"Efficacy, Safety, and Tolerability of Switching EFV/TDF/FTC to BIC/FTC/TAF in Virologically Suppressed Adults With HIV-1 Infection."
Phase: PHASE4
Conditions: Human Immunodeficiency Virus
Sponsor: Midland Research Group, Inc.

 
 
BIKTARVY® (BIC/FTC/TAF)                 Protocol IN-US-380-4543                   Midland Research Group, Inc.  
 
 
 
 Version: Original, Date: 21 Feb 2018 
CONFIDENTIAL 
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Efficacy, Safety, and Tolerability of Switching 
EFV/TDF/FTC to BIC/FTC/TAF in Virologically 
Suppressed Adults with HIV-1 Infection. 
 
 
Protocol Number: 
IN-US-380-4543 
 
Protocol Version/Date:        Original: 
21 February 2018 
 
Indication: 
HIV-1 Infection 
 
Sponsor: 
Midland Research Group, Inc. 
 
 
 
 
1421 East Oakland Park Blvd.  Suite 200 
 
 
 
 
Oakland Park, FL 33334 
 
 
 
 
Phone: 954-375-1275 
 
 
 
 
Fax: 954-283-7618 
 
 
 
 
Email: research@midlandresearchgroup.com 
 
Principal Investigator: 
Noah Lee, DO  
 
Sub-investigator: 
Erik Lowman, DO 
 
 
Study Contact:    
Noah Lee, DO 
 
 
 
 
Phone: 954-375-1275 
 
 
 
 
Fax: 954-283-7618 
 
 
 
 
Email: nlee@midlandresearchgroup.com 
 
Protocol Funding 
Provided By: 
Gilead Sciences, Inc. 
 
 
333 Lakeside Drive 
 
 
Foster City, CA 94404 
 
Reviewing Investigational 
Review Board (IRB):            Chesapeake IRB 
 
Clinical Trials.gov 
Identifier: 
 
              Not Available 
CONFIDENTIALITY STATEMENT 
 
The information contained in this document, particularly unpublished data, is the property or under 
control of Midland Research Group, Inc., and is provided to you in confidence as a consultant, for 
review, and an applicable Institutional Review Board or Independent Ethics Committee. The information 
is only to be used by you in connection with authorized clinical studies of the investigational drug 
described in the protocol. You will not disclose any of the information to others without written 
authorization from Midland Research Group, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 

 
 
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TABLE OF CONTENTS 
ABBREVIATIONS 
 
 
 
 
 
 
 
 
 
 
6 
1. 
INTRODUCTION 
 
 
 
 
 
 
 
 
 
7 
 
1.1 
Rationale for the Study  
 
 
 
 
 
 
 
7 
2.  
STUDY OBJECTIVES  
 
 
 
 
 
 
 
 
8 
 
2.1  
Primary Objective  
 
 
 
 
 
            
 
8 
 
2.2  
Secondary Objective 
 
 
 
 
 
 
            
8 
3. 
STUDY ENDPOINTS 
 8 
 
3.1  
Primary Endpoint 
 
 
 
 
 
 
            
8 
 
3.2  
Secondary Endpoint 
 
 
 
 
 
            
 
8 
4. 
STUDY DESIGN 
 8 
 
4.1  
Study Summary 
 
 
 
 
 
 
 
 
8 
 
4.2  
Study Design 
 
 
 
 
 
 
 
 
 
8 
 
4.3  
Sample Size  
 
 
 
 
 
 
 
 
 
8 
 
4.4  
Target Population 
 
 
 
 
 
 
 
 
8 
 
4.5  
Eligibility Criteria 
 
 
 
 
 
 
 
 
9 
 
 
4.5.1 
 Inclusion Criteria 
 
 
 
 
 
 
 
9 
 
 
4.5.2  
Exclusion Criteria 
 
 
 
 
 
 
 
9 
 
4.6  
Risks/Benefits  
 
 
 
 
 
 
 
 
9 
5. 
STUDY DATA 
 10 
6.      
STUDY DRUG/STUDY PROCEDURES  
 
 
 
 
 
 
10 
 
6.1  
Study Drug 
 
 
 
 
 
 
 
 
 
10 
 
 
6.1.1  
 
Formulation 
 
 
 
 
 
 
 
10 
 
 
6.1.1.1  
Packaging and Labeling  
 
 
 
 
 
10 
 
 
6.1.1.2  
Storage and Handling 
 
 
 
 
 
 
10 
 
 
6.1.2 
 
Dosage and Administration 
 
 
 
 
 
10 
 
 
6.1.3 
 
Prior and Concomitant Medications 
 
 
 
 
10 
 
 
6.1.4 
 
Accountability for Study Drug 
 
 
 
 
 
11 
 
 
6.1.5 
 
Product Return or Disposal 
 
 
 
 
 
11 
 
6.2  
Study Procedure 
 
 
 
 
 
 
 
 
11 
 
 
6.2.1 
 
Subject Enrollment 
 
 
 
 
 
 
11 
 
 
6.2.2 
 
Assessments 
 
 
 
 
 
 
 
11 
 
 
6.2.2.1  
Screening Visit  
 
 
 
 
 
 
12 
 
 
6.2.2.2  
Day 1/Baseline Visit 
 
 
 
 
 
 
12 
 
 
6.2.2.3  
Treatment Assessments ( Weeks 4-48)  
 
 
 
12 
 
 
6.2.2.4  
Early Study Drug Discontinuation Assessment 
 
 
 
13 
 
 
6.2.2.5  
Criteria for Discontinuation of Study Treatment  
 
 
13 
 
 
6.2.3 
 
Post Study Care 
 
 
 
 
 
 
14 

 
 
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6.2.4 
 
Clinical Laboratory Assessments 
 
 
 
 
14 
 
 
6.2.4.1  
Blood Samples  
 
 
 
 
 
 
14 
 
 
6.2.4.2  
Urine Samples  
 
 
 
 
 
 
14 
 
 
6.2.5 
 
Virologic Failure 
 
 
 
 
 
 
14 
 
 
6.2.5.1  
Management of Viral Rebound  
 
 
 
 
14 
 
 
6.2.5.2  
Subjects with HIV-1 RNA ≥ 50 copies/mL at Study Drug   
 
 
 
 
 
Discontinuation or Week 48 
 
 
 
 
 
15 
7. 
ADVERS EVENTS AND TOXICITY MANAGEMENT 
 15 
7.1  
Definition of Adverse Events, Adverse Reactions, and Serious Adverse Events 
 
15 
 
7.1.1 
 
Adverse Events  
 
 
 
 
 
 
15 
 
7.1.2 
 
Serious Adverse Events  
 
 
 
 
 
16 
 
7.1.3 
 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as  
 
 
 
Adverse Events or Serious Adverse Events 
 
 
 
16 
7.2  
Assessment of Adverse Events  
 
 
 
 
 
 
16 
 
7.2.1 
 
Assessment of Causality for Study Drugs and Procedures 
 
17 
 
7.2.2 
 
Assessment of Severity  
 
 
 
 
 
17 
7.3  
Adverse Events and Serious Adverse Events 
 
 
 
 
 
17 
 
7.3.1 
 
Adverse Events  
 
 
 
 
 
 
17 
 
7.3.2 
 
Serious Adverse Events  
 
 
 
 
 
17 
7.4  
Toxicity Management 
 
 
 
 
 
 
 
 
17 
 
7.4.1  
 
Grades 1 and 2 Clinical Events or Laboratory Abnormality 
 
18 
 
7.4.2 
 
Grade 3 Clinical Events or Laboratory Abnormality 
 
 
18 
 
7.4.3 
 
Grade 4 Clinical Events or Laboratory Abnormality 
 
 
18 
 
7.4.4 
 
ALT Flare 
 
 
 
 
 
 
 
18 
 
7.4.4.1  
Management of ALT Flare 
 
 
 
 
 
18 
 
7.4.5 
 
Management of Potential Hepatobiliary Toxicity  
 
 
19 
7.5  
Hepatitis C Management 
 
 
 
 
 
 
 
19 
7.6  
Special Situation Reports 
 
 
 
 
 
 
 
19 
 
7.6.1 
 
Definitions of Special Situations  
 
 
 
 
19 
 
7.6.2 
 
Instructions for Reporting Special Situations 
 
 
 
19 
 
7.6.2.1  
Instructions for Reporting Pregnancies  
 
 
 
19 
 
7.6.2.2  
Reporting Other Special Situations 
 
 
 
 
20 
8. 
STATISTICAL CONSIDERATIONS 
 20 
 
8.1  
Analysis 
 
 
 
 
 
 
 
 
 
20 
 
 
8.1.1 
 
Primary Endpoint 
 
 
 
 
 
 
20 
 
 
8.1.2 
 
Secondary Endpoints 
 
 
 
 
 
 
20 
 
8.2  
Analysis Conventions 
 
 
 
 
 
 
 
 
20 

 
 
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8.2.1 
 
Analysis Sets 
 
 
 
 
 
 
 
20 
 
 
8.2.2 
 
Full Analysis Set 
 
 
 
 
 
 
20 
 
 
8.2.3 
 
Safety  
 
 
 
 
 
 
 
20 
 
8.3  
Data Handling Conventions 
 
 
 
 
 
 
 
21 
 
8.4  
Demographic Data and Baseline Characteristics  
 
 
 
 
21 
 
8.5  
Efficacy Analysis 
 
 
 
 
 
 
 
 
21 
 
 
8.5.1 
 
Primary Analysis 
 
 
 
 
 
 
21 
 
 
8.5.1.1  
United States FDA-defined Snapshot Algorithm  
 
 
21 
 
 
8.5.1.2  
Analysis of Primary Efficacy Endpoint 
 
 
 
 
21 
 
 
8.5.2 
 
Secondary Analysis 
 
 
 
 
 
 
21 
 
8.6  
Safety Analysis  
 
 
 
 
 
 
 
 
22 
 
 
8.6.1 
 
Extent of Exposure 
 
 
 
 
 
 
22 
 
 
8.6.2 
 
Adverse Events  
 
 
 
 
 
 
22 
 
 
8.6.3 
 
Laboratory Evaluations  
 
 
 
 
 
22 
 
 
8.6.4 
 
Other Safety Evaluations 
 
 
 
 
 
22 
 
8.7  
Patient Reported Outcomes 
 
 
 
 
 
 
 
22 
 
8.8  
Sample Snapshots 
 
 
 
 
 
 
 
 
22 
 
8.9  
Analysis Schedule 
 
 
 
 
 
 
 
 
23 
9. 
RESPONSIBILITIES 
 
 
 
 
 
 
 
 
 
23 
 
9.1  
Good Clinical Practice  
 
 
 
 
 
 
 
23 
 
9.2  
Investigator Responsibilities 
 
 
 
 
 
 
 
23 
 
 
9.2.1 
 
General Responsibilities 
 
 
 
 
 
23 
 
 
9.2.2 
 
Control of Study Drug 
 
 
 
 
 
 
23 
 
 
9.2.3 
 
Medical Decision Making 
 
 
 
 
 
23 
 
 
9.2.4 
 
IRB/IEC Review and Approval  
 
 
 
 
23 
 
 
9.2.5 
 
Informed Consent 
 
 
 
 
 
 
24 
 
 
9.2.6 
 
Confidentiality  
 
 
 
 
 
 
24 
 
 
9.2.7 
 
Study Files and Retention of Records 
 
 
 
 
24 
 
 
9.2.7.1  
Records Retention as Required  
 
 
 
 
24 
 
 
9.2.7.2  
Record Tranfer or Record Destruction 
 
 
 
 
24 
 
 
9.2.8 
 
Case Report Forms 
 
 
 
 
 
 
24 
 
 
9.2.9 
 
Study Drug Accountability and Return 
 
 
 
 
25 
 
 
9.2.10  
Protocol Compliance 
 
 
 
 
 
 
25 
 
9.3 
Sponsor Responsibilities 
 
 
 
 
 
 
 
25 
 
 
9.3.1 
 
Protocol Modifications  
 
 
 
 
 
25 
 
 
9.3.2      
Study Report and Publications  
 
 
 
 
25 
 
 
9.3.3 
 
Payment Reporting 
 
 
 
 
 
 
25 

 
 
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9.3.4 
 
Access to informations for monitoring 
 
 
 
 
25 
 
 
9.3.5 
 
Access to Information for Auditing or Inspeciton  
 
 
25 
 
 
9.3.6 
 
Study Discontinuation 
 
 
 
 
 
 
25 
10. 
PUBLICATIONS 
 
 
 
 
 
 
 
 
 
25 
11. 
REFERENCES  
 
 
 
 
 
 
 
 
 
26 
12.  
APPENDIXES  
 
 
 
 
 
 
 
 
 
28 
 
Appendix 1. 
Schedule of Study Visits 
 
 
 
 
 
 
28 
 
Appendix 2.  
Grading Scale fo Severity of Adverse Events and Laboratory Abnormalities 
29 
 
Appendix 3. 
PRO Questionnaires 
 
 
 
 
 
 
 
36 
 
 
LIST OF IN-TEXT TABLES 
 
Table 1  
Prior and Concomitant Medications 
 
 
 
 
 
11 
 
LIST OF IN-TEXT FIGURES 
 
Figure 1 
Management of Virologic Rebound 
 
 
 
 
 
15 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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ABBREVIATIONS  
ABC  
 
Abacavir  
AE  
 
Adverse event 
ATR  
 
Atripla®, EFV/FTC/TDF  
BIC  
 
Bictegravir 
BMI  
 
Body Mass Index 
CD4  
 
Helper T lymphocytes positive for surface glycoprotein CD4 
CI  
 
Confidence interval  
DLP  
 
Distal symmetrical polyneuropathy 
DM2  
 
Diabetes mellitus 2  
EFV  
 
Efavirenz 
FDC  
 
Fixed dose combination  
HAART  
Highly active antiretroviral therapy 
HBsAg  
Hepatitis B virus surface antigen serology 
HBV  
 
Hepatitis B virus 
HCV  
 
Hepatitis C virus 
HCV Ab 
Hepatitis C virus antibody  
HTN  
 
Hypertension 
IRB  
 
Institutional review board  
NNRTI   
Non-nucleoside reverse transcriptase inhibitor  
NRTI   
Nucleoside/nucleotide reverse transcriptase inhibitor  
PI  
 
Protease inhibitor  
PIN  
 
Patient identification number 
PVR  
 
Pure virologic response  
PRO  
 
Patient reported outcomes 
RAL  
 
Raltegravir  
RPV  
 
Rilpivirine 
RTV 
 
/R, Ritonavir  
TAF  
 
Tenofovir alafenamide  
TDF  
 
Tenofovir disoproxil fumarate 
TFV  
 
Tenofovir  
VL  
 
HIV viral load 
 
 

 
 
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1. 
INTRODUCTION 
 
Human Immunodeficiency Virus-1 (HIV) is a life threatening and serious infection throughout the world.  
The World Health Organization estimates between 30-43 million people are living with HIV worldwide. The 
natural progression of the disease cripples the immune system, leading to unchecked infections and 
ultimately death. 
 
 
With the advent of highly active antiretroviral therapy (HAART), we saw HIV transform from a terminal 
infection into a chronic disease that was managed with drugs. This transformation, however, required three 
drug combination regimens to prevent HIV from developing resistance to the drug. This resulted in 
numerous pills taken at strict dosing intervals frequently throughout the day. As treatments evolved, therapy 
required fewer pill numbers and decreased dosing intervals. This trend eventually gave way to 
efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) co-formulated into a single tablet, 
ATRIPLA®. This was the advent of the single tablet regimen—one pill, once a day. ATRIPLA® has many 
years of proven efficacy and improved patient adherence1 
 
 
With the continued evolution of potent HAART, virologically suppressed HIV-infected patients are often 
switched to safer and better tolerated drugs1. Both older patients with age associated comorbidities and 
younger patients, who can fairly expect to be on antivirals for many years to come, are rightly concerned 
about side effects and toxicities of long term exposure to highly potent medications. Patients depend on 
their providers to optimize long term safety and tolerability in their antiretroviral therapy. 
 
1.1 
Rationale for the Study  
 
Therapeutic dosage of the tenofovir disoproxil fumarate (TDF) component of ATRIPLA® requires plasma 
concentrations of the drug that are associated with nephrotoxicity and decreased bone mineral density3.  
Tenofovir alafenamide fumarate (TAF) has a unique metabolism that results in higher intracellular levels of 
the active phosphorylated moiety tenofovir-diphosphate2. Compared with TDF, the therapeutic dosage of 
TAF reduces tenofovir plasma concentrations by over 90%. This reduction in plasma concentration results 
in decreased renal and bone risks.  TAF has the potential to improve on the efficacy and safety profile of 
TDF. 
 
 
Efavirenz, another component of ATRIPLA® is widely associated with neuropsychiatric side-effects, 
including sleep disturbances, depression, and anxiety4. Switching from Efavirenz to an integrase inhibitor 
is associated with improvements in mood5,6.  
 
 
Bictegravir (BIC) is a novel, once daily integrase inhibitor. It has been shown to have potent antiviral activity, 
a favorable pharmacokinetic profile, good tolerability and an improved resistance profile when compared to 
previous integrase inhibitors.10,11. In a phase 2 trial investigating previously untreated people with HIV, 
bictegravir plus emtricitabine and tenofovir alafenamide (BIKTARVY®) vs dolutegravir, plus emtricitabine 
and tenofovir alafenamide both showed high efficacy up to 24 weeks and both regimens were well 
tolerated.12 
 
 
Additionally, switching HAART experienced patients to BIKTARVY® has been shown to be non-inferior to 
continuation of regimens containing Atazanavir or Darunavir, when they were given with either 
lamivudine/abacavir or FTC/TDF.13 
 
 
We plan to evaluate in a real world setting the efficacy, safety and tolerability of switching from the older, 
established single tablet regimen of ATRIPLA® (EFV/FTC/TDF) to a new single tablet regimen of 
BIKTARVY® (BIC/FTC/TAF). 
 
 
Within the limitations of a real-world study, we have attempted to replicate the protocol of Gilead Science’s 
Phase 3 study evaluating a switch to BIC/FTC/TAF from dolutegravir plus either FTC/TAF or FTC/TDF14.  
This will have the potential benefit of comparing different regimen switches as well as potentially adding 
robustness to the body of data regarding BIC/FTC/TAF. 
 

 
 
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2. 
STUDY OBJECTIVES 
2.1. 
The primary objective of the study is: 
• 
To evaluate the proportion of participants with virologic failure determined by HIV-1 RNA ≥ 50 
copies/mL at week 48 in virologically suppressed patients with HIV-1 infection   switching from 
ATRIPLA® to BIKTARVY®. 
 
2.2. 
The secondary objectives of the study are: 
• 
To determine the safety of switching from ATRIPLA® to BIKTARV®Y in virologically suppressed 
patients with HIV-1 infection as determined by the proportion of participants with virologic failure, a 
rise in serum creatinine values, a change in lipid parameters, and change in CD4 cell count from 
baseline.   
• 
To determine the efficacy of switching from ATRIPLA® to BIKTARVY® in virologically suppressed 
patients with HIV-1 infection as determined by the proportion of participants with HIV-1 RNA < 50 
copies/Ml. 
• 
To evaluate tolerability, durability of BIKTARVY® in virologically suppressed patients with the aid 
of 2 Patient Reported Outcomes (PRO) questionnaires (see appendix 3).  
 
3. 
STUDY ENDPOINTS 
3.1.  
 Primary Endpoint  
• 
The primary efficacy endpoint is the proportion of subjects that have HIV-1 RNA ≥ 50 copies/mL at week 
48, as defined by the FDA snapshot analysis. 
3.2. 
  Secondary Endpoints  
• 
The proportion of subjects that have HIV-1 RNA < 50 copies/mL at week 48, as defined by the FDA 
snapshot analysis. 
• 
The change from baseline in serum creatinine at Week 48 
• 
The change from baseline in CD4 cell count at Week 48 
• 
The change from baseline in lipid parameters at Week 48 
• 
The change in responses to the PROs from baseline at Week 4, 12, and 48 
 
4. 
STUDY DESIGN 
4.1. 
Study Summary 
Prospective 48 week single cohort study to evaluate the efficacy and safety of switching from ATRIPLA to 
BIKTARVY® in HIV-1 infected adult subjects who are virologically suppressed (HIV-1 RNA < 50 copies/mL).  
 
4.2. 
Study Design 
This protocol describes a prospective study involving the switch of HIV infected patients currently on 
ATRIPLA® that are virologically suppressed (HIV-1 RNA < 50 copies/mL) to BIKTARVY® and monitoring 
them over a 48-week period. 
4.3. 
Sample Size  
 
All patients meeting eligibility will be included in the study, the expected sample size being a total number 
of subjects: 100 HIV-infected adults. 

 
 
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4.4. 
Target Population 
HIV-1 infected adults (≥ 18 years) with HIV-1 RNA < 50 copies/mL on a stable ATRIPLA® regimen prior to 
screening. 
4.5. 
Eligibility Criteria:  
4.5.1.    Inclusion Criteria.  
Subjects must meet all, of the following criteria:  
• 
≥18 years of age 
• 
HIV positive 
• 
On a stable antiretroviral regimen consisting of ATRIPLA® for at least the 6 consecutive months 
preceding Screening Visit. 
• 
Plasma HIV-1 RNA concentrations at undetectable levels for at least 6 consecutive months prior to the 
screening visit and have HIV RNA< 50 copies/mL at the Screening Visit. 
• 
Estimated GFR ≥30mL/min according to the Cockcroft-Gault formula for creatinine clearance. 
• 
Hepatic transaminases (AST and ALT) ≤5x upper limit of normal (ULN) 
• 
Total bilirubin ≤1.5 mg/dL, or normal direct bilirubin. 
• 
Adequate hematologic function (hemoglobin ≥ 8.5g/dL; platelets ≥ 50,000/mm3; absolute neutrophil count 
≥1,000/mm3) 
• 
Female subjects of reproductive potential using a reliable and consistent method of birth control for at least 
three months prior to study dosing. Male subjects should use condoms when engaging in intercourse of 
reproductive potential. 
• 
The ability to understand and sign a written informed consent form, which must be obtained prior to initiation 
of study procedures. 
 
4.5.2.    Exclusion Criteria 
• 
A new AIDS-defining condition diagnosed within 30 days prior to screening. 
• 
Individuals with decompensated cirrhosis. (i.e. ascites, encephalopathy, etc.) 
• 
Pregnancy 
• 
A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy other than 
cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, noninvasive cutaneous squamous 
carcinoma. Individuals with cutaneous KS are eligible but must not have received any systemic therapy for 
KS within 30 days prior to baseline.  
• 
Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy 
within 30 days prior to baseline.  
• 
Life expectancy < 1 year. 
• 
Subject participation in any clinical trial without prior approval from the Investigator. 
• 
Concomitant use of disallowed agents from Table 2 
• 
Participation in any other investigation study 30 days prior to enrollment. 
 
4.6. 
Risks/ Benefits  

 
 
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There are potential risks for adverse reactions and for patient intolerance to the investigational drug. 
Benefits include the potential loss of neuropsychiatric effects of efavirenz as well as the documented 
reduced nephrotoxicity and bone mineral loss with switching from TDF to TAF. 
5. 
STUDY DATA 
 
Demographic summaries will include sex, race/ethnicity, age, prior antiviral therapies and (if available) 
pertinent prior mutations. Data relevant to endpoint evaluation includes subject HAART regimen, viral load 
(VL), CD4 T-cell count, fasting lipid panel, serum creatinine, PRO, at initial screening, weeks 4, 8, 12, 24, 
36 and 48.  
 
6. 
STUDY DRUG/STUDY PROCEDURES 
6.1 
STUDY DRUG 
6.1.1 
Formulation 
The BIKTARVY® (BIC/FTC/TAF 50/200/25 mg) tablets are capsule-shaped, film coated purplish-brown, 
debossed with “GSI” on one side of the tablet and “9883” on the other side of the tablet. Each tablet core 
contains 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide. In addition to 
the active ingredients the BIKTARVY® tablets contain croscarmellose sodium, magnesium stearate, and 
microcrystalline cellulose. The tablet cores are film-coated with iron oxide red, iron oxide black, polyethylene 
glycol, polyvinyl alcohol, talc, titanium dioxide. 
6.1.1.1 Packaging and Labeling 
 
BIKTARVY® is packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 
tablets, silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, continuous 
thread, child-resistant polypropylene screw cap with an induction-sealed and aluminum-faced liner. 
6.1.1.2 Storage and Handling 
Study drug will be stored at controlled room temperature of 25°C (77°F); excursions are permitted between 
15°C and 30°C (59°F and 86°F). Storage conditions are specified on the label. Until dispensed to the 
subjects, all bottles of study drugs should be stored in a securely locked area, accessible only to those 
authorized site personnel. 
To ensure the stability and proper identification, study drug should not be stored in a container other than 
the container in which they were supplied. Keep the bottle tightly closed to protect from moisture. 
Consideration should be given to handling, preparation, and disposal through measures that minimize drug 
contact with the body. Appropriate precautions should be followed to avoid direct eye contact or exposure 
through inhalation when handling. 
6.1.2 
Dosage and Administration 
BIKTARVY® will be provided by Gilead. Study drug is taken once daily, at approximately the same time 
every day.  Each BIKTARVY® tablet contains 50mg of bictegravir (BIC), 200mg of emtricitabine (FTC), and 
25mg of tenofovir alafenamide (TAF). 
 
 
6.1.3 
Prior and Concomitant Medications 
With the following exceptions, subjects should continue to receive treatment for other conditions, 
prophylactic vaccines as per local medical guidelines and primary provider recommendations.  
The use of medications for the treatment of HIV, other than the study drug, is prohibited. 
Medications and herbal/natural supplements listed in the following table are disallowed or should be used 
with caution while subjects are participating in the study. Subjects will refrain from consumption of grapefruit 
juice and Seville orange juice throughout participation in the study. 
 

 
 
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Table 1 Prior and Concomitant Medications 
Drug Class 
Use for a minimum of 2 hours before and 2 hours after any 
dose of study drug 
Antacids 
Tums or Rolaids 
Buffered medications 
The ulcer medication sucralfate (Carafate), supplements 
that contain calcium, iron or zinc  
Drug Class 
Agents Disallowed-- must be discontinued at least 30 days 
prior to the Day 1 visit and for the duration of the study. 
Antiarrhythmic Agent 
Dofetilide 
Anticonvulsants 
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine 
Antimycobactrerials 
Rifampin, Rifapentine, Rifabutin 
Antiretrovirals 
Any antiretroviral that is not part of the study regimen 
GI motility Agents 
Cisapride 
Herbal/Natural Supplements 
St. John’s Wort, Echinacea 
If subjects need to initiate treatment with any excluded concomitant medication, the Investigator must be 
consulted prior to initiation of the new medication. 
 
6.1.4 
Accountability for Study Drug 
Subjects will be instructed to bring all study medication in the original container at each clinic visit for drug 
accountability. The Investigator will be responsible for maintaining accurate records for all study drug bottles 
dispensed and tablets returned. The inventory and dispensing logs must be available for inspection. Study 
medication supplies, including partially used or empty bottles, must be accounted for by the study staff prior 
to destruction of return. 
The Investigator is responsible for ensuring adequate accountability of all used and unused study drug. 
This included acknowledgement of receipt of each shipment of study drug (quality and condition). All used 
and unused study drug dispensed to subjects must be returned to the site. 
Study Drug accountability records will: 
• 
Date received and quantity of IP kits 
• 
Date, subject number, subject initials, the IP kit number dispensed 
• 
Date, quantity of used and unused IP returned, along with the initials of the person recording the 
information  
 
6.1.5 
Product Return or Disposal 
Study drug return or disposal will be performed on site. Unopened drugs that were not dispensed will be 
returned to Gilead. 
6.2  
Study Procedure 
The study procedures to be conducted for each subject enrolled are as follows (also in table form in 
appendix 2).  

 
 
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6.2.1 
Subject Enrollment  
It is the responsibility of the Investigator to ensure that subjects are eligible for study prior to their 
enrollment.  
6.2.2    Assessments 
6.2.2.1 Screening Visit 
Subjects will be screened within 30 days before Day 1 to determine eligibility for participation in the study. 
The following will be performed and documented at screening: 
• 
Obtain written informed consent(s) 
• 
Obtain medical history, including history of HIV-1 disease related events and current medications 
as well as any medications within 30 days of the screening visit 
• 
If available, obtain documentation of historical genotype(s) and Hepatitis B immunity. 
• 
Obtain measurements of blood pressure, pulse, temperature, height and weight 
• 
Complete physical exam (genital/rectal exam, if clinically indicated) 
• 
Obtain blood and urine samples as described in section 6.2.9 
• 
Record all AE/SAE’s to any protocol mandated procedures occurring after signing of the consent 
form 
Subjects meeting all inclusion criteria and no exclusion criteria will return to the clinic within 30 days for 
the Day 1Visit. Subjects must continue their current HAART up until their scheduled Day 1 Visit 
6.2.2.2  Day 1/Baseline Visit 
The Investigator must have confirmed eligibility before proceeding with the Day 1 Visit. 
The subject must complete prior to being administered the study drug: 
• 
Subject will read PRO questionnaires (appendix 3) and write/mark answers directly onto 
questionnaire. 
• 
Review/record SAE/AE’s and changes in concomitant medications 
• 
Obtain measurements of blood pressure, pulse, temperature, height and weight 
• 
Complete physical exam (genital/rectal exam, if clinically indicated) 
• 
Obtain blood and urine samples as described in section 6.2.9 
• 
Dispense study drug 
• 
Observe first dose administration of study drug. 
• 
Subjects will be counseled regarding the importance of adherence and taking the study 
medication at the same time each day. 
• 
Record all AE/SAE’s to any protocol mandated procedures 
 
 
6.2.2.3  Treatment Assessments (Week 4-48) 
The following evaluations are to be completed at Weeks 4, 8, 12, 24, 36, and 48. 
Study visits are to be completed within ±2 days of the protocol specified visit date (based on the Day 1 visit) 
through Week 12, visits for Week 12, 24, 36 and 48 should be completed ±6 days of the protocol specified 
date.  If the subject is not evaluated within the visit window, the database will reflect missing/no available 
data for that visit. 
Regularly scheduled evaluations will be made on all the subjects, even if they no longer are receiving study 
drug. 
The following will be completed at each visit: 
• 
Subject will read PRO questionnaires (appendix 3) to themselves and write/mark answers directly 
onto questionnaire. 
• 
Review/record of SAE/AE’s and changes in concomitant medications 

 
 
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• 
Obtain measurements of blood pressure, pulse, temperature, height and weight 
• 
Complete or symptom directed physical exam, as clinically indicated 
• 
Subjects will be reminded of the importance of adherence and taking the study medication at the 
same time each day 
• 
Obtain blood and urine samples as described in section 6.2.4.1 
• 
Document dispensing of study drug and accountability for all study drugs. 
• 
Subjects should be reminded of the importance of adherence and taking the study medication at 
the same time each day. 
• 
Record all AE/SAE’s to any protocol mandated procedures 
• 
Subjects who meet criteria for virologic failure will be managed according to the Management of 
Virologic Rebound Section 6.2.5. 
 
A prescription will be provided for continuation of antiviral therapy at the final study appointment. The 
subject will receive an additional 7 day supply of the study drug to prevent lapse in therapy. 
 
6.2.2.4 Early Study Drug Discontinuation Assessment 
If the subject discontinues the study drug prior to the Week 48 Visit, the subject will be asked to return to 
the clinic within 5 days of stopping study drug for the Early Study Drug Discontinuation Visit. Every attempt 
should be made to keep the subject in the study and continue to perform the required follow ups and 
procedures through to the Week 48 Visit (see Section 6.2.2.3). If this is not acceptable to the subject or 
investigator, the subject may be withdrawn from the study. 
If the subject discontinues the study drug and without notifying the Investigator within 5 days, the subject 
may be withdrawn from the study, at the Investigator’s discretion. 
At the Early Study Discontinuation Visit, any evaluations showing abnormal results indicating that there is 
a possible or probable causal relationship with the study drug will be repeated weekly (or as often as 
deemed prudent by the Investigator) until the abnormality is resolved/returns to baseline (based on Day 1 
Visit) or is otherwise explained. 
The following will be completed: 
• 
Review/record of SAE/AE’s and changes in concomitant medications 
• 
Obtain measurements of blood pressure, pulse, temperature, height and weight 
• 
Complete or symptom directed physical exam, as clinically indicated 
• 
Obtain blood and urine samples as described in section 6.2.4.1 
• 
Document accountability for all study drugs. 
 
6.2.2.5 Criteria for Discontinuation of Study Treatment 
Study Medication will be discontinued in the following instances 
• 
Unacceptable toxicity, or toxicity that in the judgement of the investigator compromises the ability 
to continue study specific procedures or is considered to not be in the subject’s best interest 
• 
Subject request to discontinue for any reason 
• 
Pregnancy during the study 
• 
Development of active tuberculosis 
• 
Discontinuation of the study at the request the IRB 
Study medication may be discontinued in the following instances: 
• 
Intercurrent illness that would in the judgement of the investigator affects assessments of clinical 
status to a significant degree. Following resolution of the intercurrent illness, the subject may 
resume study dosing at the discretion of the investigator. 
• 
Lack of efficacy 

 
 
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• 
Subject noncompliance 
6.2.3  
Post Study Care 
After a subject has completed/terminated their participation in the study, long-term care for the subject will 
remain the responsibility of their primary treating provider. 
6.2.4  
Clinical Laboratory Assessments 
Blood and urine samples will be collected throughout the study as outlined below, within Section 6.2, and 
also in Appendix 1 Study Procedure Table. 
6.2.4.1  Blood Samples 
Blood sample collection for the following: 
• 
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total protein, 
albumin, CPK, bicarbonate, blood urea nitrogen (BUN), chloride, creatinine, glucose, potassium, sodium 
• 
Fasting glucose and lipid panel (total cholesterol, HDL, LDL, and triglycerides) at Day 1, Weeks 12, 24, 
48. 
▪ 
If the patient is not fasting (no food or drinks except water for at least 8 hours prior to blood 
collection. 
▪ 
If the subject has not fasted prior to the visit, the visit may proceed but the subject must 
return within 72 hours in a fasted state to draw labs 
• 
Hematology profile: complete blood count (CBC) with differential and platelet counts 
• 
CD4+ cell count and percentage 
• 
Plasma Quantitative HIV-1 RNA 
• 
If no documented Hepatitis B immunity: Hepatitis B surface antigen, surface antibody and core antibody 
at Screening, Week 48. 
▪ 
The following tests will be conducted if the following criteria are met: 
• 
If positive surface antigen: plasma qualitative and quantitative 
HBV DNA, Hepatitis B virus e-antigen and antibody 
• 
If positive core antibody with negative surface antigen and 
surface antibody: plasma qualitative and quantitative HBV DNA, 
Hepatitis B virus e-antigen and antibody 
• 
For subjects who are coinfected with Hepatitis B, plasma quantitative Hepatitis B DNA 
• 
Hepatitis C Virus (HCV) antibody (subjects who are HCV antibody positive will have HCV RNA test 
performed) at Screening and Week 48.  
• 
Plasma and serum storage sample for safety or virology testing (all visits except Screening Visit). 
6.2.4.2  Urine samples 
Urine samples will be collected for the following: 
• 
Urinalysis 
• 
Urine pregnancy testing (If positive at screening, subject will not be enrolled. If positive at subsequent 
visit, study medication will be discontinued) 
6.2.5  
Virologic Failure 
Virologic failure is defined as virologic rebound or having HIV-1 RNA ≥ 50 copies/mL at study 
discontinuation or week 48   
6.2.5.1  Management of Viral Rebound 
Subjects who meet either of the criteria listed below will be considered to have virologic rebound: 
• 
At any post Day 1 Visit, an HIV-1 RNA ≥ 50 copies/mL which is subsequently confirmed at the following 
visit (scheduled or unscheduled) 
• 
Any subject with HIV-1 RNA ≥ 50 copies/mL at study drug discontinuation  
Following the unconfirmed virologic rebound, subjects will be asked to return to the clinic for a blood draw, 
4 weeks after the date of the original test that had an RNA ≥50 copies/mL.  If virologic rebound is confirmed 

 
 
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and the HIV-1 RNA is ≥ 200 copies/mL, the blood sample from the confirmation visit will be the primary 
sample used for HIV-1 genotypic and phenotypic testing. After a subject’s first post-baseline resistance 
test, additional testing will be conducted on a case-by-case basis. Any subject may be discontinued at 
Investigator’s discretion or per local treatment guidelines. 
If no resistance is detected from the genotype or phenotype, the subject may remain on study drug and 
HIV-1 RNA test should be again repeated 2-3 weeks later. If HIV-1 RNA ≥ 50 copies/mL remains 
Investigators should carefully evaluate the risks and benefits of remaining on study drug and document this 
assessment in the on-site medical record. 
Subjects who are nonadherent on an ongoing basis will be considered for discontinuation per the 
Investigator’s discretion or local treatment guidelines. Sub-investigators who opt to discontinue study drugs 
for an individual subject must discuss with the Investigator prior to study drug discontinuation. 
For subjects who are off study drug but remain in study, it will be the Investigator’s discretion to manage 
virologic rebound. 
 
Figure 1 
 
 
6.2.5.2 Subjects with HIV-1 RNA ≥ 50 copies/mL at Study Drug Discontinuation or Week 48 
Subjects with HIV-1 RNA ≥ 50 copies/mL at Study Drug Discontinuation, last Visit, or Week 48 will be 
considered virologic failures. Subjects with HIV-1 RNA ≥ 50 copies/mL at Week 48 will be asked to return 
for an unscheduled visit within 4 weeks for a retest as detailed in Section 6.2.5. Subjects with HIV-1 RNA 
≥ 200 copies/mL will also have resistance testing as detailed in Section 6.2.5. 
 
7 
ADVERSE EVENTS AND TOXICITY MANAGEMENT 
7.1 Definition of Adverse Events, Adverse Reactions, and Serious Adverse Events 
7.1.1 Adverse Events 
Rebound in HIV-ͳ RNA to ≥ 5Ͳ copies/mL
Confirm results with 5 days
confirmed ≥ 5Ͳ copies/mL
remain on study drug, check HIV-1 
genotype
If NO new Reverse Transcriptase or 
Integrase mutations detected, 
contiue on study drug. Repeat viral 
load in 4 weeks.
If new Reverse Transcriptase or 
Integrase mutations detected, 
discontinue study drug and construct 
new ART regimen
repeat result <50 copies/mL
remain on current regimen, 
resume typical study protocol

 
 
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An adverse event (AE) is any untoward medical occurrence in a clinical study subject which does not 
necessarily have a causal relationship with the medicinal product. An AE can be any unfavorable and/or 
unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether 
or not considered related to the medicinal product. AEs may also include pre or post treatment 
complications that occur, as a result of protocol specified procedures, lack of efficacy, over dose, drug 
abuse/misuse reports, or occupational exposure. Preexisting events that increase in severity or change in 
nature during or as a consequence of participation in the clinical study will also be considered AEs. 
 
An AE does not include the following: 
• 
Medical or surgical procedures such a surgery, endoscopy, tooth extraction, and transfusion. The condition 
that led to the procedure may be an adverse event and must be reported. 
• 
Preexisting diseases, conditions, or laboratory abnormalities present or detected before the screening visit 
that do not worsen. 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for elective 
surgery, social or convenience admissions) 
• 
Overdose without clinical sequalae (see Section 7.6.1) 
• 
Any Medical condition or clinically significant laboratory abnormality with an onset date before the consent 
form is signed and not related to a protocol associated procedure is not an AE. It is considered to be 
preexisting and should be documented in the medical record. 
7.1.2 Serious Adverse Events 
 
A serious adverse event (SEA) is defined as an event that, at any dose, results in the following: 
• 
Death 
• 
Life-threatening event in which the subject is at risk of death at the time of event. It does not refer to an 
event that hypothetically might have caused death if it were more severe. 
• 
Inpatient hospitalization or prolongation of an existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect in offspring of study subject born after subject received study drug 
• 
A medically important event or reaction that may not immediately result in death, hospitalization, or life-
threatening event but may jeopardize the subject or may require intervention to prevent an SAE from 
occurring. Medical and scientific judgement must be exercised to determine whether such an event is 
reportable under expedited reporting rules. Examples of this type of occurrence would include intensive 
treatment for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
development of drug dependency/abuse. For the avoidance of doubt, infections resulting from 
contaminated medical product will be considered a medically important event and subject to expedited 
reporting requirements. 
7.1.3 Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or Serious     
Adverse Events 
 
Laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that require medical or 
surgical intervention or lead to study drug interruption, modification or discontinuation must be recorded 
as an AE or SAE. In addition, laboratory or other abnormal assessments (e.g., EKG, x-rays, and vital 
signs) that are associated with signs and/or symptoms must be recorded as an AE or SAE if they meet 
the definition detailed in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, 
record the syndrome or diagnosis, not the laboratory result (i.e. “anemia,” not “decreased hemoglobin”). 
 
For specific information on handling of clinical laboratory abnormalities in this study, please refer to Section 
7.5. 
7.2  
Assessment of Adverse Events 

 
 
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The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for causality and 
severity as well as for final review and confirmation of accuracy of event information and assessments. 
7.2.1  
Assessment of Causality for Study Drugs and Procedures 
 
The investigator or qualified sub-investigator is responsible for assessing the relationship to the study drug 
using clinical judgement and the following considerations: 
• 
No: Evidence exists that the adverse event has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (e.g., preexisting condition, underlying disease, 
intercurrent illness, or concomitant medication). 
• 
Yes: There is reasonable possibility that the event may have been caused by the study drug.  
 
It should be emphasized that ineffective treatment should not be considered as causally related in the 
context of adverse reporting. 
 
The relationship to study procedures (e.g., invasive procedures such as venipuncture) should be assessed 
using the following considerations: 
• 
No: Evidence exists that the adverse event has an etiology other than the study procedure. 
• 
Yes: The adverse event occurred, as a result of protocol procedures. 
7.2.2  
Assessment of severity 
 
AE severity should be recorded and graded according to the Grading Scale for Severity of Adverse Events 
and laboratory Abnormalities (Appendix 2). For AE associated with laboratory abnormalities, the event 
should be graded on the basis of the clinical severity in the context of the underlying conditions; which might 
not be in agreement with the grading of the laboratory abnormality. 
 
The distinction between the seriousness and the severity of an AE should be noted. Severe is a measure 
of intensity; a severe reaction is not necessarily a serious reaction. For example, a subject might have a 
headache that is described as severe but would not be considered a SAE unless it met one of the criteria 
for serious events. 
7.3  
Adverse Events and Serious Adverse Events 
7.3.1  
Adverse Events 
 
Following initiation of study medication, all AEs regardless of cause or relationship until end of study must 
be reported to the study database. 
 
All AEs should be followed up until resolution/return to baseline or until the adverse event is stable, if 
possible.  
7.3.2  
Serious Adverse Events 
 
All SAEs regardless of cause or relationship that occurs after the subject signs the informed consent and 
until the duration of the study, including the protocol defined follow-up period, must be reported. This also 
includes any SAEs resulting from protocol associated procedures performed after informed consent is 
signed. 
 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; however, 
if the investigator learns of any SAEs that occur after study participation has concluded and the event is 
deemed relevant to the use of the study drug, they should promptly document and report the event. 
7.4        Toxicity Management 
 
All clinical events and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 2 and as outlined below. 
• 
Clinical events and clinically significant laboratory abnormalities will be graded according to the 
Grading Scale for Severity of Adverse Events and laboratory Abnormalities (Appendix 2). 

 
 
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• 
Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat testing 
within 7 calendar days of receiving results and before study drug discontinuation, unless such a delay 
is not consistent with good medical practice. 
 
Any questions regarding toxicity management should be directed to the Investigator. 
7.4.1  
Grades 1 and 2 Clinical Event or Laboratory Abnormality  
 
Continue study drug at the discretion of the Investigator 
7.4.2  
Grade 3 Clinical Event or Laboratory Abnormality 
 
For Grade 3 clinical event or clinically significant laboratory abnormality, study drug may be continued if the 
event is considered to be unrelated to study drug. 
 
For a Grade 3 clinical event or clinically significant laboratory abnormality confirmed by repeat testing that 
is considered to be related to the study drug, study drug will be withheld until the toxicity returns to ≤ grade 
2. When restarting study drug following resolution of the adverse event, the study drug should be restarted 
at full dose. 
 
If following re-challenge with study drug a laboratory abnormality returns to ≥ Grade 3 and is considered to 
be related to the study drug, then the study drug will be permanently discontinued and the subject managed 
according to local practice. Recurrence of laboratory abnormalities considered unrelated to the study drug 
may not require permanent discontinuation. 
7.4.3  
Grade 4 Clinical Events or Laboratory Abnormality 
 
For a Grade 4 clinical event or clinically significant laboratory abnormality confirmed by repeat testing that 
is considered to be related to the study drug, the study drug will 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 significant Grade 4 laboratory abnormality that is not confirmed by repeat testing should be 
managed according to the algorithm for the new toxicity grade. 
 
Study drug may be continued without dose interruption for a clinically non-significant Grade 4 laboratory 
abnormality (e.g., elevated CK after significant exercise or triglyceride elevation on a non-fasting specimen) 
or a clinical event considered unrelated to the study drug, but must be discussed with the Investigator. 
7.4.4  
ALT Flare 
 
Defined as: serum ALT > 10 x upper limit of normal (ULN) and > 2 times Day 1 value, confirmed with repeat 
testing within 3 days of original results receipt, with or without associated symptoms 
7.4.4.1 Management of ALT Flare 
 
When initial results are received, schedule subject to return to the clinic as soon as possible (ideally within 
3 days of initial blood draw). During the visit, in addition to redrawing blood for repeat CMP testing, clinical 
assessment of the subject will be performed. The assessment should include a physical examination and 
evaluation of the subject’s mental status. 
 
If ALT elevation is confirmed, the following labs should be performed: plasma HBV DNA, HBV serology 
(HBsAg and HBsAb), HAC IgM, HCV serology, quantitative HDV RNA.  
 
Based on the results of the confirmatory tests, the following treatment modifications are recommended: 
Elevated liver enzymes, normal or stable total bilirubin relative to Day 1 
 
If ALT levels are elevated (as specified in Section 7.4.4) with normal or stable total bilirubin, the 
subject may remain on the study drug and should be monitored weekly until ALT levels return to 
normal or Day 1 level. During monitoring, if the ALT values remain persistently elevated, the 
Investigator considers whether the study drug should be discontinued. 
Elevated liver enzymes, elevated total bilirubin 

 
 
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If ALT levels are elevated (as specified in Section 7.4.4) and total bilirubin is confirmed to be ≥ 2 x 
Day 1 value and is > ULN, the investigator should consider discontinuing the study drug. The subject 
should be monitored weekly until ALT and total bilirubin levels return to normal or Day 1 level. 
During monitoring, if the ALT values and the liver function tests remain persistently elevated, the Investigator 
should consider discontinuing the study drug. 
 
7.4.5  
Management of Potential Hepatobiliary Toxicity 
 
Any subject exhibiting signs/symptoms or laboratory abnormalities suggestive of possible hepatobiliary 
toxicity should undergo thorough examination and clinical workup as deemed appropriate by the 
Investigator. Consideration should be given to appropriate imaging studies (e.g., ultrasound of the liver and 
biliary tree) and potential consultation with a gastroenterologist with specialty training in hepatobiliary 
diseases. 
7.5  
Hepatitis C Management 
 
If a subject, tests positive for HCV RNA at screening or develops signs or symptoms of active Hepatitis C 
Virus, local medical practice is followed at the discretion of the Investigator. Study drug may be continued 
without interruption. Should the Investigator decide to initiate Hepatitis C treatment the investigator confirms 
that no drug-drug interactions are expected. Subjects should return to the clinic for scheduled or 
unscheduled follow up visits according to local medical practice for laboratory evaluations.  
7.6  
Special Situations Reports 
7.6.1  
Definitions of Special Situations 
 
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports of adverse 
events associated with product complaints, reports of adverse reactions in infants following exposure from 
breastfeeding, occupational exposure with an adverse event, and pregnancy reports regardless of an 
associated AE. 
 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a medicinal 
product while in the control of the health care provider, subject or consumer. 
 
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a subject. 
 
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in accordance 
with the protocol instructions or the local prescribing information. 
 
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal product 
given per administration or cumulatively which is above the maximum recommended dose per protocol or 
in the product labelling (as it applies to the daily dose of the subject in question). In cases of a discrepancy 
in drug accountability, overdose will be established only when it is clear that the subject has taken the 
excess dose(s). Overdose cannot be established when the subject cannot account for the discrepancy 
except in cases in which the investigator has reason to suspect that the subject has taken the additional 
dose(s). 
 
Product complaint is defined as complaints arising from potential deviations in the manufacture, packaging, 
or distribution of the medicinal product. 
 
Occupational exposure is defined as exposure to a medicinal product as a result of one’s professional or 
non-professional occupation. 
7.6.2  
Instructions for Reporting Special Situations 
7.6.2.1  Instructions for Reporting Pregnancies 
 
The Investigator will report pregnancies in subjects that are identified after initiation of the study drug and 
throughout the study to Gilead. 
 
The subject should receive appropriate monitoring and care until the conclusion of the pregnancy.  

 
 
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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a pregnancy 
without medical reasons. 
 
Any premature termination of pregnancy (e.g., spontaneous abortion, induced therapeutic abortion due to 
complications or other medical reasons) must be reported within 24 hours as an SAE. The underlying 
medical reason for this procedure should be recorded as the AE term.  
 
A spontaneous abortion is always considered to be an SAE and will be reported as described in section 
7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study will be reported to 
Gilead. 
 
The outcome should be reported to Gilead via email or fax to: 
 
Email: Safety_FC@gilead.com 
 
Fax: 650-522-5477 
7.6.2.2 Reporting Other Special Situations 
 
Any inappropriate use of concomitant medications prohibited by this protocol should not be reported as 
“misuse,” but may be more appropriately documented as a protocol deviation. 
 
Refer to Section 7.3 for full instructions on the mechanism of special situation reporting.  
 
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs at the 
same time using the AE EMR and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available.  
 
8. 
STATISTICAL CONSIDERATIONS 
8.1  
Analysis   
The efficacy analysis endpoints are as follows:  
8.1.1 
Primary Endpoint 
The primary efficacy endpoint is the proportion of subjects that have HIV-1 RNA ≥ 50 copies/mL at week 
48, as defined by the FDA snapshot analysis. 
8.1.2 
Secondary Endpoints  
1. 
The proportion of subjects that have HIV-1 RNA <50 copies/mL at Week 48, as defined by the FDA 
snapshot analysis. 
2. 
The change in serum creatinine from Day 1 to Week 48 
3. 
The change in CD4 cell count at Day 1 to Week 48 
4. 
The change in lipid parameters at Day 1 to Week 48 
5. 
The change in responses to the PRO at Day 1, Week 4, 12, and 48 
 
8.2 
Analysis Conventions 
8.2.1 
Analysis Sets 
8.2.2 
Full Analysis Set 
 
The primary analysis set for efficacy analyses is defined as FAS, which will include all subjects who have 
received at least 1 dose of study drug. Subjects who do not receive at least 1 dose of study drug will be 
excluded from all analysis. 
8.2.3 
Safety 

 
 
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The primary analysis set for safety analysis is defined as safety analysis set, which will include all subjects 
who have received at least 1 dose of study drug. All the data collected up to 30 days after subjects 
permanently discontinue their study drug will be included in the safety summaries, unless specified 
otherwise. 
8.3 
Data Handling Conventions 
 
For analysis purposes, laboratory data that are continuous in nature but are ≤ the lower limit or ≥ the upper 
limit of quantitation will be inputted to the value of the lower limit minus 1 or upper limit plus 1 significant 
digit, respectively (e.g., If HIV-1 RNA results of ‘No HIV-1 RNA detected’ and ‘≤ 50 copies/mL HIV-1 RNA 
detected’ will be inputted as 49 copies/mL). 
 
Missing data can have an impact upon the interpretation of the trial data. In general, values for missing data 
from the specified visit will not be inputted. However, a missing pre-treatment laboratory result would be 
treated as normal (i.e. No toxicity grade) for the laboratory abnormality summary. 
 
All available data for subjects that do not complete the study will be included in data listings. 
8.4 
Demographic Data and Baseline Characteristics  
Demographic and baseline characteristics will be summarized using standard descriptive methods 
including sample size, mean, SD, median, minimum, and Maximum for continuous variables and frequency 
and percentages for categorical variables. 
Demographic data will include sex, race, ethnicity, and age. 
Baseline characteristics will include body weight, height, creatinine, lipid parameters and CD4 at baseline.  
8.5 
Efficacy Analysis 
8.5.1 
Primary Analysis 
 
The primary analysis will consist of a descriptive analysis of switching from EFV/TDF/FTC to BIC/FTC/TAF 
with respect to the proportion of subjects with HIV-1 RNA ≥ 50 copies/mL at Week 48 as defined by the US 
FDA-defined snapshot algorithm. The primary analysis of the efficacy endpoint will be based on the FAS. 
8.5.1.1 US FDA-defined Snapshot Algorithm 
 
All HIV-1 RNA data collected on-treatment (i.e. including data collected up to 1 day after the last dose date 
of the study drug) will be used in the snapshot algorithm. Virologic outcome will be defined as the following 
categories: 
• 
HIV-1 RNA < 50 copies/mL:  subjects who meet this criteria by result of the last available on-
treatment laboratory result in the Week 48 analysis window 
• 
HIV-1 RNA ≥ 50 copies/mL:  subjects who meet this criteria by result of the last available on-
treatment laboratory result in the Week 48 analysis window or do not have laboratory results in the 
Week 48 window and who discontinue study drug either: 
▪ 
due to lack of efficacy or 
▪ 
for reason other than lack of efficacy and have the last available on-treatment 
HIV-1 RNA ≥ 50 copies/mL 
• 
No virologic Data in the Week 48 Analysis Window: subjects who do not have on-treatment HIV-
1 RNA data in the Week 48 window because 
▪ 
Discontinuation of the study drug for reason other than lack of efficacy and have 
the last available on-treatment HIV-1 RNA < 50 copies/mL or 
▪ 
Missing data during the Week 48 window but remain on study drug 
8.5.1.2 Analysis of Primary Efficacy Endpoint 
 
The evaluation will be based on the proportion of subjects with HIV-1 RNA ≥ 50 copies/mL at Week 48.  
8.5.2 
Secondary Analyses 

 
 
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The proportion of subjects with HIV-1 RNA <50 copies/mL at Week 48 as defined by the US FDA-defined 
snapshot algorithm will also be summarized.  
 
The Change from baseline in CD4+ cell count at Week 48 will be summarized by treatment using descriptive 
statistics.  
 
8.6 
Safety Analysis 
 
All safety analyses will be performed using the full analysis set.  
 
All safety a data collected on or after the date of the study drug was first administered up to the date of the 
last dose of study drug plus 30 days, unless specified otherwise, will be summarized for subjects in the 
safety analysis set. 
 
Data for the pretreatment period and the period past the date of last dose of study drug plus 30 days will 
be included in data listings for all enrolled subjects. 
8.6.1 
Extent of Exposure 
 
Duration of exposure to study drug will be expressed as the number of weeks between the first and last 
dose of the study drug, inclusive, regardless of temporary interruptions in study drug administration and 
summarized by treatment. 
8.6.2 
Adverse Events 
 
Clinical and laboratory adverse effects will be coded using the definitions detailed in Appendix 2 and 
recorded in the study database. 
 
Summaries (number and percentages of subjects) of treatment-emergent adverse events (by SOC, HLT [if 
applicable], and PT) will be provided by treatment. Additional summaries will include summaries for adverse 
events by grade, Investigator’s assessment of relationship to study drug and effect on study drug dosing.  
 
On an ongoing basis adverse events will be reviewed for event that might meet the definition of Stage 3 
Opportunistic Illnesses in HIV that are indicative of an AIDS-Defining Diagnosis. The Principal Investigator  
will review the possible Stage 3 events and approve the events that meet the definition. Those events that 
do meet the Stage 3 Opportunistic Illnesses definition of an AIDS-Defining Diagnosis will be listed in 
Appendix 2. 
8.6.3 
Laboratory Evaluations 
 
Selected laboratory data (using conventional units) will be summarized using only observed data. Absolute 
values and changes from baseline at all scheduled visits will be summarized. 
 
Graded laboratory abnormalities will be defined using the Grading of Laboratory Abnormalities in Appendix 
2. 
 
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 1 toxicity 
grade from baseline at any time post baseline up to and including the date of last dose of study drug plus 
30 days will be summarized. If baseline data are missing, then any graded abnormality (i.e., at least a 
Grade1) will be considered treatment emergent. The maximum post baseline toxicity grade will be 
summarized by laboratory parameter. 
 
Laboratory abnormalities that occur before the first dose of study drug or after the last dose of study drug 
plus 30 days will be included in a data listing.   
8.6.4 
Other Safety Evaluations 
 
Vital signs will be summarized as appropriate 
8.7 
Patient Reported Outcomes 
 
The PRO measures based on questionnaires (HIV Symptom Index and Pittsburg Sleep Quality Index, see 
Appendix 2) may be summarized by visit using descriptive statistics.   

 
 
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8.8 
Sample Size 
 
A total of approximately 100 HIV-1 infected subjects  
8.9 
Analysis Schedule 
 
The Week 48 analysis will be conducted after all subjects either complete their Week 48 visit or prematurely 
discontinue from the study drug, respectively. Final analysis will be performed after all subjects complete 
the study or prematurely discontinue from the study 
 
9. 
RESPONSIBILITIES 
9.1 
Good Clinical Practice 
The rights and welfare of the individual clinical research subject must always be the paramount 
consideration in conducting clinical research. Accordingly, clinical research must be conducted in a 
manner that protects the rights, welfare and confidentiality of the human subject and also assures data 
credibility by protecting the integrity of accurate data that has been demonstrably collected according to 
the approved protocol. 
9.2 
Investigator Responsibilities 
9.2.1 
General Responsibilities 
 
The Investigator is responsible for:  
 
• 
Ensuring that the study is conducted according to the signed investigator statement/agreement, 
the investigational plan (study protocol), applicable regulations 
• 
Ensuring that all persons assisting with the trial are adequately informed about the protocol, the 
study drug, their trial-related duties and functions 
• 
Protection of the rights, safety, and welfare of subjects under the investigator’s care 
• 
Control of the study drug included in the investigation. 
• 
Assuring that each subject’s informed consent is obtained appropriately 
• 
Proper delegation of authority for the conduct of various aspects of the study so that the 
investigator retains control and knowledge of the study 
 
9.2.2 
Control of Study Drug 
 
The investigator shall control the study drug. The Investigator is responsible to ensure that: 
• 
The study drug is administered only to subjects under the investigator’s personal supervision or 
under the supervision of a qualified sub-investigator responsible to the investigator. 
• 
The study drug is not to be supplied/provided to any person not authorized to receive it. 
• 
Adequate records of the disposition of the study drug are maintained, including dates, quantity, 
receipt, distribution to subjects, and disposition.  
 
 
9.2.3 
Medical Decision Making 
 
An MD/DO must be designated as responsible for all trial-related medical decisions. Medical decisions 
must be made by a qualified person permitted by state licensure laws to make or enact such decisions. 
The investigator should: 
• 
Ensure that adequate medical care is provided to a subject for any adverse events related to the 
trial, during and as follow-up to a subject's participation. 
• 
Inform a subject when medical care is needed for intercurrent illness(es) of which the 
investigator becomes aware. 
• 
Inform the subject's primary physician about the subject's participation in the trial if the subject 
agrees to the primary physician being informed and has signed a HIPAA Authorization form 
permitting such disclosure. 
9.2.4 
IRB/IEC Review and Approval 

 
 
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The investigator shall assure that initial and continuing review of the proposed clinical study is performed 
according to the policies and procedures of the Central Institutional Review Board (IRB), as well as with 
any other IRB that has jurisdiction. 
Continuous approval from the IRB must be maintained. 
All unanticipated problems involving risk to human subjects or others are promptly reported to the IRB. All 
serious adverse events are reported to the IRB within twenty-four hours of time investigator is aware of 
the event. 
Any changes in the research activity are promptly reported to the IRB. 
No changes are made in the research without IRB approval, except where necessary to eliminate 
apparent immediate hazards to human subjects. 
 
9.2.5 
Informed Consent 
 
The Investigator is responsible for obtaining written informed consent from each individual participating in 
this study after adequate explanation of the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study related procedures. The investigator must use the most current IRB/IEC-
approved consent form for documenting written informed consent. Each informed consent (or assent as 
applicable) will be appropriately signed and dated by the subject’s legally authorized representative and the 
person conducting the consent discussion, and also by an impartial witness if required by IRB/IEC or local 
requirements. The consent form will inform subjects about sample retention. 
9.2.6 
Confidentiality 
The investigator will assure that subjects’ anonymity will be strictly maintained and that their identities are 
protected from unauthorized parties. All information and data will be collected by the investigator. All 
collected data concerning participants or their participation in this study will be considered confidential and 
maintained in a HIPAA-compliant electronic medical recording system. Subject data pertinent to the study 
will be de-identified and access limited only to personnel directly involved in this research study. All data 
used in the analysis and reporting of this evaluation will be used in a manner without identifiable reference 
to the participant. Study data will not be transmitted nor disclosed to a third-party. Paper records will be 
kept in secure files and electronic records will be password protected. 
9.2.7 
Study Files and Retention of Records 
  
The investigator shall keep and maintain adequate and accurate records, including: 
• 
Case histories on each individual study subject that record all observations and other data 
pertinent to the investigation 
• 
Screening, enrollment, and informed consent documentation; demonstrating that informed 
consent was obtained prior to participation in the study 
• 
Study reports, including reports of progress, safety, financial disclosure and final completion 
 
9.2.7.1 Records Retention as Required 
 
Midland Research Group, Inc. will use on-site facility and if storage becomes unavailable due to capacity 
of documents, then Midland Research Group, Inc., will use an offsite facility once documents are ready to 
be retained for retention, if applicable. 
FDA regulation requires an investigator to retain records a minimum of two years after the close of the 
study or after the records are no longer required to support a drug or marketing application, whichever is 
longer.  Contract commitments must be met. 
 
9.2.7.2 Record Transfer or Record Destruction  
All record transfers or record destruction will be verified and documented. 
 

 
 
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9.2.8 
Case Report Forms 
 
For each subject consented, a study file will be completed by an authorized study staff member who has 
completed training for this function. The study file will only capture the data required per the protocol 
schedule of events and procedures. The Inclusion/Exclusion Criteria and Enrollment should be completed 
only after all data related to eligibility have been received. Subsequent to data entry, a second staff member 
will perform source data verification.  
9.2.9 
Study Drug Accountability and Return 
 
Unused study drug supplies will be returned to Gilead.  Investigator will assist with disposal procedures and 
provide appropriate instruction for destruction of used study drug supplies.  
 
 
9.2.10 Protocol Compliance 
 
The Investigator is responsible for ensuring the study is conducted in accordance with the procedures and 
evaluations described in this protocol. 
9.3 
Sponsor Responsibilities 
9.3.1 
Protocol Modifications 
 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be made 
only by the Investigator, who must submit all protocol modifications to the IRB in accordance with local 
requirements and receive documented IRB approval before modifications can be implemented. 
9.3.2 
Study Report and Publications 
The Investigator is responsible for submitting any reports within time periods and according to procedures 
called for by: 
• 
Midland Research Group, Inc. or applicable division or departmental policy or procedures, including the 
Institutional Review Board (IRB) 
• 
Contractual agreements with collaborators, etc. 
9.3.3 
Payment Reporting 
 
Investigators and their study staff may be asked to provide services performed under this protocol. If 
required under applicable statutory and regulatory requirements, Midland Research Group Inc. will capture 
and disclose to Federal and State agencies any expenses paid or reimbursed for such services, including 
any clinical trial payments, meal, travel expenses or reimbursements, consulting fees, and any other 
transfer of value. 
9.3.4 
Access to Information for Monitoring 
 
As per Gilead contract 
9.3.5 
Access to Information for Auditing or Inspection 
 
9.3.6 
Study Discontinuation 
 
The investigator reserves the right to terminate the study at any time. Should this be necessary, they will 
arrange discontinuation procedures and notify the appropriate regulatory authorities and the IRB. In 
terminating the study, the Investigator will assure that adequate consideration is given to the protection of 
the subjects’ interests. 
10. 
PUBLICATIONS  
Midland Research Group, Inc. shall adhere to the Recommendations for the Conduct, Reporting, Editing 
and Publication of Scholarly Work in Medical Journals established by the International Committee of 
Medical Journal Editors.   
 
 

 
 
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11. 
REFERENCES 
1. 
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral 
agents in HIV-1 infected adults and adolescents. Department of Health and Human Services. July 14, 
2016; 1-288. www.aidsinfo.nih.gov/guidelines. 
 
2. 
Lee WA et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus 
reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic 
tissue. Antimicrobial Agents Chemotherapy 2005; 49(5):1898-906. 
 
3. 
VIREAD® (tenofovir disoproxil fumarate) Tablets and Powder. US Prescribing Information. Gilead 
Sciences, Inc. Foster City, CA. Revised 04/2017. 
 
4. 
Clifford DB et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected 
individuals. Ann Intern Med 143 (2005):714-21. 
 
5. 
Nguyen A et al. A randomized cross-over study to compare raltegravir and efavirenz (SWITCH-ER) study. 
AIDS 25 online edition: doi: 10.1097/QAD: 0b013e328248dab0, 2011. 
 
6. 
Shamblaw D Et al. Switching from ATRIPLA® to Tenofovir Alafenamide (TAF) based Single tablet 
regimen: Week 48. Data in virologic suppressed adults. Presented at Interscience Conference on 
Antimicrobial Agents and Chemotherapy (ICAAC-ASM) 2015. 
 
7. 
GENVOYA® (Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) Tablets. US Prescribing 
Information. Gilead Sciences, Inc. Foster City, CA. Revised 04/2017. 
 
8. 
Gallant JE et al. Efficacy and Safety of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil fumarate 
(TDF), given as fixed dosed combinations containing emtricitabine as backbones for treatment of  HIV-1 
infection in virologically suppressed adults: A randomized, double blind, active controlled phase 3 trial.  
Lancet HIV, April 2016; 3(4):e158-165. 
 
9. 
Mills A, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral 
regimens for virologically suppressed adults with HIV-1 infection: a randomized, active –controlled, 
multicenter, open-label, phase 3, and non-inferiority study. Lancet Infect Dis.2016 Jan;16(1):43-52.   
doi:10.1016/S1473-3099(15)00348-5. Epub 2015 Nov2. 
 
10. 
Gallant JE et al. Antiviral activity, safety, and pharmacokinetics of Bictegravir as 10-day monotherapy in 
HIV-1 infected adults. J Acquir Immune Defic Syndr (in press). Presented at ASM Microbe, June 16-20, 
2016 Boston MA. 
 
11. 
Tsiang M et al. Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer 
Inhibitor with an Improved Resistance Profile. Antimicrob Agents Chemother. 2016 Nov 21; 60(12):7086-
7097. Print 2016 Dec. 
 
12. 
Sax PE et al.Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial 
treatment of HIV-1 infection: a randomized, double-blind, phase 2 trial. The Lancet HIV. 2017 Feb. DOI: 
http//:dx.doi.org/10.1016/S2352-3018(17)30016-4. 
 

 
 
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13. 
Daar E, et al. A Phase 3 Randomized Controlled Trial of Switching to Fixed –dose 
Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) from Boosted Protease Inhibitor –based 
Regimens in Virologically Suppressed Adults: Week 48 Results.ID Week 2017. San Diego, CA. Oral LB-4 
 
14. 
Gilead Sciences. Switching to a Fixed Dose Combination of Bictegravir/Emtricitabine/Tenofovir 
Alafenamide (B/F/TAF) in HIV-1 Infected Adults Who Are Virologically Suppressed. Protocol Version 
Original Feb 6, 2017. Amendment 1 Mar 20, 2017. ClinicalTrials.gov identifier: NCT03110380. 
15. 
Justice, A.C et al. Development and validation of a self-completed HIV symptom index. Journal of Clinical 
Epidemiology , Volume 54 , Issue 12 , S77 - S90  
16. 
Buysse,D.J., Reynolds,C.F., Monk,T.H., Berman,S.R., & Kupfer,D.J. (1989). The Pittsburgh Sleep 
Quality Index (PSQI): A new instrument for psychiatric research and practice. Psychiatry 
Research, 28(2), 193-213 
 

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APPENDIX 1.  SCHEDULE OF STUDY VISITS 
 
SCREENING 
VISIT 
DAY 
1 a 
WEEK 
4 a 
WEEK 
8 a 
WEEK 
12 b 
WEEK 
24 b 
WEEK 
36 b 
WEEK 
48 c 
EARLY 
DISCONTINUATION 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Patient Questionnaires 
 
X 
X 
 
X 
 
 
X 
X 
Height  
X 
 
 
 
 
 
 
 
 
Weight  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Medical History & 
Physical Exam 
X 
 
 
 
 
 
 
 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess for Adverse 
Experiences 
 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviated History & 
Physical Exam 
 
X 
X 
X 
X 
X 
X 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CD4 Profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV- RNA Quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Lipid Profile 
 
X 
 
 
X 
X 
X 
X 
X 
Plasma and serum Storage 
Sample 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B Surface antigen, 
Surface antibody, and Core 
Antibody d 
X 
 
 
 
 
 
 
 
X 
Hepatitis C antibody e 
X 
 
 
 
 
 
 
 
X 
Plasma Hepatitis B viral 
load f  
X 
 
X 
X 
X 
X 
X 
X 
X 
Females of childbearing 
potential: Pregnancy Test 
(Urine)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensing or 
Administration of Study 
Drug 
 
X 
X 
X 
X 
X 
X 
 
 
Counting of Returned Study 
Drug 
 
 
X 
X 
X 
X 
X 
X 
X 
a  2 days 
b  6 days 
c     6 weeks 
d     If Hepatitis B Surface antigen positive or if Ag/Ab negative with Core antibody positive: plasma 
qualitative and quantitative HBV DNA, Hepatitis B virus e-antigen and antibody 
e    If Hepatitis C antibody positive, HCV RNA will be performed 
f    If Hepatitis B coinfected  

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APPENDIX 2.  GRADING SCALE FOR SEVERITY OF ADVERSE EVENTS AND LABORATORY 
ABNORMALITIES 
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
8.5-10.0 
7.5-8.49 
6.5-7.49 
<6.5 
ANC 
1000-1300 
750-999 
500-749 
<500 
Platelets 
100-125 
50-99 
25-49 
<25 
WBC 
2.0-2.5 
1.5-1.99 
1.0-1.49 
<1 
Hyponatremia 
>130 
125-129 
121-124 
<121 
Hypernatremia 
<150 
150-154 
154-159 
>159 
Hypokalemia 
>3 
2.5-3.0 
2.0-2.49 
<2.0 
Hyperkalemia 
5.6-6.0 
6.01-6.5 
6.51-7.0 
>7.0 
Hypoglycemia 
55-64 
40-54.9 
30-39.9 
<30 
Hyperglycemia, 
Fasting 
110-125 
126-250 
251-500 
>500 
Hypocalcemia 
(corrected) 
Below normal 
but above 7.8 
7.0-7.8 
6.1-6.9 
<6.1 
Hypercalcemia 
(corrected) 
Above normal 
but below 11.5 
11.5-12.5 
12.6-13.5 
>13.5 
Total Bilirubin 
Up to 1.5 ULN 
1.5-2.5 x ULN 
2.5-5.0 x ULN 
>5.0 x ULN 
BUN 
1.25-2.5 x ULN 
2.6-5.0 x ULN 
5.1-10 x ULN 
>10 x ULN 
Creatinine 
1.5-2.0 
2.01-3.00 
3.01-6.00 
>6.00 
Bicarb 
16-LLN 
11-15.9 
8-10.9 
<8.0 
Triglycerides 
(fasting)  
NA 
500-750 
751-1200 
>1200 
LDL (fasting) 
130-160 
161-190 
>190 
 NA 
CK 
3-6 x ULN 
6.1-10 x ULN 
10.1-20 ULN 
>20 x ULN 
AST 
1.25-2.5 x ULN 
2.6-5.0 x ULN 
5.1-10 x ULN 
>10 x ULN 
ALT 
1.25-2.5 x ULN 
2.6-5.0 x ULN 
5.1-10 x ULN 
>10 x ULN 
GGT 
1.25-2.5 x ULN 
2.6-5.0 x ULN 
5.1-10 x ULN 
>10 x ULN 
Alk Phos 
1.25-2.5 x ULN 
2.6-5.0 x ULN 
5.1-10 x ULN 
>10 x ULN 
lipase 
1.0-1.5 x ULN 
1.51-3.0 x ULN 
3.01-5.0 x ULN 
>5.0 x ULN 
Albumin 
NA 
2.0 to <LLN 
<2.0 
NA 
Hematuria 
>ULN-10 
>10-75 
>75 
NA 
Proteinuria 
1+ 
2-3+ 
4+ 
NA 
Glycosuria 
1+ 
2-3+ 
4+ 
NA 

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Cardiac Arrhythmia 
Asymptomatic 
and no 
intervention 
indicated 
Asymptomatic and 
non-urgent 
intervention 
indicated 
Symptomatic and 
non-urgent 
intervention 
indicated 
Life threatening or 
urgent intervention 
indicated 
Cardiac 
ischemia/infarct 
NA 
NA 
Stable angina or 
testing with 
ischemia 
Unstable angina or 
acute MI 
Hemorrhage 
NA 
Symptomatic, no 
transfusion 
indicated 
Symptomatic, ≤ 2 
units PRBC’s 
transfusion 
indicated 
Life threatening or 
> 2 units PRBC’s 
transfusion indicated  
Hypertension 
Systolic: 140-
159 
Diastolic: 90-99 
Systolic: 160-179 
Diastolic: 100-109 
Systolic: >179 
Diastolic: 110 
Life threatening (i.e. 
malignant 
hypertension) or 
requiring hospital 
admission 
Hypotension 
NA 
Symptomatic, 
corrected with oral 
fluids 
Symptomatic, IV 
fluids indicated 
Refractory shock 
Pericardial effusion 
Asymptomatic, 
small 
Asymptomatic, 
mod-large 
Physiologic 
consequences, 
no urgent 
intervention 
indicated 
Physiologic 
consequences, 
urgent intervention 
indicated 
PR prolongation 
0.21-.025 
>0.25 
Type II 2nd degree 
AV block 
Complete AV block 
Prolonged QTc 
450-470 
Or increase <30 
above baseline 
471-499 
Or increase 30-50 
above baseline 
>499 
Or increase >50 
above baseline 
Life threatening 
dysrhythmia  
Thrombus 
NA 
DVT, no 
intervention or 
anticoagulation 
indicated 
DVT, intervention 
or anticoagulation 
indicated 
PE or life-
threatening 
embolism 
Vasovagal episode 
No LOC 
LOC 
NA 
NA 
Ventricular 
dysfunction 
NA 
Asymptomatic and 
intervention 
indicated 
New/worsening  
symptomatic CHF 
Life threatening 
CHF 
 
Bronchospasm 
FEV1 70-80% 
FEV1 50-69% 
FEV1 25-49% 
FEV1<25%, 
cyanosis or 
intubation 
Dyspnea 
On exertion, 
minimal, without 
impact on 
activities 
On exertion, 
moderate, with 
impact on 
activities 
At rest, unable to 
perform typical 
activities 
Resp. failure with 
vent support 
indicated 
Uveitis 
Asymptomatic 
Symptomatic or 
intervention 
indicated 
Posterior or pan-
uveitis or 
Disabling visual loss 

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operation 
indicated 
Visual changes 
from baseline 
minimal, without 
impact on 
activities 
moderate, with 
impact on 
activities 
unable to perform 
typical activities 
Disabling visual loss 
Alopecia 
Thinning 
detectable by 
subject  
Thinning/patchy 
hair loss 
detectable by 
provider 
Complete hair 
loss 
NA 
Rash 
Localized 
macular rash 
Diffuse rash or 
target lesions; no 
vesicles, bulla or 
ulceration. No 
mucosal 
involvement 
Diffuse rash or 
target lesions; 
with vesicles, few 
bulla or 
superficial 
ulceration.  
mucosal 
involvement of 
one site 
Extensive bullous 
lesions/more than 
one site of mucosal 
involvement, 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
Pigmentation 
changes 
Slight or 
localized 
Marked or 
generalized 
NA 
NA 
pruritus 
minimal, without 
impact on 
activities 
moderate, with 
impact on 
activities 
Severe, unable to 
perform typical 
activities 
NA 
Anorexia 
Mild, not 
decreasing 
intake 
Decreased intake, 
no significant 
weight loss 
Significant weight 
loss 
Aggressive 
intervention 
indicated (i.e. 
feeding tube) or life 
threatening 
Ascites 
Asymptomatic 
Symptomatic, 
Intervention 
indicated  
Symptomatic 
despite 
intervention 
Life threatening 
consequences 
Cholecystitis 
NA 
Medical 
intervention 
indicated 
Procedure 
indicated 
Life threatening 
consequences 
(sepsis/perforation) 
Constipation 
NA 
Persistent, 
requiring regular 
use of diet 
modification, 
laxatives/enemas 
Obstipation with 
manual 
evacuation 
indicated 
Life threatening 
consequences 
(obstruction) 
Diarrhea 
Transient/ 
intermittent or 
increase of >3 
stools over 
baseline/24 hr. 
 
Persistent or 
increase of 4-6 
stools over 
baseline/24 hr. 
Bloody diarrhea 
or increase of >6 
stools over 
baseline/24 hr. 
Life threatening 
consequences 
(shock) 
Dysphagia 
Able to eat 
usual diet 
Causes alteration 
of diet, but no 
medical 
Causes severe 
alteration of diet, 
medical 
Life threatening 
reduction of oral 
intake 

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intervention 
indicated 
intervention 
indicated 
 
Mucositis/stomatitis 
Erythema 
Patchy 
Ulcerations or 
pseudo-
membranes 
Confluent 
Ulcerations or 
pseudo-
membranes or 
mucosal bleeding 
Tissue necrosis or 
diffuse mucosal 
bleeding or life 
threatening 
consequences 
Nausea 
Transient or 
intermittent 
Persistent 
resulting in 
decreased oral 
intake 24-48 hours 
Persistent 
resulting in 
minimal oral 
intake >48 hours 
or aggressive 
rehydration 
indicated 
Life threatening 
consequences 
Pancreatitis 
NA 
Symptomatic, no 
hospitalization 
indicated 
Symptomatic, 
hospitalization 
indicated 
Life threatening 
consequences 
Proctitis 
Discomfort 
Minimal 
interference with 
usual activities or 
medical 
intervention 
indicated 
Unable to 
perfume usual 
activities or 
operative 
intervention 
indicated 
Life threatening 
consequences  
Vomiting 
Transient or 
intermittent 
Persistent 
resulting in 
decreased oral 
intake 24-48 hours 
Persistent 
resulting in 
minimal oral 
intake >48 hours 
or aggressive 
rehydration 
indicated 
Life threatening 
consequences 
Psychiatric issues 
(i.e. anxiety, 
agitation, 
depression, mania, 
psychosis) 
minimal, without 
impact on 
activities 
moderate, with 
impact on 
activities 
Severe, unable to 
perform typical 
activities 
Behavior potentially 
harmful to 
self/others or unable 
to perform self-care 
AMS 
minimal, without 
impact on 
activities 
lethargy, with 
impact on 
activities 
Confusion, 
memory 
impairment 
lethargy, or 
somnolence, 
unable to perform 
typical activities 
Delirium/obtundation 
or coma 
Ataxia  
Minimal but 
detectable on 
exam, without 
impact on 
activities 
moderate, with 
impact on 
activities 
marked, unable to 
perform typical 
activities 
Disabling causing 
inability to care for 
self 
Cognitive and 
behavior (including 
Minimal, without 
impact on 
moderate, with 
impact on 
marked, unable to 
perform typical 
Disabling causing 
inability to care for 

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dementia and 
ADD) 
activities. No 
special 
resourced 
indicated 
 
activities or part-
time special 
resourced 
indicated 
activities or full-
time special 
resourced 
indicated 
self or 
institutionalization 
CNS Ischemia 
NA 
NA 
Transient 
ischemic attach 
CVA/stroke with 
neurological deficit 
headache 
Minimal but 
detectable on 
exam, without 
impact on 
activities 
moderate, with 
impact on 
activities 
severe, unable to 
perform typical 
activities 
Disabling causing 
inability to care for 
self or 
hospitalization 
indicated 
Insomnia 
NA 
moderate, with 
impact on 
activities or part-
time special 
resourced 
indicated 
marked, unable to 
perform typical 
activities or full-
time special 
resourced 
indicated 
Disabling causing 
inability to care for 
self 
Neuromuscular 
Weakness 
Asymptomatic 
but detectable 
on exam, 
without or 
minimal impact 
on activities 
moderate, with 
impact on 
activities 
severe, unable to 
perform typical 
activities 
Disabling causing 
inability to care for 
self or respiratory 
failure 
Sensory alteration 
Asymptomatic 
but detectable 
on exam, 
without or 
minimal impact 
on activities 
moderate, with 
impact on 
activities 
severe, unable to 
perform typical 
activities 
Disabling causing 
inability to care for 
self or respiratory 
failure 
Seizure, new onset 
NA 
1 seizure 
2-4 seizures 
Prolonged or 
repetitive seizures 
or difficult to control  
Seizure, pre-
existing 
NA 
Increased 
frequency, no 
change in 
character 
Change from 
baseline in either 
duration or quality 
Prolonged or 
repetitive seizures 
or difficult to control 
Syncope (not 
associated with a  
procedure) 
NA 
Present 
NA 
NA 
vertigo 
without impact 
on activities 
moderate, with 
impact on 
activities 
severe, unable to 
perform typical 
activities 
Disabling causing 
inability to care for 
self or respiratory 
failure 
Arthralgia 
without impact 
on activities 
moderate, with 
impact on 
activities 
severe, unable to 
perform typical 
activities 
Disabling causing 
inability to care for 
self or respiratory 
failure 
 

BIKTARVY® (BIC/FTC/TAF)                 Protocol IN-US-380-4543                 Midland Research Group, Inc. 
 
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Bone Mineral Loss 
BMP t-score or 
z-score -2.5 to -
1.3 
BMP t-score or z-
score <-2.5 
Pathological 
fracture 
Pathological fracture 
causing life 
threatening 
consequences 
myalgia 
without impact 
on activities 
moderate, with 
impact on 
activities 
severe, unable to 
perform typical 
activities 
Disabling causing 
inability to care for 
self or respiratory 
failure 
Osteonecrosis 
NA 
Asymptomatic but 
with radiologic 
findings and no 
surgical 
intervention 
indicated 
symptomatic with 
radiologic findings 
or surgical 
intervention 
indicated 
Disabling bone pain 
with radiologic 
findings causing  
inability to care for 
self 
Acute systemic 
allergic reaction 
Localized 
urticaria with no 
medical 
intervention 
indicated 
Localized urticaria 
with mild 
angioedema with 
no medical 
intervention 
indicated 
Gen urticaria or 
angioedema with 
medical 
intervention 
indicated or 
bronchospasm 
Anaphylaxis, 
laryngeal 
angioedema, 
laryngeal edema or 
life threatening 
bronchospasm 
chills 
without impact 
on activities 
moderate, with 
impact on 
activities 
severe, unable to 
perform typical 
activities 
NA 
Fatigue/malaise 
without impact 
on activities 
moderate, with 
impact on 
activities 
severe, unable to 
perform typical 
activities 
Incapacitating 
symptoms, unable 
to perform basic 
self-care 
Fever 
99.8-101.5 
101.6-102.8 
102.9-104.9 
>104.9 
pain 
without impact 
on activities 
moderate, with 
impact on 
activities 
severe, unable to 
perform typical 
activities 
Incapacitating 
symptoms, unable 
to perform basic 
self-care 
Unintentional 
weight loss 
NA 
5-9% loss of body 
weight 
10-19% loss of 
body weight 
>19% loss of body 
weight or aggressive 
intervention 
indicated (feeding 
tube, TPN) 
Lipodystrophy or 
lipoatrophy 
detectable by 
subject 
Detectable by 
provider 
Obvious or 
disfiguring 
NA 
Diabetes mellitus 
(new onset) 
NA 
without indication 
for medications 
Medications 
indicated 
Life threatening 
consequences 
Diabetes mellitus 
(existing) 
NA 
Requiring 
modification of  
medications 
Lack of control 
despite 
medication 
modification 
Life threatening 
consequences 
gynecomastia 
detectable by 
subject 
Detectable by 
provider 
Obvious or 
disfiguring 
NA 

BIKTARVY® (BIC/FTC/TAF)                 Protocol IN-US-380-4543                 Midland Research Group, Inc. 
 
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CONFIDENTIAL 
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Hyperthyroidism 
asymptomatic 
Symptoms 
causing moderate 
impact of activities 
OR medication 
indicated 
Symptoms 
causing inability 
to perform 
activities OR 
medication 
indicated 
 
Life threatening 
consequences 
hypothyroidism 
asymptomatic 
Symptoms 
causing moderate 
impact of activities 
OR medication 
indicated 
Symptoms 
causing inability 
to perform 
activities OR 
uncontrolled 
despite 
medication 
Life threatening 
consequences 
Intermenstrual 
bleeding 
Spotting 
≤ typical 
menstrual cycle 
≥ typical 
menstrual cycle 
Hemorrhage with life 
threatening 
hypotension 
Urinary obstruction 
(i.e. stone) 
NA 
Without hydro-
nephrosis or acute 
kidney injury 
With hydro-
nephrosis or 
acute kidney 
injury 
Life threatening 
consequences 
Infection (other 
than HIV) 
Localized, no 
systemic 
antimicrobial 
treatment 
indicated AND 
symptoms 
causing minimal 
impact on 
activities 
Systemic 
antimicrobial 
treatment 
indicated OR 
symptoms causing 
>minimal impact 
on activities 
Systemic 
antimicrobial 
treatment 
indicated AND 
symptoms 
inability to 
perform activities 
OR operation 
intervention 
indicated (beyond 
simple I&D) 
Life threatening 
consequences (i.e. 
septic shock) 
 
 
 
 
 
 
 
 
 

BIKTARVY® (BIC/FTC/TAF)                 Protocol IN-US-380-4543                 Midland Research Group, Inc. 
 
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CONFIDENTIAL 
Page 36 of 38 
 APPENDIX 3.  PRO QUESTIONNAIRES  
 
Self-completed HIV Symptom Index15 
 
INSTRUCTIONS: The following questions ask about symptoms you might have had during the past four 
weeks. Please answer the following questions by placing a checkmark in the appropriate box. 
 
Symptom 
Did not 
have this 
symptom 
Symptom 
did not 
bother me 
Symptom 
bothers 
me a little
Symptom 
bothers me
Symptom 
bothers me 
a lot 
Fatigue or loss of energy 
 
 
 
 
 
Fevers, chills or sweats 
 
 
 
 
 
Feeling dizzy or lightheaded 
 
 
 
 
 
Pain, numbness or tingling in the hands 
or feet 
 
 
 
 
 
Trouble remembering 
 
 
 
 
 
Nausea or vomiting 
 
 
 
 
 
Diarrhea or loose bowel movements 
 
 
 
 
 
Felt sad, down, or depressed 
 
 
 
 
 
Felt nervous or anxious 
 
 
 
 
 
Difficulty falling or staying asleep 
 
 
 
 
 
Skin problems, such as rash, dryness 
or itching 
 
 
 
 
 
Cough or trouble catching your breath 
 
 
 
 
 
Headache 
 
 
 
 
 
Loss of appetite or a change in the 
taste of food 
 
 
 
 
 
Bloating, pain, or gas in your stomach 
 
 
 
 
 
Muscle aches or joint pain 
 
 
 
 
 
Problems with having sex, such as loss 
of interest or lack of satisfaction 
 
 
 
 
 
Changes in the way your body looks 
such as fat deposits or weight gain 
 
 
 
 
 
Problems with weight loss or wasting 
 
 
 
 
 
Hair loss or changes in the way your 
hair looks 
 
 
 
 
 
 
 
 
 
 
 
 

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Pittsburgh Sleep Quality Index16 
Instructions: The following questions relate to your usual sleep habits during the past month only. Your answers 
should indicate the most accurate reply for the majority of days and nights of the past month. Please 
answer all questions. 
1. During the past month, what time have you usually gone to bed at night?  
BEDTIME____________ 
2. During the past month, how long (in minutes) has it usually takes you to fall asleep each night? 
NUMBER OF MINUTES _______________ 
3. During the past month, what time have you usually gotten up in the morning? 
GET UP TIME _________________ 
4. During the past month, how many hours of actual sleep did you get at night? (this may be different than the 
number of hours you spent in bed.) 
HOURS OF SLEEP PER NIGHT __________________ 
 
For each of the remaining questions, check the one best response. Please answer all questions. 
5. During the past month, how often have 
you had trouble sleeping because you… 
Not during 
past month 
Less than 
once a week 
Once or 
twice a 
week 
Three or 
more times a 
week 
a) Cannot get to sleep within 30 minutes 
 
 
 
 
b) Wake up in the middle of the night or early 
morning 
 
 
 
 
c) Have to get up to use the bathroom 
 
 
 
 
d) Cannot breathe comfortably 
 
 
 
 
e) Cough or snore loudly 
 
 
 
 
f) Feel too cold 
 
 
 
 
g) Feel too hot 
 
 
 
 
h) Had bad dreams 
 
 
 
 
i) Have pain 
 
 
 
 
j) Other reason(s), please describe and mark 
how often it occurs: 
 
 
 
 
 
 
 
 
 
 
 
6. During the past month, how would you rate your sleep quality overall? 
Very Good ________ 
Fairly Good ________ 
Fairly Good________ 
Very Good________ 

BIKTARVY® (BIC/FTC/TAF)                 Protocol IN-US-380-4543                 Midland Research Group, Inc. 
 
Version Original, Date: 21 Feb 2018 
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Not during 
past month 
Less than 
once a week 
Once or 
twice a 
week 
Three or 
more times a 
week 
7. During the past month, how often have you 
taken medicine to help you sleep (prescribed 
or “over the counter”)? 
 
 
 
 
8. During the past month, how often have you 
had trouble staying awake while driving, eating 
meals, or engaging in social activity? 
 
 
 
 
 
9. During the past month, how much of a problem has it been for you to keep up enough enthusiasm to get things 
done? 
No problem at all  
    ________ 
Only a very slight problem ________ 
Somewhat of a problem     ________ 
A very big problem 
    ________ 
10. Do you have a bed partner or a roommate? 
No bed partner or room mate 
 
   ________ 
Partner/roommate in other room  
   ________ 
Partner in same room, but not same bed   ________ 
Partner in same bed 
 
 
   ________ 
 
If you have a roommate or bed partner, ask 
him/her how often in the past month you 
have had… 
Not during 
past month 
Less than 
once a week 
Once or 
twice a 
week 
Three or 
more times a 
week 
a) Loud snoring 
 
 
 
 
b) Long pauses between breaths while asleep 
 
 
 
 
c) Legs twitching or jerking while you sleep 
 
 
 
 
d) Episodes of disorientation or confusion 
during sleep 
 
 
 
 
e) Other restlessness while you sleep; please 
describe and mark how often it occurs: