV-infected Individuals Receiving HAART
Lipid Abnormality
First Choice
Second Choice (or if Additional 
Treatment is Needed)
Comments
Isolated high LDL 
cholesterol
Statin*
Fibrate
Start with low doses of statins and 
titrate upward.
Patients receiving PIs may be at 
increased risk of statin-induced 
myopathy.
Combined 
hyperlipidemia (high 
cholesterol and high 
triglycerides)
Fibrate or statin*
If starting with fibrate, add statin*
If starting with statin*, add fibrate
Combining statin and a fibrate may 
increase risk for myopathy
Isolated 
hypertriglyceridemia
Fibrate
Statin*
Combining statin and a fibrate may 
increase risk for myopathy.
* Statins should be dosed at bedtime. Simvastatin and lovastatin are not allowed in patients receiving DRV.
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Approved, Date: 16 November 2017
Attachment 6: Cardiovascular Safety: Definitions of Abnormalities
Vital Signs
Abnormality Code
Pulse 
(bpm)
DBPa
(mmHg)
SBPa
(mmHg)
Abnormally low
50 
50
90 
Grade 1 or mild
-
>90 - <100 
>140 - <160 
Grade 2 or moderate
-
100 - <110 
160 - <180 
Grade 3 or severe
-
110 
180 
Abnormally high
120 
-
-
a
Classification of adverse events related to hypotension/hypertension should be done according to the DAIDS 
grading table (Attachment 2).
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Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
Attachment 7: HIV-Treatment Satisfaction Questionnaire (HIVTSQs)
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Clinical Protocol TMC114FD2HTX3002 Amendment 1
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Approved, Date: 16 November 2017
Attachment 8: 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†

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 years32
† 
Condition that might be diagnosed presumptively
§ 
Only among adults and adolescents aged >13 years31
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Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether considered to be anticipated events 
and will be reported to the sponsor as described in Section 12.3.1, All Adverse Events. Any anticipated 
event that meets serious adverse event criteria will be reported to the sponsor as described in 
Section 12.3.2, Serious Adverse Events. These anticipated events are exempt from expedited reporting as 
individual single cases to Health Authorities. However if based on an aggregate review, it is determined 
that an anticipated event is possibly related to study drug, the sponsor will report these events in an 
expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
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Approved, Date: 16 November 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):
R. Nettles
Institution:
Janssen Scientific Affairs, LLC.
Signature:
[electronic signature appended at the end of the protocol]
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
NCT03227861


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Richard Nettles
29Nov2017, 14:17:02 PM, UTC
Document Approval
NCT03227861

SAP_001.pdf: 
1
Approved, Date: 18 September 2019
Janssen Scientific Affairs, LLC *
Statistical Analysis Plan
A Phase 3, Single-arm, Open-label Study to Evaluate the Efficacy and Safety of 
Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Once Daily 
Fixed-dose Combination (FDC) Regimen in Newly Diagnosed, Antiretroviral Treatment-
naïve Human Immunodeficiency Virus Type 1 (HIV-1) Infected Subjects Receiving Care in 
a Test and Treat Model of Care
Protocol TMC114FD2HTX3002; Phase 3
D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir 
alafenamide 10 mg)
Status:
Approved
Date:
18 September 2019
Prepared by:
Janssen Scientific Affairs, LLC
Document No.: EDMS-ERI-148054579, 4.0
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.
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
2
Approved, Date: 18 September 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
1.2.
Trial Design ...................................................................................................................................... 7
1.1.
Statistical Hypotheses for Trial Objectives..................................................................................... 10
1.2.
Sample Size Justification ............................................................................................................... 10
1.3.
Randomization and Blinding .......................................................................................................... 11
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 11
2.1.
Visit Windows................................................................................................................................. 11
2.2.
Analysis Sets.................................................................................................................................. 12
2.2.1.
All Subjects ................................................................................................................................. 12
2.2.2.
All Enrolled Analysis Set............................................................................................................. 12
2.2.3.
Efficacy Analysis Set(s) .............................................................................................................. 12
2.2.3.1.
Primary Efficacy Analysis Set.................................................................................................. 13
2.2.3.2.
Secondary Efficacy Analysis Set............................................................................................. 13
2.2.4.
Safety Analysis Set..................................................................................................................... 13
2.3.
Definition of Subgroups.................................................................................................................. 13
2.4.
Study Day and Relative Day .......................................................................................................... 14
2.5.
Baseline and Endpoint ................................................................................................................... 14
2.6.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 15
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 16
4.
SUBJECT INFORMATION................................................................................................................ 16
4.1.
Demographics and Baseline Characteristics ................................................................................. 16
4.2.
Disposition Information................................................................................................................... 17
4.3.
Treatment Compliance (Adherence).............................................................................................. 18
4.4.
Extent of Exposure......................................................................................................................... 19
4.5.
Protocol Deviations ........................................................................................................................ 19
4.6.
Prior and Concomitant Medications ............................................................................................... 20
4.7.
Medical History............................................................................................................................... 20
4.8.
Retention in Care Analyses ........................................................................................................... 20
5.
EFFICACY ......................................................................................................................................... 21
5.1.
Analysis Specifications................................................................................................................... 21
5.1.1.
Level of Significance................................................................................................................... 21
5.1.2.
Data Handling Rules................................................................................................................... 21
5.1.3.
Virologic Response Definitions................................................................................................... 21
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 23
5.2.1.
Definition..................................................................................................................................... 23
5.2.2.
Estimand..................................................................................................................................... 23
5.2.3.
Analysis Methods........................................................................................................................ 23
5.3.
Major Secondary Endpoints........................................................................................................... 23
5.3.1.
Definition..................................................................................................................................... 23
5.3.2.
Analysis Methods........................................................................................................................ 24
5.4.
Resistance Analysis....................................................................................................................... 24
5.4.1.
Definition..................................................................................................................................... 24
5.4.2.
Analysis Methods........................................................................................................................ 25
5.4.2.1.1.
Genotype.............................................................................................................................. 25
5.4.2.1.2.
Phenotype ............................................................................................................................ 26
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Statistical Analysis Plan TMC114FD2HTX3002
3
Approved, Date: 18 September 2019
6.
SAFETY............................................................................................................................................. 27
6.1.
Adverse Events .............................................................................................................................. 27
6.2.
Analysis Methods ........................................................................................................................... 29
6.3.
Clinical Laboratory Tests................................................................................................................ 30
6.4.
Vital Signs and Physical Examination Findings ............................................................................. 30
7.
PATIENT REPORTED OUTCOME ................................................................................................... 31
7.1.
HIV-Treatment Satisfaction Questionnaire (HIVTSQs).................................................................. 31
7.2.
4-Day Self Report........................................................................................................................... 32
8.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 32
8.1.
Pharmacokinetics........................................................................................................................... 32
9.
HEALTH ECONOMICS ..................................................................................................................... 32
9.1.
Medical Resource Utilization and Health Economics .................................................................... 32
REFERENCES............................................................................................................................................ 34
ATTACHMENTS......................................................................................................................................... 35
ATTACHMENT 1:
Schema for Follow-up of Subjects who Meet the Criteria for Protocol-Defined 
Virologic Failure.......................................................................................................... 35
ATTACHMENT 2:
Adverse Events of Special Interest ............................................................................ 37
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Statistical Analysis Plan TMC114FD2HTX3002
4
Approved, Date: 18 September 2019
AMENDMENT HISTORY
The SAP is not amended for changes after database lock.
ABBREVIATIONS
ADA
anti-drug antibody
AE
adverse event
ALT/SGPT
alanine aminotransferase
ANCOVA
analysis of covariance
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic Class
AUC
area under the curve
BMI
body mass index
BSA
body surface area
CI
confidence interval
CL
total systemic clearance
Cmax
maximum concentration
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
D/C/F/TAF 
DMC
DRV 800 mg + COBI 150 mg + FTC 200 mg + TAF 10 mg FDC
Data Monitoring Committee
DPS
Data Presentation Specifications
DRV
DSUR
Darunavir
Development of safety update report
ECG
electrocardiogram
eCRF
electronic case report form
eGFR 
ESTD
F (%)
Estimated glomerular filtration rate
early study treatment discontinuation
absolute SC bioavailability
FAS
full analysis set
FDA
Food and Drug Administration
FTC
emtricitabine
HRU
ICH
healthcare resource utilization
International Conference on Harmonization
IQ
interquartile
IVRS
interactive voice response system
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MDRD
MedDRA
Modification of Diet in Renal Disease 
Medical Dictionary for Regulatory Activities
MRD
minimum required dilution
NAb
neutralizing antibodies
OI
PD
Opportunistic infection 
pharmacodynamic
PI
principal investigator
PK
pharmacokinetic(s)
PP
per protocol
RPV
rilpivirine
RTV
ritonavir
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SMQs
standardised MedDRA queries
TAF
tenofovir alafenamide
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D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
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Approved, Date: 18 September 2019
TEAE
treatment-emergent adverse event
TDF
tenofovir disoproxil fumarate
TLOVR
time to loss of virologic response
Tmax
time to maximum concentration
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
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D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
6
Approved, Date: 18 September 2019
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the interim analysis when last subject has been 
assessed for safety and resistance stopping rules and Week 48 primary analysis that will be 
performed after the last subject enrolled in the D/C/F/TAF arm completes the Week 48 visit, or 
prematurely discontinues from the study. At the Interim analysis only selected endpoints will be 
analyzed, while at the week 48 Primary analysis, all endpoints will be analyzed. Data collected 
after primary analysis from subjects in the Extension treatment period will be analyzed 
separately.  Details of each analysis contents will be described in DPS.
1.1.
Trial Objectives
The primary objective of this study is to assess the efficacy of D/C/F/TAF FDC in a Test and 
Treat model of care in newly diagnosed HIV-1-infected, treatment-naive subjects as determined 
by the proportion of virologic responders defined as having HIV-1 ribonucleic acid (RNA)
<50 copies/mL at Week 48 (Food and Drug Administration [FDA]-defined intent to treat [ITT] 
snapshot analysis). 
The secondary objectives of this study are:

To assess virologic and immunologic changes in the study population through 12, 24, and 
48 weeks of treatment 

To evaluate the incidence of grade 3 and 4 adverse events, serious adverse events, and 
premature discontinuations due to adverse events through 24 and 48 weeks of treatment, and 
during the extension phase.

To evaluate the frequency of discontinuation of D/C/F/TAF FDC due to protocol-specific 
stopping rules (refer to the section Overview of Study Design below)

To assess baseline viral resistance in the study population 

To assess the development of viral resistance in the study population through 24 and 
48 weeks of treatment, and during the extension phase

To assess the proportion of subjects retained in care after discontinuation of study drug 
before Week 48

To evaluate the influence of various intrinsic and extrinsic factors on retention in care 

To assess the proportion of subjects lost to follow-up through 24 and 48 weeks of treatment

To evaluate adherence by pill count to D/C/F/TAF FDC in the study population through 
24 and 48 weeks of treatment 

To evaluate adherence by subject self-report, using a 4-day recall period through Weeks 24 
and 48

To describe predictors of suboptimal adherence (<95% adherence by pill count) in the study 
population 

To assess the HIV Treatment Satisfaction Questionnaire-status version (HIVTSQs) at 
Weeks 4, 24, and 48
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Statistical Analysis Plan TMC114FD2HTX3002
7
Approved, Date: 18 September 2019

To evaluate healthcare resource utilization (HRU) and cost and their temporal trends in the 
study population through 48 weeks of treatment
1.2.
Trial Design
Figure 1:
Schematic Overview of the Study
Scr/BL   #Day 3     ^Week 4
(Day 1)                           ~Interim analysis              
              Week 48
       Primary analysis
^^End of 
Extension
Treatment phase
Extended 
Trt. phase
*30-day 
Follow-up
**90-day 
Follow-up
Treatment: D/C/F/TAF once daily (n=100)
ESTD and/or 
30-day 
FU visit
Retention in 
care 
assessment 
visit
                             
    
                                                                            Extended Treatment phase
#Assessment of safety labs stopping rule, day3+1 week. 
^Assessment of drug resistance stopping rule, week4±1 week. 
*Subjects with ongoing AEs/SAEs at the time of last study visit.                               
   **Discontinued subjects from day 1 to week 48.
~analysis will be performed when last subject has been assessed for safety and resistance stopping rules
^^ subjects will continue D/C/F/TAF treatment during an extension period until the D/C/F/TAF FDC tablet becomes 
commercially available and is reimbursed, or can be accessed through another source  or until the sponsor terminates clinical 
development. 
This is a single-arm, open-label, prospective, multicenter Phase 3 study to assess the efficacy and 
safety of D/C/F/TAF FDC in newly diagnosed (ie, within 2 weeks of the screening/baseline visit 
[Day 1]) HIV-1 infected treatment-naïve subjects at least 18 years of age as part of a Test and 
Treat model of care in the USA.
A target of approximately 100 subjects will participate in this study. 
After obtaining informed consent, a blood sample will be collected for central laboratory testing. 
The in- and exclusion criteria will be reviewed to confirm the subject’s eligibility. The 
screening/baseline visit (Day 1) should take place no later than 2 weeks following evidence of 
newly documented HIV-1 infection. 
Study drug will be dispensed before the results from the screening/baseline safety and resistance 
laboratory tests are available. Subjects will receive treatment in a single-arm open-label fashion 
as follows: 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
8
Approved, Date: 18 September 2019
D/C/F/TAF: DRV 800 mg + COBI 150 mg + FTC 200 mg + TAF 10 mg FDC
Subjects must start treatment within 24 hours of the screening/baseline visit. 
Following initiation of treatment, a safety assessment will be performed by the investigator at 
Day 3 +1 week, or as soon as the final screening/baseline laboratory report becomes available.
Subjects meeting any of the below safety stopping rules (based on the receipt of the 
screening/baseline laboratory findings) will be contacted to return to the study site for possible 
early study treatment discontinuation (ESTD) and for additional follow-up.

Estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal 
Disease (MDRD) formula <50 mL/min. 

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5×upper limit of 
normal (ULN) 

Serum lipase ≥1.5×ULN 

Positive serum human chorionic gonadotropin pregnancy test (β-hCG) in women of child 
bearing potential

Laboratory results that the investigator believes should result in discontinuation of study 
medication (Note: It is recommended that the investigator contacts the sponsor’s medical 
monitor to discuss the discontinuation)

Subjects identified with active hepatitis C virus (HCV) infection that in the opinion of the 
investigator requires HCV treatment immediately or expected to be needed during the 
course of the study with drugs not compatible with D/C/F/TAF FDC.
Retesting of abnormal screening/baseline safety laboratory values noted above will be allowed 
once. Retesting will take place during an unscheduled visit.
The investigator will review the ARV screening/baseline resistance data at Week 4 ±7 days or 
sooner, depending on the availability of the screening/baseline HIV genotypic drug resistance 
testing results from the central laboratory. Subjects who do not show full sensitivity to all drugs 
in the FDC study regimen according to the susceptibility assessment in the GenoSure Prime®
report will be contacted to return to the study site for ESTD. Subjects with identified resistance 
to lamivudine/FTC, attributed to the presence of the M184I/V mutation alone will be permitted 
to remain in the study.
Subjects will be treated for 48 weeks and will return to the site for visits at Weeks 2, 4, 8, 12, 24, 
36, and 48. Assessment of drug accountability and reasons for non-adherence, and recording of 
concomitant therapies, adverse events, vital signs (including the subject’s body weight), and 
physical examinations (complete or symptom-directed) will be performed at each visit from 
baseline onwards. Laboratory evaluations for efficacy and safety (HIV-1 viral load, 
biochemistry, hematology, and urinalysis) will be performed at all study visits. CD4+/CD8+ cell 
count will be assessed at Weeks 4, 8, 12, 24, 36, and 48. Patient-reported outcome (PRO) 
measures will be assessed at Weeks 4, 24, and 48 using the validated 10-item HIVTSQs 
(Version 2006)1. Medical resource utilization data will be collected from all subjects throughout 
the study. 
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D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
9
Approved, Date: 18 September 2019
Subjects who are on study drug and who experience a protocol-defined virologic failure (see 
below) will undergo genotypic and phenotypic resistance testing, preferably at the time of the 
confirmed virologic failure visit if the HIV-1 RNA is ≥400 copies/mL. If resistance testing is not 
able to be performed at the time of confirmed virologic failure, resistance testing may be 
performed at the point of unconfirmed virologic failure or a later time point if HIV-1 RNA is 
≥400 copies/mL. Subjects who have persistent HIV-1 RNA ≥400 copies/mL past Week 24 but do 
not meet the definition of virologic failure, should have their viral load monitored closely, and if 
appropriate undergo genotypic and phenotypic resistance testing. In case resistance to study 
drugs is observed, the subject may be discontinued from the study at the investigator's discretion.
If the investigator makes the decision that the subject can continue in the study, additional 
resistance testing may be performed as deemed necessary. Protocol defined virologic failure is 
not considered a stopping rule.
Protocol defined virologic failure (PDVF) will be defined in this study as follows:
Virologic Nonresponse: 

HIV-1 RNA <1 log10 reduction from baseline, AND
HIV-1 RNA ≥400 copies/mL at the Week 12 visit, subsequently confirmed at an
unscheduled visit conducted within 2 to 4 weeks after Week 12
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 a
scheduled or unscheduled visit conducted within 2 to 4 weeks of the HIV-1 RNA result; 
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 conducted within 2 to 
4 weeks of the HIV-1 RNA result. 
Viremic at Final Time Point:

Any subject with on-treatment HIV-1 RNA ≥400 copies/mL at the study endpoint or 
study discontinuation after Week 12 
Subjects who meet the criteria for Virologic Nonresponse or Virologic Rebound will be managed 
according to the schema provided in Attachment 1 at the end of the document.
Unscheduled visits can be conducted as needed based on individual tolerability issues, or 
virologic reasons (ie, suspected virologic failure) that occur between scheduled visits.
Subjects who prematurely discontinue study treatment during the treatment period (between 
Day 1 and Week 48) will be required to complete ESTD assessments as soon as possible but no 
later than 1 week of discontinuing study treatment. 
In addition, a follow-up visit is required for any subject who has an ongoing adverse event or 
serious adverse event at the time of his/her last study visit. These subjects are required to return 
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D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
10
Approved, Date: 18 September 2019
to the site 30 days (±7 days) after completion of the last study-related visit (unless consent is 
withdrawn). 
Subjects who have completed the Week 48 visit will be given the opportunity to continue
D/C/F/TAF treatment during an extension period until the D/C/F/TAF FDC tablet becomes
commercially available and is reimbursed, or can be accessed through another source, or until the 
sponsor terminates clinical development. During the extension period, subjects will return to the 
site once every 6 months.
Subjects who undergo ESTD will resume routine clinical care with their care provider who will 
determine the future care of that subject. For those subjects discontinuing therapy before Week
48, the investigator will be asked to monitor the subject’s retention in care defined as having one 
documented clinic visit within 90 days of discontinuing the study treatment (unless consent is 
withdrawn). 
The end of the study is defined as completion of the last data collection visit for the last subject 
participating in the study, which will be a maximum of 52 weeks after enrollment to allow for a 
30-day follow-up visit as needed. A subject will be considered to have completed the study if 
data collection as required per protocol through the complete course of 48 weeks of ART has 
been completed.
An interim analysis is planned once all subjects have been assessed for safety and resistance 
stopping rules.
The primary analysis of this study will be performed once all subjects have completed the Week 
48 visit and the 30-day follow-up visit (if applicable), or discontinued earlier.
Extension treatment period data will be reported when all subjects discontinued study treatment
or transition to commercial D/C/F/TAF.
1.1.
Statistical Hypotheses for Trial Objectives
No formal hypothesis will be tested. The findings from this study will be used to generate data 
on the efficacy and safety profile of D/C/F/TAF FDC in newly diagnosed HIV-1 infected, 
treatment-naïve subjects using a Test and Treat model of care.
1.2.
Sample Size Justification
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 (ITT). As this is an exploratory study with 
no formal hypothesis testing on the primary endpoint, no formal sample size calculation was 
performed. With a sample size of 100 subjects and an expected virologic response rate ranging 
from 60-80%, the exact corresponding 95% confidence intervals (CIs) are: 60% (49.7%, 69.7%), 
70% (60.0%, 78.8%), and 80% (70.8%, 87.3%). The half-width of the exact corresponding 2-
sided 95% CI is 10.0%, 9.4%, and 8.3%, respectively, and is therefore less than 10% across the 
range of expected outcomes which is the desired precision. Additionally, with a sample size of 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
11
Approved, Date: 18 September 2019
100 subjects, the probability to observe an adverse event with a true incidence of 1% or 4% is 
63% and 98% respectively. 
1.3.
Randomization and Blinding
Treatment Allocation
As this is single-arm study, randomization is not applicable. All subjects will receive the same 
treatment.
Blinding
As this is an open-label study, blinding procedures are not applicable.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
As subjects, do not always adhere to the protocol visit schedule, the following rules are applied 
to assign actual visits to analysis visits. Listed below are the visit windows and the target days 
for each visit. The reference day is Study Day 1. If a subject has 2 or more actual visits in one 
visit window, the visit closest to the target day will be used as the protocol visit for that visit 
window. The other additional visit(s) will not be used in the summaries or analyses but they can 
be used for determination of clinically important endpoints. If 2 actual visits are equidistant from 
the target day within a visit window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the endpoint. Listed below 
(Table1 are the visit windows and the target days for each visit defined in the protocol.
Table 1– Visit Windows
Parameter
Analysis 
Period
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)
Efficacy and 
safety 
Assessments
1-2
1
Screening/ Baselinea
Day -3 - Day 1
1
1-2
2
Week 2
Day 2 – Day 21
15
1-2
3
Week 4
Day 22 – Day 42
29
1-2
4
Week 8
Day 43 – Day 70
57
1-2
5
Week 12
Day 71 – Day 126
85
1-2
6
Week 24
Day 127 – Day 210
169
2
7
Week 36
Day 211 – Day 294
253
2
8
Week 48
Day 295 – Day 378
337
3
9
Extension 
Day 139- Day 222 of 
extension period 
181
3
10`
Extension 
Day 319 of Day 403 
extension period 
361
1-2
24
30 day Follow-up
Day 1 of FU onwards
31
1-2
25
90 day Follow-up
Day 1 of FU onwards
91
*Relative to Study Day 1 , Analysis period 1: Interim Analysis, Analysis Period 2: Week 48 Primary Analysis, 
Analysis period 3: Only extension treatment period data after Primary analysis.
`if there are more extension visits, visit numbers will continue to label 11, 12…
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D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
12
Approved, Date: 18 September 2019
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.
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 or day 1 of treatment 
whichever the last visit before first dose. 
Treatment
Phase
Date of the first intake 
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)
Extension 
Treatment
phase
Week 48 visit date +1 day
Date of transition to commercial D/C/F/TAF or Trial 
Termination date. 
^Follow-up
End of treatment phase +1 day
Trial termination date for all groups (date of last 
contact)
*90 day FU
Date of premature study 
discontinuation + 1day
Date of retention in care assessment. 
*90 day FU visit planned only discontinued subjects from day 1 to week 48 visit. 
^30 day FU visit required for any subject who has ongoing AE or SAE at the time of his last study visit.
Data up to each subject’s Week 48 visit are in scope for this primary analysis, and if applicable, 
any (confirmatory) viral load or genotype/phenotype results immediately subsequent to Week 48. 
Retention in care assessment is planned 90 days after discontinuation.
2.2.
Analysis Sets
2.2.1.
All Subjects
All subject analysis set population includes subjects who were screened. 
2.2.2.
All Enrolled Analysis Set
The all enrolled analysis set includes all subjects who were not screen failures and were 
dispensed treatment.
2.2.3.
Efficacy Analysis Set(s)
The Intent to treat analysis set (ITT) includes all enrolled subjects who received at least 1 dose of 
study drug.
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
13
Approved, Date: 18 September 2019
Efficacy analysis set (EAS) includes all ITT analysis set subjects who did not discontinue study 
due to safety or resistance stopping rules or did not discontinue study due to violation of 
inclusion criteria caused by un-confirmed HIV positive test.
The per protocol analysis set (PP) includes a subset of subjects in the intent to treat analysis set
(ITT) who are in-compliance with the protocol. Compliance is defined as subjects who are not 
having major protocol deviation that is considered to have an impact on the safety or efficacy 
assessments. 
2.2.3.1.
Primary Efficacy Analysis Set
The ITT analysis set is the primary analysis set for efficacy analysis.
2.2.3.2.
Secondary Efficacy Analysis Set
Secondary end points will be analyzed using ITT, EAS and PP. Details of analysis and study 
population will be described in the DPS.
2.2.4.
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.
Definition of Subgroups
Subgroup
Version
Definition
Applied 
Analysis 
Race 
White
Black of African American
Asian
American Indian or Alaska 
Native
Native Hawaiian or Pacific 
Islander
Other
Efficacy 
Safety 
Gender
Female
Male
Efficacy 
Safety
Time from initial HIV diagnosis to Enrolment

[0-1[ day

[1-2[ days

[2-3[ days

[3-7[ days

[7-14[ days
Efficacy
Baseline Viral Load categories
>100K
≤100K
Efficacy
MRU
Baseline Viral Load categories2
≤100K
100K-500K
>500K
Efficacy
Baseline CD4+ categories
>200
≤ 200
Efficacy
MRU
Baseline CD4+ categories2
<50
50-200
Efficacy
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
14
Approved, Date: 18 September 2019
Subgroup
Version
Definition
Applied 
Analysis 

>200
Adherence based on pill count
> 95%
≤ 95%
Efficacy
Age Group
1(Adult)
Adults
18-25
26-50
51-64
≥65
Efficacy 
Safety
Age Group2
1(Adult)
Adults
18-30
≥30
MRU
BMI
1
underweight <18.5 kg/m2
normal 18.5-<25 kg/m2
overweight 25-<30 kg/m2
obese ≥30 kg/m2
Efficacy 
Safety
HIV-1 subtype 
B
non-B
Efficacy
Any PI RAMs (primary + secondary
0-3
4-6
7-9
≥10
Efficacy
Presence of one or more primary and/or DRV 
RAMs,

Yes/No
Efficacy
Presence of one or more NRTI RAMs

Yes/No
Efficacy
Presence of one or more NNRTI RAMs

Yes/No
Efficacy
Presence of one or more M184I/V

Yes/No
Efficacy
Presence of one or more Primary INI RAMs

Yes/No
Efficacy
Presence of one or more Secondary INI RAMs

Yes/No
Efficacy
HIV Acquisition Risk Factor

Heterosexual contact 
Efficacy 
Safety

Intravenously injectable drug use 

MSM

Multiple

Other
2.4.
Study Day and Relative Day
Study Day 1 or Day 1 refers to the start of the first study drug administration. If subjects start 
medication a day after baseline/screening visit, actual treatment administration date will be used 
as Day 1 instead of screening/baseline visit date.
All efficacy and safety assessments at all visits will be assigned a day relative to this date.
2.5.
Baseline and Endpoint
Baseline is defined as the last observation prior to start of study drug.
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
15
Approved, Date: 18 September 2019
Endpoint is defined as the last available postbaseline result within the analysis period. 
Unscheduled visit results are included in this definition and will be considered as the endpoint 
value if the unscheduled visit result is the last postbaseline result available within the analysis 
period.
2.6.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
Partial AE onset dates will be imputed as follows:

If the onset date of an adverse event is missing day only, it will be set to:

First day of the month that the AE occurred, if month/year of the onset of AE is 
different than the month/year of the study treatment start 

The day of study treatment start, if the month/year of the onset of AE is the same as 
month/year of the study treatment start date and month/year of the AE resolution date is 
different

The day of study treatment start or day of AE resolution date, whichever is earliest, if 
month/year of the onset of AE and month/year of the study treatment start date and 
month/year of the AE resolution date are same

If the onset date of an adverse event is missing both day and month, it will be set to the 
earliest of:

January 1 of the year of onset, as long as this date is on or after the study treatment start 
date

Month and day of the study treatment start date, if this date is the same year that the AE 
occurred

Last day of the year if the year of the AE onset is prior to the year of the study treatment 
start date,

The AE resolution date.

Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an adverse event is missing day only, it will be set to the earliest of 
the last day of the month of occurrence of resolution or the day of the date of death, if the 
death occurred in that month.

If the resolution date of an adverse event is missing both day and month, it will be set to the 
earliest of December 31 of the year or the day and month of the date of death, if the death 
occurred in that year.

Completely missing resolution dates will not be imputed.
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
16
Approved, Date: 18 September 2019
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
An interim analysis is planned once all subjects have been assessed for safety and resistance 
stopping rules. There will be no DMC analysis planned.
Interim analysis contents will be defined in DPS.
4.
SUBJECT INFORMATION
The number of subjects in each analysis set will be summarized. In addition, the distribution of 
subjects by site ID will be presented unless otherwise noted.
4.1.
Demographics and Baseline Characteristics
Table 2 presents a list of the demographic variables that will be summarized, for the ITT, EAS
and PP analysis set(s).  Demographics will also be summarized by study subgroups using the ITT 
analysis set. Additionally, all demographics and baseline disease characteristics data will be 
listed Substance use (alcohol consumption and nicotine use) data will be listed only. 
Table 02: Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Categorical Variables:
Frequency distribution with the 
number and percentage of subjects 
in each category.
Age ([18-25 years, 26-50 years, 51-64 years, and >65 years])
Gender (male, female, undifferentiated)
Race (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Other, 
Unknown, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
BMI ([underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese ≥30 kg/m2])
Woman of childbearing potential (Of childbearing potential/Permanently 
Sterilized/ Postmenopausal/ NA)
Nicotine use (Never used, current user, former user)
Alcohol consumption (Never used, current user, former user)
Highest education level (Less than high school, …)
Marital status (Single- newer married, married, …)
Employment status (Employed full time for wages, …)
State belongs to (Alabama, …) 
Have insurance (Yes/no)
Social support of the subject (Friend, Family member, …)
Current housing situation
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'
Table 03: Baseline HIV disease characteristics
Continuous Variables:
Summary Type
Baseline CD4+ (absolute count and %)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Time since diagnosis of HIV infection to study enrolment (days)
Baseline-screening eGFR
Baseline HIV-1 Viral load (absolute count )
% of subjects receving PrEP prior to baseline
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
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Approved, Date: 18 September 2019
Categorical Variables:
Frequency distribution with the 
number and percentage of subjects 
in each category.
All assays used to determine initial HIV diagnosis (HIV-1 Rapid Antibody 
Assay (4th generation), …)  
HIV confirmatory test results (Yes/No) 
CDC Disease Classification (Stage A,…)
Worst clinical stage of HIV-infection according to WHO (Clinical stage 1 
(asymptomatic), …)
HIV Acquisition Risk Factor (MSM, …)
Screening and Baseline viral load (<100K , ≥ 100K HIV-1 RNA
copies/mL)
Baseline CD4 cell count (<200, ≥200 [200≤x<350, 350≤ x≤500, >500] 
cells/mm3)
HCV/HBV coinfection status
Time from HIV diagnosis to enrolment (0-1) days, [1-2),days, [2-3) days, 
[3-7) days, [7 -14) days
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 

primary and/or DRV RAMs,

NRTI RAMs,

NNRTI RAMs,

M184I/V, 

Primary INI RAMs, 

Secondary INI RAMs
If multiple race categories are indicated, the Race is recorded as 'Multiple'
4.2.
Disposition Information
Screened subjects and reason for screen failures will be listed only.
The number of subjects in the following disposition categories will be summarized throughout 
the study:

Subjects receiving study drug

Subjects completing the study

Subjects who discontinued study drug

Reasons for discontinuation of study drug

Subjects who terminated study prematurely

Reasons for termination of study
The above categories will include summaries. 
Additionally, discontinued subject due to stopping rules (safety or resistance) will be tabulated 
by stopping rule type and reason of stopping. 
A listing of subjects will be provided for the following categories:

Subjects who discontinued study drug
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
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Approved, Date: 18 September 2019

Subjects who terminated study prematurely

Subjects who discontinued study treatment due to safety stopping rule

Subjects who discontinued study treatment due to resistance stopping rule
4.3.
Treatment Compliance (Adherence)
Treatment adherence defined based on pill count.
Study drug compliance will be summarized descriptively and frequency tabulations. Cumulative 
treatment adherence through Week 48 will be determined.
Amount to be taken through Week 48 = (number of days since start of treatment × number of tablets to 
be taken per day).
Number of days since start of treatment 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.
-
Week 48 visit date
In addition, the cumulative treatment adherence up to time point where not more than one bottle is 
missing, or if available, up to Week 48, 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.
“If medication kit was not returned, did subject take all the tablets?” question in CRF answered ‘Yes’, 
number of tables returned will be set to zero.  
Study drug compliance (%) (Level of adherence) = (actual amount taken / amount to be taken) × 100%
Treatment adherence is defined as:
- adherent: the level of adherence is >95%, 
- sub-optimal-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%
The number and percentage of subjects who have at least 95% study drug compliance through 
the study timepoints and overall will be summarized.
Predictors of suboptimal adherence will be assessed among below intrinsic and extrinsic factors. 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
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Approved, Date: 18 September 2019
Intrinsic / Extrinsic factors: Gender, age category, race, ethnicity, BMI category, current tobacco 
use, current alcohol consumption, highest education level, employment status, social support of 
the subject, marital status, current housing situation, have an insurance, clinical stage of HIV 
infection and time to start of the study treatment. 
Logistic regression model will be used to assess predictors of suboptimal adherence (<95% 
adherence by pill count) in the study population at week 24 and week 48 analysis timepoints. 
Univariate logistic regression models will be used to assess the effect of the covariates to the 
adherence over specified timepoints.
A Final multivariate logistic regression model will be fitted to any covariate with significant 
affect (at 15% level) based on the univariate modeling. If any of the selected covariates is no 
longer significant at (10% significance level) in the multivariate model, it will be excluded again. 
Exclusion of covariates is performed stepwise with backward elimination procedure, starting 
with the covariate that is least significant. Covariates in the model with 10% significant level will 
be concluded as predictors of suboptimal adherence.   
4.4.
Extent of Exposure
The number and percentage of subjects who receive study drug will be summarized.
Descriptive statistics of study drug duration, in weeks, (N, mean, SD, median, and range 
(minimum, maximum)) will be presented for the ITT analysis set.
Subject-weeks of exposure are calculated as (days of exposure)/7. Subject-weeks will be 
presented.
Study drug duration is defined as (date of last dose of study drug – date of first dose of study 
drug) +1.  Duration will be tabulated in weeks with dividing duration of exposure by 7. 
Total dose days of exposure is defined as the total number of days that study drug was 
administered to the subject (excluding days of known study drug interruption). If dates of study 
drug interruptions are not fully known, in terms of start and end date of interruption, these 
interruptions will not be excluded from total days of exposure. 
4.5.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
subjects’ rights, safety or well-being, or the integrity and/or result of the clinical study. Subjects 
with major protocol deviations will be identified prior to database lock and the subjects with 
major protocol deviations will be summarized by category.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy inclusion/exclusion criteria

Received a disallowed concomitant treatment
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
20
Approved, Date: 18 September 2019

Received incorrect dose

Other
4.6.
Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the [World Health Organization Drug 
Dictionary (WHO-DD)]. Prior medications are defined as any therapy used up to 30 days before 
the day of first dose (partial or complete) of study drug. Concomitant medications are defined as 
any therapy used on or after the same day as the first dose of study drug, including those that 
started before and continue on after the first dose of study drug.
Prior and concomitant therapies will be also grouped as follows for specific drugs, using a list of 
dictionary derived terms provided as metadata. These groups will be tabulated (n, %) per 
analysis phase:

lipid lowering drugs

antidiabetic drugs

antihypertensive drugs

drugs for cardiovascular disease

antiosteoporotic drugs

antidepressants

opportunistic infection (OI) /prophylaxis drugs
Summaries of concomitant medications will be presented by ATC term. The proportion of 
subjects who receive each concomitant medication will be summarized as well as the proportion 
of subjects who receive at least one concomitant medication. 
Prior medications will be summarized by ATC term.
4.7.
Medical History
Subjects past and/or concomitant diseases will be tabulated by medical history categories general 
medical history and family history separately. Tabulation (n, %) will be done by body system 
and medical term. Additionally, all medical history will be listed by medical history category.  
4.8.
Retention in Care Analyses
Number of subjects with early study treatment discontinuation and number of subjects with a 
documented clinic visit within 90 days of discontinuing study drug (providing consent is not 
withdrawn) who attend to retention of care assessment will be tabulated. 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
21
Approved, Date: 18 September 2019
5.
EFFICACY
5.1.
Analysis Specifications
5.1.1.
Level of Significance
There will be no formal statistical testing.
5.1.2.
Data Handling Rules
Plasma viral load will be measured using a validated assay at a central laboratory.  
Imputation of left censored HIV-1 RNA values: viral load results recorded as “< 20cp/mL HIV 
RNA detected” “< 20cp/mL HIV RNA copies/mL Not Detected” and “NO HIV-1 RNA 
DETECTED
” will be scored at 19.
If there are retesting, repeating the same analyze from same collected sample, last or retested 
results will be used in analysis. 
5.1.3.
Virologic Response Definitions
The following imputation methods will be used to calculate virologic response at a given time 
point addition with applying 50/200 copies/mL as threshold.
Five imputation mechanisms are considered:
1. Observed
2. NC=F
3. M=F
4. TLOVR
5. FDA Snapshot 
The first mechanism, Observed, does not require an imputation procedure. subjects with a 
missing value are disregarded in the analysis for that time point.
In the second mechanism, NC=F, non-completers (NC) get imputed values of failure after the 
moment of study treatment discontinuation. For intermediate missing values, response is imputed 
when the previous and next observed data are response. If a subject is still ongoing or has 
completed study treatment and no next observed assessment is available, missing values will be 
imputed via LOCF. Otherwise, intermediate missing values are imputed with failure.
In the third mechanism, M=F, all missing values are imputed as failure.
In the fourth mechanism 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:
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
22
Approved, Date: 18 September 2019
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.
The fifth mechanism FDA snapshot approach: The snapshot mechanism is based on the last 
available plasma HIV-1 RNA level within the window of an analysis time point. This does not 
necessarily coincide with the HIV-1 RNA assessment with USE = ‘Y’.
The snapshot approach will classify subjects into 3 outcome categories: “virologic success”, 
“virologic failure”, or “no viral load data in the Week 48 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 category. If a subject 
discontinues in the time window but also has an HIV-RNA value in the time window, then the 
viral load data will be used to classify the subject’s category. 

Virologic success: 
o
HIV RNA <50/200 copies/mL in the Week 48 visit window (Week 42-54)

Virologic failure:
o
HIV RNA ≥50/200 copies/mL in the Week 48 visit window (Week 42-54)
o
Virologic failure leading to discontinuation
o
Discontinued due to other reason (i.e., other than AE/death or virologic failure) 
and last available HIV RNA ≥50/200 copies/mL

No viral load data in the Week 48 visit window:
o
Discontinued due to AE/death (subjects will be classified in this category if 
discontinued prior to Week 48 window regardless of HIV RNA level)
o
Discontinued due to other reason (i.e., other than AE/death or virologic failure) 
and the last available HIV RNA <50/200 copies/mL (or missing)
o
Missing data during the Week 48 visit window but on study
An identified subject will be classified to the snapshot categories as follows:
Virologic response will then be categorized as follows: Yes (virologic success), or No (virologic 
failure and no viral load data in the Week 48 visit window).
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
23
Approved, Date: 18 September 2019
The snapshot approach will also be displayed over time by analysis time points, and will follow 
the same logic as defined above week 48 time point. (please see Section Visit Windows for visit 
intervals)
5.2.
Primary Efficacy Endpoint(s)
5.2.1.
Definition
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 (see section 5.1.3).
5.2.2.
Estimand
Population: Type 1 (HIV-1) Infected treatment naïve subjects using the ITT population.
Endpoint: Proportion of subjects who have HIV-RNA<50 copies/mL at Week 48 as defined by 
the FDA snapshot analysis
Measure of Intervention: Effect of the initial treatment. Missing data and discontinued subjects 
are included to the primary estimation as defined by the FDA snapshot algorithm.  
5.2.3.
Analysis Methods
The proportion of subjects who have HIV-1 RNA<50 copies/mL will be calculated along with 
the 95% CIs. The Wilson (Score) method for the CI will be used.
Similar analysis will be performed for the per protocol (PP) population and EAS population as 
sensitivity analysis. 
Subgroup analysis of primary endpoint will be performed for subgroups of baseline VL 
categories, baseline CD4+ categories, adherence rate categories, race, age, gender, time to initial 
diagnosis of HIV to start of study and presence of the M184/V mutation at baseline.
5.3.
Major Secondary Endpoints
5.3.1.
Definition

Proportion of subjects who have HIV-1 RNA <50 copies/mL at Week 24 as defined by 
the FDA snapshot analysis in ITT, EAS and PP populations.

Proportion of subjects who have HIV-1 RNA <50 copies/mL at Week 24 and week 48 as 
defined by the TLOVR algorithm in ITT, EAS and PP populations.  

Proportion of subjects experiencing protocol defined virologic failure at Week 24 and 
Week 48 and during the extension phase in ITT population.

Proportion of subjects lost to follow-up through 24 and 48 weeks of treatment in ITT 
populations. 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
24
Approved, Date: 18 September 2019

Mean log10 change in HIV-1 viral load from baseline through Week 24 and Week 48 
analysis timepoints in ITT populations.

Changes from baseline in CD4+ cell count at Weeks 12, 24, and 48 in ITT population.
5.3.2.
Analysis Methods
As secondary analyses, the proportion of subjects with HIV-1 RNA <50 copies/mL at each time 
point as defined by the FDA snapshot analysis will be analyzed using the same method as for the 
primary efficacy endpoint. 
In addition, confirmed virologic response defined as HIV-1 RNA <50 copies/mL at Week48 
determined by the TLOVR algorithm will be analyzed. TLOVR algorithm is defined at section 
5.1.3. 
Actual and changes from baseline 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). 
Mean actual and change from baseline over time data will be presented box plot.  
For the change from baseline following imputation methods will be used.
Two imputation mechanisms will be considered:
1. Change (observed)
2. Change (NC=F)
“Change (observed)” means: No imputation is done.
“Change (NC=F)” means: 
For subjects who discontinued study treatment, all time points after discontinuation are imputed 
with the baseline value and thus a change of 0 (NC=F). Intermittent missing results are imputed 
with the last post-baseline observation carried forward (LOCF).
5.4.
Resistance Analysis
5.4.1.
Definition

The number of PR, RT, IN mutations will be tabulated based on resistance tests 
performed at the screening/baseline visit. 

The number of treatment-emergent PR, and RT as well as specific mutations associated 
with resistance to DRV, FTC, and TAF based on the observed virologic failures through 
the study period.

The proportion of subjects meeting resistance stopping rules, requiring discontinuation of 
study drug, based on the findings of screening/baseline resistance testing will be reported 
at week 24 and week 48 analysis. 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
25
Approved, Date: 18 September 2019

Fold change (FC) in 50% effective concentration (EC50) of ARVs may be analyzed and 
tabulated dependent on the number of virologic failures and phenotypes available through 
the study period.
5.4.2.
Analysis Methods
5.4.2.1.1.
Genotype
At screening HIV-1 PR/RT/IN genotype will be assessed by the GenoSure Prime® assay. Post-
screening HIV-1 PR/RT genotype will be assessed by the PhenoSenseGT™ assay  
Evaluation of screening and treatment-emergent RAMs will be based on PI, N(t)RTI, NNRTI
and INI (only at screening) mutations 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, RT and IN at only screening) 
and time point. Mutations will be marked by lists and if they emerged.
At screening, a tabulation will present the number of patients with a specific mutation or number 
of patients with at least one PR or RT or IN 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”. 
PR, RT and IN mutations specified below.
Protease mutations
-
IAS-USA2 Primary PI RAMs (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-USA2 Secondary PI RAMs s (n=52)
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
26
Approved, Date: 18 September 2019
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-USA2 DRV RAMs (n=11)
V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V 
RT mutations 
-
IAS-USA2 NRTI RAMs (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-USA2 NNRTI RAMs (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-USA2 Thymidine Analogue Mutations (TAMs) (n=8)
M41L, D67N, K70R, L210W, T215Y/F, K219Q/E 
-
IAS-USA2 TFV RAMs
K65R/E/N, K70E
-
IAS-USA2 FTC RAMs
K65R/E/N, M184I/V
IN mutations 
-    IAS-USA2 primary INI RAMs (n=11)
    T66I, E92Q, F121Y, Y143C/H/R, S147G, Q148H/K/R, N155H
-   IAS-USA2 secondary INI RAMs (n=10)
   T66A/K, L74M, E92G, T97A, E138A/K, G140A/S, R263K
5.4.2.1.2.
Phenotype
Predicted phenotype based GenoSure Prime®, and 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 will be tabulated. 
Loss of phenotypic susceptibility may be analyzed depending on the number of PDVF with post 
baseline genotype/phenotype data.
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.
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
27
Approved, Date: 18 September 2019
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
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
2.5
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
6.
SAFETY
6.1.
Adverse Events
6.1.1.
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 or higher version.
Adverse Drug Reaction (ADR) 
ADRs will be presented. A current list of all ADRs is in Attachment 3, and upon further clinical 
evaluation, additional (grouped) terms might need to be added.  The medical assessment of the 
safety data will be performed according to a pre-specified algorithm (attached to the DPS) and 
will lead to the final list of ADRs. In case multiple lists are available (US definition), ADRs will 
be tabulated separately per list. 
Events of interest 
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.
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
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Approved, Date: 18 September 2019
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,
Bone Loss/atrophy,
Fracture, possibly osteoporotic,
Fracture other,
Other Bone Events
-
Dyslipidaemia AEOI 
-
Liver AEOI
Subgroups: Cholestasis and jaundice of hepatic origin
Hepatic failure, fibrosis and cirrhosis and other liver damage related conditions
Liver-related investigations, signs and symptoms
                       Hepatitis, non infectious
-
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,
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
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Approved, Date: 18 September 2019
Torsade de pointes/QT prolongation
-
Convulsion AEOI
Incidence of treatment-emergent adverse events of interest will be summarized as AE summary 
tables.
A listing of subjects who died will be provided.
6.2.
Analysis Methods
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after 
the initial administration of study drug through the day of last dose plus 1 day is considered to be 
treatment emergent. If the event occurs on the day of the initial administration of study drug, 
then the event will be assumed to be treatment emergent. If the event date is recorded as partial 
or completely missing, then the event will be considered to be treatment emergent unless it is 
known to be prior to the first administration of study drug based on partial onset date or 
resolution date. All reported treatment-emergent adverse events will be included in the analysis.  
For each adverse event, the number and percentage of subjects who experience at least 1 
occurrence of the given event will be summarized. 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. 
Incidences of AEs for above mentioned analyses will also be presented by SOC and preferred 
term.  A listing of all AEs will be provided. There will be no formal statistical testing.
Summary of 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.
AE listings will be provided for subjects who:
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
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Approved, Date: 18 September 2019

Had SAEs

Had AEs leading to discontinuation of study drug.

Had grade 3 or 4 AE

Who had each AEoI category 
Selected safety endpoints will be explored by subgroups defined in Section 2.3. Details for 
subgroup analyses of safety endpoints will be provided in the DPS.
6.3.
Clinical Laboratory Tests
All clinical laboratory tests will be displayed for the subjects included in the ITT analysis set.
Descriptive statistics will be presented for all chemistry, hematology, and urinalysis laboratory 
tests at scheduled time points. If there are retesting, repeating the same analyze from same 
collected sample, last or retested results will be used in analysis.
Change from baseline to each scheduled time points will be summarized for chemistry, 
hematology, and urinalysis (pH, and specific gravity) tests. A box plot of change from baseline 
to analysis timepoints will be provided for the following laboratory tests: eGFR, ALT and AST
Descriptive statistics by DAIDS toxicity grade over time will be presented. Shift summaries from 
baseline DAIDS toxicity grade to the worst on-treatment toxicity grade will also be presented.
If the DAIDS grading is not available, shift tables will be provided summarizing the shift in 
laboratory values from baseline to week 48 analysis time points with respect to abnormality 
criteria (low, normal, high).
6.4.
Vital Signs and Physical Examination Findings
Continuous vital sign parameters including height, weight, pulse, blood pressure (systolic and 
diastolic), will be summarized at each assessment time point. 
Changes from Baseline will be summarized for the each scheduled time points. Descriptive 
statistics (mean, standard deviation, median, minimum and maximum) will be presented. 
Cross-tabulations for the worst abnormalities versus reference per vital signs test will be produced. 
Physical examination findings and changes from baseline at each scheduled time point will be 
tabulated per treatment arm. Abnormal physical examination findings will also be listed.
A listing of subjects with treatment-emergent clinically important vital signs will be presented, 
along with a listing of all vital sign measurements.
Vital Signs
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
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Approved, Date: 18 September 2019
Abnormality Code
Pulse 
(bpm)
DBPa
(mmHg)
SBPa
(mmHg)
Abnormally low
50 
50
90 
Grade 1 or mild
-
>90 - <100 
>140 - <160 
Grade 2 or moderate
-
100 - <110 
160 - <180 
Grade 3 or severe
-
110 
180 
Abnormally high
120 
-
-
a
Classification of adverse events related to hypotension/hypertension should be done according to the DAIDS 
grading table (Attachment 2 at protocol).
In determining abnormalities, the following rules are applied:
-
worst grades/abnormalities are determined over the whole observational period for each trial 
period separately, including post-reference scheduled and unscheduled measurements of that 
phase.
-
The abnormalities ‘abnormally low’ and ‘abnormally high’/grades are considered equally 
important, i.e. if a subject has as well an abnormally low as an abnormally high or graded 
value post-reference, both abnormalities are shown in the tables. (This means that the sum of 
the percentages can be more than 100%).
Definition treatment-emergent:
An abnormality will be considered treatment-emergent in a particular period if it is worse than 
the reference corresponding to this period. If the reference is missing, the abnormality is always 
considered as treatment-emergent. A shift from ‘abnormally low’ at reference to ‘abnormally 
high’ or ‘grade …’ post reference (or vice versa) is also treatment-emergent.
7.
PATIENT REPORTED OUTCOME
7.1.
HIV-Treatment Satisfaction Questionnaire (HIVTSQs)
HIVTSQs will be scored as below. 
Each test question (idem) will be scored a scale from 6 to 0.  
Treatment satisfaction:
All the items are summed up to produce Treatment satisfaction score (range 0 to 60). The higher 
the score, the greater the satisfaction with treatment. 
General satisfaction/Clinical subscale:  Items 1,2, 3, 9 and 10. 
All the items are summed to produce a score (range:0-30).  The higher the score, the greater the 
satisfaction within this subscale. 
Lifestyle/Ease subscale: items 4, 5, 6, 7 and 8 
All the items are summed to produce a score (range:0-30).  The higher the score, the greater the
satisfaction within this subscale. 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
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Approved, Date: 18 September 2019
In case of missing item score, overall score of a subject will be calculated as below, providing 
the number of missing values does not exceed the number tolerable without unacceptable loss of 
reliability:
    1.Sum, the existing idem scores,
    2.Divide this sum by the number of existing item scores     
    3. Then multiply by 10.
Descriptive statistics for absolutes values and changes in HIVTSQs scores will be calculated for 
each question, for each subscale and overall at each timepoint, where applicable. Overall mean 
HIVTSQs scores and mean changes over time will be demonstrated graphically. 
7.2.
4-Day Self Report 
Patient self-reported adherence to study medication will be measured by 4-day recall self-report 
as collected Drug Adherence page of eCRF.
Patient-reported adherence rates to study treatment will be presented descriptively per analysis 
time point. Additionally, all self-reported adherence will be listed. 
8.
PHARMACOKINETICS/PHARMACODYNAMICS
8.1.
Pharmacokinetics
Plasma concentrations of DRV and COBI may be determined in subjects experiencing protocol-
defined virologic failure, or subjects who have persistent HIV-1 RNA ≥400 copies/mL past 
Week 24 but do not meet the definition of virologic failure, using stored blood samples collected 
throughout the study period, if deemed necessary.
Plasma concentration will be listed only. 
9.
HEALTH ECONOMICS
9.1.
Medical Resource Utilization and Health Economics
The number of medical resource utilization will be tabulated by the type of resource (e.g., 
overnight hospitalization, Emergency Room visit, Outpatient visit, General practitioner visit, 
Specialist visit, etc.) and by classification of MRU (HIV-related, All-cause HRU). For each 
overnight hospitalization, further classification will be by intensive care unit use (yes, no).
Descriptive statistics of overall length of hospital stay and overall length of intensive care unit 
use will be tabulated throughout the study.
Costs of care will be calculated by assigning costs based on Centers for Medicare & Medicaid 
Services (CMS) fee schedule or MEPS as appropriate, to assessed MRU on a per subject per 
month basis. Descriptive statistics will be calculated to compare the costs of care from baseline 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
33
Approved, Date: 18 September 2019
to Weeks 12, 24, and 48. Exploratory analysis might be performed examining relationship 
between HRU and HIVTSQs scores. 
All-cause and HIV-specific HRU during the study period will be summarized overall and by 
category as the counts per patient per month (PPPM). Monthly average counts per subject and 
percent change over time will also be calculated to show the temporal trend for each category. 
Direct medical costs will be calculated in United States (USA) dollars based on HRU noted 
above 
Additionally, all MRU data will be listed. 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
34
Approved, Date: 18 September 2019
REFERENCES
1.
HIV-Treatment Satisfaction Questionnaire. Available at 
http://www.healthpsychologyresearch.com/sites/default/files/guidelines/HIVTSQ%20Summary_rev.11.8.15.pd
f . Accessed 3 March 2017
2.
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 https://www.iasusa.org/sites/default/files/tam/24-4-132.pdf
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
35
Approved, Date: 18 September 2019
ATTACHMENTS
ATTACHMENT 1:
Schema for Follow-up of Subjects who Meet the Criteria for Protocol-
Defined Virologic Failure 
Virologic Nonresponse Schema 
Screening/
Baseline
Treatment Phase
ESTD
Week 12
Unscheduled visit, 
within 2-4 weeks after
Week 12 HIV-1 RNA result
HIV-RNA 
1 log10 reduction 
from baseline 
AND
400 copies/mL 
Blood drawn for repeat of HIV-1 
RNA testing
and potential genotype/phenotype
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.
Unconfirmed virologic 
nonresponse: remain on 
study druga
Confirmed virologic 
nonresponseb
HIV-1 
genotype/phenotypec,d
If no resistance to study 
drug is detected, continue 
on study drug at the 
investigator’s discretion
If resistance to study drug 
is detected, study drug may 
be discontinued at the 
investigator’s discretione
a
If virologic nonresponse is not confirmed, the subject will continue 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 (PhenoSense GT®) will be analyzed.
d
In case of early discontinuation, an HIV-1 resistance report, if available, will be forwarded to the treating 
physician to assist in the selection of a new ARV regimen.
e
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 
drug for an individual subject must inform the sponsor’s medical monitor before study drug discontinuation. 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
36
Approved, Date: 18 September 2019
Virologic Rebound Schema 
Screening/
Baseline
Treatment Phase
ESTD
At any visit, after achieving confirmed consecutive HIV-1 RNA 
<50 copies/mL, a rebound in HIV-1 RNA to ≥50 copies/mL, 
OR
At any visit, a >1 log10 increase in HIV-1 RNA from the nadir
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.
Within 2-4 weeks of HIV-1 RNA result, return for 
scheduled/unscheduled visit for repeat of HIV-1 RNA testing
and potential genotype/phenotype
Unconfirmed virologic rebound: 
remain on study druga
Confirmed virologic reboundb
HIV-1 genotype/phenotypec,d
If no resistance to study drug is 
detected, continue on study drug at 
the investigator’s discretion
If resistance to study drug is detected, 
study drug may be discontinued at the 
investigator’s discretione
a
If virologic rebound is not confirmed, the subject will continue study drug 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 (PhenoSense GT®) will be analyzed.
d
In case of early discontinuation, an HIV-1 resistance report, if available, will be forwarded to the treating 
physician to assist in the selection of a new ARV regimen.
e
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 
drug for an individual subject must inform the sponsor’s medical monitor before study drug discontinuation. 
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
37
Approved, Date: 18 September 2019
ATTACHMENT 2:
Adverse Events of Special Interest
Adverse events of special interest are defined as follows:
Adverse Events of Interest: List of Preferred Terms
AEOI
AEDECOD (MedDRA v20)
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 morbiliform, 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
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
38
Approved, Date: 18 September 2019
AEOI
AEDECOD (MedDRA v20)
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 hypertension, 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 triaditis  
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
39
Approved, Date: 18 September 2019
AEOI
AEDECOD (MedDRA v20)
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, Liver palpable subcostal
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
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
40
Approved, Date: 18 September 2019
AEOI
AEDECOD (MedDRA v20)
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, Hyperosmolar 
hyperglycaemic state, 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, 
Hyperglycaemic hyperosmolar nonketotic syndrome
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
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
41
Approved, Date: 18 September 2019
AEOI
AEDECOD (MedDRA v20)
Lipodystrophy AEOI
Body fat disorder, Facial wasting, Fat redistribution, Fat tissue decreased, HIV 
lipodystrophy, Lipoatrophy, Lipodystrophy acquired, Lipohypertrophy, Partial 
lipodystrophy
Immune reconstitution inflammatory 
AEOI
Immune reconstitution syndrome, Mycobacterium avium complex immune 
restoration disease, Immune Reconstitution Inflammatory Syndrome 
associated tuberculosis, Immune Reconstitution Inflammatory Syndrome 
associated Kaposi’s sarcoma,
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, Cardiac enzymes 
increased
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
42
Approved, Date: 18 September 2019
AEOI
AEDECOD (MedDRA v20)
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, Genital 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
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 
trypsine 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
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
43
Approved, Date: 18 September 2019
AEOI
AEDECOD (MedDRA v20)
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, 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, Convulsion, Grand mal 
convulsion
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
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
44
Approved, Date: 18 September 2019
AEOI
AEDECOD (MedDRA v20)
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, Urine amino acid level abnormal, Urine 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
Bone AEOI (for fractures) /
Osteomalacia
Hypophosphataemic rickets, Osteomalacia, Renal osteodystrophy , 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, Fracture treatments (excl skull and 
spine), 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
NCT03227861


D/C/F/TAF  (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg)
Statistical Analysis Plan TMC114FD2HTX3002
45
Approved, Date: 18 September 2019
AEOI
AEDECOD (MedDRA v20)
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
NCT03227861