A Phase 2b Randomized, Active-Controlled, Staged, Open-Label Trial to Investigate Safety and Efficacy of BMS-955176/GSK3532795 in Combination With Dolutegravir and Atazanavir (With or Without Ritonavir) in Treatment-Experienced HIV-1 Infected Adults
Phase: PHASE2
Conditions: HIV Infections
Sponsor: ViiV Healthcare

Page:
1
Protocol Number:
AI468048
IND Number:
118,936
Ex-US
Non-IND
EUDRACT Number
N/A
Date:
28-Jan-2015
Clinical Protocol AI468048
A Phase 2b Randomized, Active-Controlled, Staged, Open-Label Trial to Investigate Safety and 
Efficacy of BMS-955176 in Combination with Dolutegravir and Atazanavir (with or without 
Ritonavir) in Treatment-Experienced HIV-1 Infected Adults
Study Director/Central Medical Monitor
 DO, MPH
5 Research Parkway
Office 201D
Wallingford, CT  06492 USA
Telephone (office): 
Fax: 
24-hr Emergency Telephone Number
USA:
International: 
Bristol-Myers Squibb Research and Development
Virology Clinical Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
5 Research Parkway
Wallingford, CT 06492
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
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be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Original 
Protocol
28-Jan-2015
Not applicable
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SYNOPSIS
Clinical Protocol AI468048
Protocol Title: A Phase 2b Randomized, Active-Controlled, Staged, Open-label Trial to Investigate Safety and 
Efficacy of BMS-955176 in Combination with Dolutegravir and Atazanavir (with or without Ritonavir) in 
Treatment-Experienced HIV-1 Infected Adults
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Subjects in each arm and per stage will begin QD dosing (in the morning, with a meal) with 
BMS-955176 in combination with atazanavir (ATV) [with or without ritonavir (RTV)] and dolutegravir (DTG), or 
tenofovir (TDF) in combination with atazanavir boosted with ritonavir (ATV/r) and DTG, for a duration of 
96 weeks.
Stage 1:

Arm 1: BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, OR

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Study Phase: 2b
Research Hypothesis: This Phase 2b study will evaluate whether the combination of BMS-955176 with ATV (with 
or without RTV) and DTG is efficacious, safe, and well-tolerated in HIV-1 infected treatment-experienced adults.
Objectives:
Primary Objective Stage 1

To assess the antiviral efficacy of BMS-955176 120 mg and a TDF 300 mg-containing arm, each when given in 
combination with ATV/r 300/100 and DTG 50 mg by determining the proportion of treatment-experienced 
subjects with plasma HIV-1 RNA < 40 c/mL at Week 24 in Stage 1.
Primary Objective Stage 2

To assess the antiviral efficacy of two doses (120 and 180 mg) of BMS-955176, each when given in 
combination with unboosted ATV 400 mg and DTG 50 mg, and to assess the antiviral efficacy of TDF 300 mg 
when given in combination with and ATV/r 300/100 mg and DTG 50 mg by determining the proportion of 
treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at Week 24 in Stage 2. 
Secondary Objectives

To assess the antiviral efficacy of BMS-955176 Arms, and the TDF-containing Arms (TDF + ATV/r + DTG), 
by determining the proportion of treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at 
Weeks 48 and 96

To assess the antiviral efficacy of BMS-955176 Arms, and the TDF-containing Arms, by determining the 
proportion of treatment-experienced subjects with plasma HIV-1 RNA < 200 c/mL at Weeks 24, 48, 96
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
To assess the emergence of HIV drug resistance in samples selected for drug resistance testing (according to 
criteria outlined in Protocol Section 5.4.1)

To assess efficacy of BMS-955176 Arms, and the TDF-containing Arms, by using the mean changes from 
baseline in log10 HIV-1 RNA, CD4+ T-cell counts, and percentage of CD4+ T-cells

To assess the safety and tolerability of BMS-955176 in treatment-experienced subjects by measuring frequency 
of SAEs and AEs leading to discontinuation

To assess disease progression as measured by the occurrence of new AIDS defining events 
(CDC Class C events)

To characterize the pharmacokinetics of BMS-955176 when co-administered with ATV (with or without 
ritonavir) and DTG in treatment-experienced HIV-1 infected subjects
Study Design: This is a randomized, active-controlled, staged, open-label clinical trial. Approximately 
200 treatment-experienced subjects total will be randomized into the study. In Stage 1, approximately 80 subjects 
will be randomized 1:1 (approximately 40 per arm) to either of the treatment arms containing BMS-955176 or TDF 
in combination with boosted atazanavir (ATV/r) and DTG. In Stage 2, approximately 120 subjects will be 
randomized 1:1:1 (approximately 40 per arm) to either of the two BMS-955176 treatment arms containing 
unboosted ATV and DTG, or to the TDF-containing Arm containing ATV/r and DTG. The randomization in both 
Stages will be stratified by HIV-1 Clade (AE versus Other). The number of subjects with HIV-1 Clade AE will be 
capped at a maximum of approximately 3 per arm.
Stage 1:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, OR

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
A Continuation Dose of BMS-955176 will be selected: A dose of BMS-955176 will be selected based on the totality 
of Week 24 data from Stage 1 and available data from study AI468-038 (BMS-955176 in ARV treatment-naive 
HIV-1 infected subjects) with which subjects in Stage 1, Arm 1 may transition to for the remainder of the study. The 
transition may occur on or after Week 48.
The totality of the data from the Week 24 analysis for AI468-038 and Stage 1, including safety, efficacy and 
resistance, will be examined in conjunction with PK/PD modeling to determine if Stage 2 of the study will be 
initiated and confirm the two doses of BMS-955176 for study in Stage 2.
After the Stage 2 Week 24 endpoint, a Continuation Dose of BMS-955176 will be selected based on the totality of 
data from Stages 1 and 2, and study AI468-038 with which subjects in Stage 2, Arms 3 and 4 will transition to for 
the remainder of the study. The switch in Stage 2 may occur sooner, between Week 24 and Week 48, or it may be 
after Week 48.
The assigned backbone for each arm, ATV and DTG, or ATV/r and DTG, will remain unaltered throughout the 
study.
All subjects in both stages are expected to receive study treatment for 96 weeks.
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Study Population:
Key Inclusion Criteria:

Men and non-pregnant women, at least 18 years of age (or minimum age as determined by local regulatory or as 
legal requirements dictate)

Antiretroviral treatment-experienced, defined as having documented evidence of having failed 1 or 2 regimens 
that include 2 or 3 classes of ARV (with or without documented resistance)

Confirmed Plasma HIV-1 RNA 400 copies/mL

CD4+ T-cell count > 50 cells/mm3

Screening genotype/phenotype indicating susceptibility to study drugs (unboosted ATV, FC < 2.2; DTG; TDF)
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Key Exclusion Criteria:

Antiretroviral treatment-experienced adults who have failed > 2 ARV regimens

Resistance or partial resistance to any study drug

Three or more of the following PI mutations, historical or documented: M36I/V, M46I/L/T, G48M/V, 
I54V/L/T/M/A, G73S/A/C/T, V82A/F/T/S/I, or L90M

Any major ATV mutations, historical or documented: I50L, I84V/A, N88D/S

Any major TDF mutation, historical or documented: K65R or T69ins

Three or more of the following non-accessory thymidine analogue mutations (TAMs): M41L, D67N, K70R, 
L210W, T215Y/F, K219Q/E

Any major mutations for raltegravir (RAL), elvitegravir (or clinically suspected INI resistance), historical or 
documented: T66IAK, E92Q, S147G, N155H, Q148H/K/R, Y143C/H/R, E157Q

Chronic HBV/HCV (Positive blood screen for HBsAg; Positive blood screen for HCV Ab and HCV RNA)

ALT or AST > 3 × ULN

Alkaline Phosphatase > 5 × ULN

Bilirubin 1.5 × ULN

History of decompensated cirrhosis or active decompensated cirrhosis

Hemoglobin < 8.0 g/dL

Platelets < 50,000 cells/mm3
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Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for AI468048
Medication 
Potency 
IMP/Non-IMP 
BMS-955176 
60 mg or 120 mga
IMP
Tenofovir (TDF)
300 mg
Non-IMP
Atazanavir (ATV)
200 mg and 300 mg
IMP
Ritonavir (RTV)
100 mg
Non-IMP
Dolutegravir (DTG)
50 mg
IMP and Non-IMP, based on 
country approval status
a The 180 mg dose of BMS-955176 will be constructed with BMS-955176 60 mg + BMS-955176 120 mg
Study Assessments: Efficacy assessments will include plasma HIV-1 RNA measurements. Safety Assessments will 
include blood chemistry and hematology, ECGs, Physical Exams and Vital Signs, and assessment of non-serious 
AEs, SAEs and AEs leading to discontinuation.
Statistical Considerations:
Sample Size:
This is an estimation study, without statistical testing, and hence there are no power considerations.
It is expected that response rate for the primary endpoint for all five arms will be somewhere around 80%. With this 
response rate, and 40 subjects per arm, an exact 95% confidence interval would run from roughly 64% to 91%.
Endpoints:
Primary Endpoint(s) for Stage 1 and Stage 2
The primary endpoint for Stage 1 and Stage 2 is the proportion of subjects with plasma HIV-1 RNA < 40 c/mL at 
Week 24. This will be assessed with the FDA snapshot algorithm. This uses the last on-treatment plasma HIV-1 
RNA measurement, within an FDA-specified visit window, to determine response
Secondary Endpoint(s)

The antiviral efficacy will be determined by the proportion of subjects with plasma HIV-1 RNA < 40 c/mL at 
Weeks 48 and 96 using the FDA snapshot algorithm

The antiviral efficacy will also be assessed by the proportion of subjects with plasma HIV-1 RNA < 200 c/mL 
at Weeks 24, 48 and 96 using the FDA snapshot algorithm approach with positive response defined as HIV-1 
RNA < 200 c/mL

The emergence of HIV drug resistance among samples sent for drug resistance testing will be assessed using the 
most recent version of the IAS-USA list of HIV-1 drug resistance mutations

Changes from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the percentage of CD4+ 
T-cells will be assessed using on-treatment laboratory results, and pre-specified visit windows
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
The frequency of SAEs and AEs leading to discontinuation (DC) will be tabulated directly from the case report 
forms (CRFs). The summary will count the number of subjects that have at least one event.

The occurrence of new AIDS defining events (CDC Class C events) will be tabulated from the CRFs. The 
summary will count the number of subjects that have at least one event.

The steady-state plasma PK of BMS-955176 will be assessed using the intensive PK data, collected at Week 2 
from a subset of subjects.
Analyses:
The first two interim analyses are scheduled to support the decision on initiating the second stage of this study. This 
decision will be based on the totality of the data, including:  safety, efficacy and resistance data from this study; 
relevant data from other studies in the development program; and PK/PD modeling.
The first interim analysis will be conducted after approximately 50% of the randomized subjects have completed 24 
weeks of therapy in Stage 1. This analysis will use the BMS equivalent of SDTM (Study Data Tabulation Model) 
data (“level 1” data) to facilitate the development of models for: population pharmacokinetics; exposure-response 
relationships; and viral kinetics.
A second interim analysis will be conducted after the last subject has completed 24 weeks of therapy in Stage 1.  
This will be a complete analysis of the available efficacy, safety and resistance data.
The schedule for additional analyses will depend upon the decision to initiate the Stage 2, as well as the recruiting 
time frame of Arms 1 & 2 relative to the time frame for Arms 3, 4, and 5. If Stage 2 is initiated, and recruiting 
follows projected timelines, then it is anticipated that analyses will be conducted when:

The last subject in Arms 3, 4 and 5 completes the Week 24 visit

The last subject in Arms 1 and 2 completes the Week 96 visit

The last subject in Arms 3, 4 and 5 completes the Week 96 visit
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale to support study design ............................................................ 
1.1.2 Rationale to support the dose selection ................................................... 
1.1.3 Rationale to support any drug combinations ........................................... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
1.4.1 Background Information BMS-955176 .................................................... 
1.4.1.1 Mechanism of Action....................................................................... 
1.4.1.2 Nonclinical studies .......................................................................... 
1.4.1.3 Clinical studies................................................................................ 
1.4.2 Background Information on TDF ............................................................ 
1.4.3 Background Information on DTG ............................................................ 
1.4.4 Background Information on ATV ............................................................. 
1.4.5 Background Information on RTV ............................................................. 
1.4.6 Drug-Drug Interactions ........................................................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Screening.................................................................................................. 
3.1.2 Day 1/Baseline Visit ................................................................................. 
3.1.2.1 Day 1/Baseline Visit for Arms 1 and 2 - Stage 1 ............................ 
3.1.2.2 Day 1/Baseline Visit for Arms 3, 4 and 5 - Stage 2 ........................ 
3.1.3 Week 2 Intensive PK Visit ........................................................................ 
3.1.4 Visits Week 4 - 96 ..................................................................................... 
3.1.5 Selection of the Continuation Dose of BMS-955176 ............................... 
3.1.5.1 Selection of the Continuation Dose, and the Switch for Stage 1 .... 
3.1.5.2 Selection of the Continuation Dose, and the Switch for Stage 2 .... 
3.1.6 End of the study ........................................................................................ 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
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3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Instructions for Dose Administration ...................................................... 
4.5.1.1 General Instructions ....................................................................... 
4.5.1.2 Specific Dosing Instructions for Initial Treatment Arm Assignment
...............................................................................................................
4.5.2 Dose Modifications .................................................................................. 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Vital Signs and Physical Examinations ................................................... 
5.3.2 Adverse Events ......................................................................................... 
5.3.3 Concomitant Medication Assessment ...................................................... 
5.3.4 Electrocardiograms ................................................................................. 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.1.1 Guidelines for Confirmatory Testing of Plasma HIV-1 RNA and 
Resistance testing .................................................................................. 
5.4.1.2 Protocol Defined Virologic Failure ................................................ 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.4.2.1 CD4+ and CD8+ T-Cells ............................................................... 
5.4.2.2 Drug Resistance Testing ................................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Intensive Pharmacokinetic Assessment .................................................... 
5.5.2 Sparse Pharmacokinetic Assessments ...................................................... 
5.6 Biomarker Assessments .................................................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
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5.8 Other Assessments ............................................................................................ 
5.9 Results of Central Assessments ........................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
6.7.1 Toxicity Management ............................................................................... 
6.7.1.1 Management of Elevations in Liver Transaminases ....................... 
6.7.1.2 Management of Renal Toxicity ....................................................... 
6.7.1.3 Management of Hyperbilirubinemia ............................................... 
6.7.1.4 Gastrointestinal Toxicity Evaluation and Management Plan ......... 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s)Stage 1 and Stage 2 ................................................. 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Efficacy Analyses .............................................................. 
8.4.2.2 Secondary Efficacy Analyses .......................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.4.1 Sparse Pharmacokinetic Analyses .................................................. 
8.4.4.2 PK/PD and PK/VK Analyses .......................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses (including Virologic Futility) ......................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
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9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 LISTINGS OF PROHIBITED AND PRECAUTIONARY 
THERAPIES ........................................................................................................... 
APPENDIX 2 AIDS-DEFINING DIAGNOSES.......................................................... 
APPENDIX 3 DAIDS TOXICITY GRADES .............................................................. 
APPENDIX 4 COCKCROFT-GAULT EQUATION TO CALCULATE SERUM 
CREATINE CLEARANCE .................................................................................... 
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1
INTRODUCTION AND STUDY RATIONALE
1.1
Study Rationale
Despite advances in prevention and care, HIV/AIDS remains a significant epidemic in both the 
US and worldwide. AIDS remains the 6th leading cause of death, internationally. Globally, 
approximately 35 million people were living with HIV infection in 2013.1 A number of these 
patients include those who are treatment-experienced. Note: the use of the term 
“treatment-experienced” herein refers to subjects who have failed at least one or two 
antiretroviral (ARV) regimens and who may be harboring drug resistant virus (current or 
archived) to at least one drug class.
In contrast to current HIV treatment guidelines for treatment-naïve patients, the recommended 
composition of combination
antiretroviral therapy (cART) is far less uniform for 
treatment-experienced subjects.2,3 The level of detail in the DHHS and EACS guidelines leads to 
a lack of uniformity in treatment for patients in later lines of therapy. Moreover, drug related 
toxicities (both short and longer term) in treatment-experienced subjects necessitate vigilance 
and continued monitoring. Thus, there is a need for new and efficacious agents with novel 
mechanisms of action (MOA) and favorable safety/tolerability profiles. Given the aging HIV-1 
infected population and overall fewer number of ARV options for treatment-experienced 
patients, there is a need for a more simplified regimen that may have a better long-term safety 
profile such as that of a nucleoside- and booster-sparing cART regimen. As discussed below, this 
study 
evaluates 
the 
merits 
of 
a 
nucleoside-sparing 
cART 
regimen 
and 
a 
nucleoside/booster-sparing cART regimen in Stage 1 and 2, respectively.
Given the aforementioned challenges with existing treatment in ARV treatment-experienced 
adults, the two primary objectives of this two stage, Phase 2b study are to: 1) To study the 
efficacy of one dose (120 mg) of BMS-955176 (a novel HIV-1 maturation inhibitor) when given 
in combination with atazanavir boosted with ritonavir (ATV/r) 300/100 mg and dolutegravir 
(DTG) 50 mg in Stage 1, and 2) to study the efficacy of two doses (120 and 180 mg) of 
BMS-955176 when given in combination with unboosted ATV 400 mg and dolutegravir (DTG) 
50 mg in Stage 2.
Ultimately this Phase 2b clinical trial will provide supportive data in the context of a therapeutic 
dose of BMS-955176 and the clinical safety/efficacy/resistance of the proposed component(s) of 
a single tablet regimen (STR, that is also a nucleoside/ritonavir sparing ARV strategy) for 
Phase 3 trial development in HIV-1 infected treatment-experienced subjects. Specifically, two 
arms in Stage 2 will contain the individual ARV components of a potential STR: BMS-955176, 
ATV, and DTG.
1.1.1
Rationale to support study design
This Phase 2b open-label clinical trial design is in general agreement with published Food and 
Drug 
Administration 
(FDA)
guidance.4
Initially,
in 
Stage 
1, 
approximately 
80 treatment-experienced HIV-1 infected subjects will be randomized 1:1 (approximately 40 per 
treatment group) to one experimental arm (Arm 1) and a TDF-containing arm (Arm 2) 
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(see Figure 3.1.6-1) to accomplish this study’s Stage 1 primary study objective: to study the 
efficacy of one dose (120 mg) of BMS-955176 when given in combination with ATV/r 
(300/100 mg) and DTG (50 mg). At the Week 24 primary endpoint, Bristol-Myers Squibb 
(BMS) will conduct an analysis of efficacy, safety, and resistance. The Week 24 analysis of 
Arms 1 and 2 together with the Week 24 analysis of all arms in the AI468038 study will be used 
to select a continuation dose for BMS-955176 in Arm 1 of study AI468048, determine if Stage 2 
of study AI468048 will be initiated, and confirm the two doses of BMS-955176 for study in 
Stage 2 of study AI468048. Note, AI468038 is a concurrent Phase 2b study in HIV-1 infected 
treatment naive adults; the primary objective is to evaluate three doses of BMS-955176 (60, 120, 
and 180 mg) and EFV when given in combination with TDF/FTC by determining the proportion 
of subjects with HIV-1 RNA < 40 c/mL at Week 24.
To mitigate the clinical concerns of a potential subtherapeutic regimen and the subsequent 
development of virologic failure/resistance, the clinical trial design will contain a second stage. 
Specifically in Stage 2, approximately 120 additional treatment-experienced HIV-1 infected 
subjects will begin randomization 1:1:1 (approximately 40 per treatment group) to Arms 3, 4,
and 5 based upon the results of two concurrent analyses:

Results of the Week 24 analysis in Stage 1 (Arms 1 and 2), including an analysis for 
virologic futility (see Section 8.4.7)

Results of the Week 24 analysis of Arms 1-4 in AI468038 (treatment-naïve HIV-1 infected 
adults)
Thus, Stage 2 (Arms 3, 4, and 5) will not enroll if the clinical pretest probability of a 
subtherapeutic regimen (in Arms 3 and 4) is high based upon the results of the Week 24 analyses 
from either AI468038 or AI468048 (Stage 1: Arms 1 and 2). Note, subjects in Arm 5 (Stage 2) 
will receive the same ARV regimen as subjects in Arm 2 (Stage 1); Arm 5 in Stage 2 exists to 
maintain similar baseline demographic and clinical characteristics among subjects who are 
randomized to the three Arms in Stage 2. This staged design allows Stage 2 (Arms 3, 4, and 5) to
begin recruitment in a clinically de-risked fashion and accomplish this study’s Stage 2 primary 
study objective: to study the efficacy of two doses (120 mg and 180 mg) of BMS-955176 when 
given in combination with unboosted ATV 400 mg and DTG 50 mg. Ultimately, the totality of 
data from the Week 24 primary endpoint of Stage 2 (Arms 3, 4, and 5), Stage 1 (Arms 1 and 2), 
and all arms in the AI468038 study will be used to select a continuation dose for BMS-955176 in 
Arms 3 and 4 of study AI468048. Across all five arms of this study, subjects will receive 
treatment with three fully-active ARVs (see Section 1.1.3, Rationale to support any drug 
combinations). Ultimately, subjects in experimental Arms 1, 3, and 4 will be given a 
continuation dose of BMS-955176 which has acceptable efficacy, safety, and tolerability
(see Figure 3.1.6-1) for subsequent development in HIV-1 treatment-experienced adults. 
In a recent clinical trial approximately 95% of randomized subjects were noted to be infected 
with HIV-1 clades B, C, and AE.5 Based on in-vitro studies, BMS-955176 is expected to be 
active against a variety of clades albeit with EC50s approximately 2-3 fold less toward HIV-1 
clade AE compared to clade B (see Section 1.4.1). Since the Phase 2a study AI468002 did not 
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include any subjects infected with HIV-1 clade AE (see Section 1.4.1.3), this multinational 
Phase 2b trial will stratify randomization to ensure each treatment arm has approximately the 
same number of HIV-1 clade AE infected subjects in their respective Stages and cap the number 
of HIV-1 clade AE subjects to a maximum of approximately 3 per treatment arm. The study 
duration is expected to be 96 weeks in length to assess durability of response and longer term 
safety and tolerability.
1.1.2
Rationale to support the dose selection
Phase 1 and Phase 2a clinical trials (AI4680016 and AI4680027) investigating BMS-955176 
utilized a spray-dried dispersion (SDD) suspension. However, this Phase 2b study will utilize a 
micronized crystalline (MC) tablet.
In the concomitant dose-finding Phase 2b study in HIV-1 infected treatment naive adults for 
BMS-955176 (AI468038), doses of BMS-955176 of 60 mg, 120 mg, and 180 mg MC tablet are 
proposed for assessment. These doses are based upon modeling and simulation and formulation 
considerations. A population pharmacokinetic model was developed using single dose 
(10 mg - 120 mg SDD) and multiple dose (10 mg to 80 mg SDD) data in healthy subjects 
(AI468001) as well as multiple dose data in HIV-1 clade B-infected subjects (5 mg to 120 mg
SDD for 10 days, AI468002). An exposure-response analysis was conducted using data from 
Part A of the Phase 2a clinical trial where HIV-1 clade B infected subjects received 
BMS-955176 monotherapy (Dose range: 5 - 120 mg) for 10 days. The exposure-response 
relationship was assessed via an Emax model using observed BMS-955176 steady state Cmin. The 
primary endpoint was predicted maximum viral load decline from baseline.
Steady state BMS-955176 Cmin values in HIV-infected subjects administered MC tablet with 
food were projected according to the following data and assumptions:

Exposures in HIV-infected subjects are 35% less than normal healthy volunteers based on 
observations from AI468001 and AI468002 study

Single dose data projected to multiple dose using accumulation index from AI468001 study

BMS-955176 exposures from the MC tablet formulation with food were projected based on 
studies AI468001 and AI468034. The impact of food on the 60 mg MC tablet dose was 
assumed to be that observed for the 40 mg MC suspension formulation in AI468001. 
Exposures to BMS-955176 120 mg MC tablet with food were determined from observed data 
in Study AI468034, where BMS-955176 C24 increased approximately 70% when 120 mg 
MC tablet was given with a high fat meal, relative to fasted conditions. Finally, exposures to 
BMS-955176 180 mg MC tablet with food were assumed to be 1.5-times that of 120 mg MC 
tablet with food
Figure 1.1.2-1 depicts the simulated maximum viral load decline in HIV-infected subjects 
administered BMS-955176 MC tablet under fed conditions.
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Figure 1.1.2-1:
Simulated Maximum Viral Load Decline from Baseline Under Fed 
Conditions1
1 Solid lines are 10th and 90th percentiles and the median of simulated data, shaded area is the 90% confidence 
interval of simulated data, vertical solid lines are the 25th to 75th percentile of the simulated steady state 
BMS-955176 Cmin for the 60 mg MC tablet dose, vertical dotted lines are the 25th to 75th percentile of the 
simulated steady state BMS-955176 Cmin for the 120 mg MC tablet dose, and vertical dashed and dotted lines 
are the 25th to 75th percentile of the simulated steady state BMS-955176 Cmin for the 180 mg MC tablet dose.
While baseline EC90 was not a covariate included in the model due to the lack of significance; 
this covariate, among others, was considered marginally significant and it is possible this 
covariate will become important with additional data.
Although data from AI468002 Part C (in HIV-1 clade C infected subjects) were not included in 
the exposure-response assessment described above, BMS-955176 doses 40 mg SDD once daily 
demonstrated median maximal reductions in HIV-1 RNA > 1 log10 in both clade B and clade C 
HIV-1-infected subjects (see Section 1.4.1.3); thus, doses of BMS-955176 60 mg, 120 mg, and 
180 mg are expected to yield a similar response in HIV-1 infected subjects of either clade.
Because the lowest dose assessed in AI468038 (BMS-955176 60 mg) has the potential for a 
suboptimal antiviral response and possible development of resistance, BMS-955176 120 mg in 
combination with ATV/r and DTG will be assessed in Stage 1 of this study. Based on previous 
data that demonstrated exposures to BMS-955176 increase approximately 50% when given in 
combination with RTV, exposures to BMS-955176 120 mg given in combination with ATV/r are 
expected to result in exposures similar to BMS-955176 180 mg given without RTV. Finally, 
BMS-955176 180 mg will not be used in Stage 1 because exposures (when administered with 
RTV) are expected to exceed those previously studied in clinical trials.
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Table 1.1.2-1 depicts the projected exposure multiples of BMS-955176 60 mg, 120 mg, and 
180 mg MC tablet with food at the NOAEL for pre-clinical findings of interest.
Table 1.1.2-1:
Exposure Multiples of BMS-955176 at NOAELa
Species/ Study 
NOAEL
Multiples
Dose 
(mg/kg/d)
Exposure
PK 
Parameter
60 mg
120 mg
180 mg
Rat/6-month (stomach 
histologic changes) 
No NOAEL
AUC
---
---
---
Dog/9-month (stomach 
histologic changes) 
1
AUC:
64.9 gh/mL
AUC 
3
2
1
Dog/1-month (heart rate)
20
Cmax:
17.8 g/mL 
Cmax
19
10
5
Dog/ Cardiovascular 
telemetry (heart rate) 
2
Cp:
1.93 g/mL 
Cmax
2
1
0.5
Mouse/EFD 
45
AUC:
197 gh/mL 
AUC
10
6
3
a Exposure multiple = animal value ÷ human value. Projected human Cmax values are 0.94, 1.79, and 3.61 g/mL and steady 
state AUC values are 19.3, 35.8, and 69.2 g•h/mL at 60, 120, and 180 mg in HIV-1 subjects receiving BMS-955176 MC 
tablets with high fat meal, respectively. High fat meal provides the highest exposure relative to other meal types or fasted 
state.
With regard to heart rate and the NOAEL of 1.93 g/mL observed in the cardiovascular 
telemetry study in dogs (N=2), it is noted that the projected exposure multiple is 1 at a dose of 
120 mg MC tablet in HIV-infected subjects. However, to date, there have been no clinically 
meaningful changes in heart rate observed in subjects treated with BMS-955176 up to 28 days
(in Part B of the Phase 2a study). With regard to stomach histologic changes, no NOAEL could 
be established based on the 6-month rat study and the projected exposure multiples from the 
9-month dog study are relatively low (eg, 2-fold at the 120 mg MC tablet dose). Despite these 
preclinical findings, a dose of BMS-955176 120mg MC tablet will provide exposures in this 
study which are expected to be generally safe and well tolerated based on existing clinical data 
(see Section 1.4.1).
Data from Study AI468034 demonstrated that BMS-955176 120 mg MC tablet AUC increased 
53% when given with a high fat meal, relative to fasted conditions. Furthermore, preliminary 
data from Study AI468049 demonstrated that a light meal, a standard meal, and a high fat meal 
increased BMS-955176 180 mg MC tablet AUC 1.8-, 2.1-, and 2.5-fold, respectively, relative to 
fasted conditions. Taken together, these data suggest that exposures to BMS-955176 MC tablet 
at doses up to 180 mg increase in a linear fashion when given with food and that similar 
exposures are observed regardless of meal type.
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In total, BMS-955176 120 mg is expected to be safe, well-tolerated, and efficacious in Stage 1 
and will inform the selection of a Stage 1 continuation dose and aspects of Stage 2 (as described 
in detail within Section 1.1.1).
If Stage 2 initiates enrollment, the doses of BMS-955176 will be based upon the Week 24 
analyses of both Stage 1 and Study AI468038. As described in this protocol, the doses in Stage 2 
may be BMS-955176 120 mg and 180 mg in Arms 3 and 4, respectively. However, a thorough 
evaluation of safety, tolerability, efficacy, and resistance will ultimately be combined with 
exposure-response and viral kinetic modeling and simulation to inform the doses of 
BMS-955176 to be given with DTG and ATV (in Arms 3 and 4 of Stage 2).
1.1.3
Rationale to support any drug combinations
This study co-administers BMS-955176, with unboosted ATV 400 mg QD or ATV/r 300/100 mg
QD, and DTG 50 mg. The drug combinations within this clinical trial design will provide 
supportive data in the context of a therapeutic dose of BMS-955176 and the clinical 
safety/efficacy/resistance of the proposed components (Stage 2, Arms 3 and 4) of a single tablet 
regimen (STR) for Phase 3 trial development. Ultimately, BMS will seek approval of 
BMS-955176 for use in treatment-experienced HIV-1 infected adults (including either a STR; 
FDC; and/or monoentity). 
The rationale for using a backbone of ATV and DTG in this treatment-experienced patient 
population is based upon established safety, efficacy, and tolerability of the individual 
components. DTG alone provides a 2.46 log10 c/mL reduction in HIV-1 RNA when administered 
as monotherapy for 10 days.8 Furthermore, DTG has been recently approved and is generally 
safe.9,10,11,12,13 Lastly, ATV/r is often used in treatment-experienced adults’ second-line therapies 
or beyond (for example, in individuals who may have failed an non-nucleoside reverse 
transcriptase inhibitor (NNRTI) and/or integrase inhibitor (INI) based regimen).2,4
This Phase 2b design allows treatment-experienced adults in the experimental Arms to be 
exposed to three fully active ARVs (from three classes). Subjects will benefit from each ARV 
(except RTV) independently providing a > 1 log10
c/mL decrease in HIV-1 RNA
(see Section 1.4.1.3 for details on Phase 2a results [AI468002]). BMS expects the combination of 
two agents (unboosted ATV and DTG) with one investigational agent (BMS-955176) to provide 
a generally improved safety/tolerability profile relative to the respective arm containing ATV/r 
(Arms 3 and 4 relative to Arm 1, respectively) or TDF (Arms 3 and 4 relative to Arm 5, 
respectively).
There is a potential risk of a subtherapeutic regimen to treatment-experienced subjects enrolled 
in Arms 3 and 4 since unboosted ATV is only approved for use in treatment-naïve HIV infected 
adults (within the US) and the therapeutic dose of BMS-955176 has not been established.
Unboosted ATV (400 mg) in treatment-naïve adults results in a 1.41 log10 c/mL reduction in 
HIV-1 RNA after two weeks of monotherapy.14 Despite the monotherapy based reduction in 
HIV-1 RNA, pharmacokinetic data of unboosted ATV in prospective clinical trials,15
cross-sectional,16 and retrospective analyses17 generally supports the finding of DHHS defined 
subtherapeutic ATV levels (< 150 ng/mL) in patients.18
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Despite lower pharmacokinetic (PK) exposure, ATV/r has demonstrated non-inferiority to 
unboosted ATV (TLVOR: 75% vs 70% VR-OC: 87% vs 76%, respectively), similar declines in 
HIV-1 RNA (approx -3.1 log10 c/mL), and increase in CD4 cell counts within treatment-naïve 
adults. However, the unboosted ATV arm had an increased number of subjects with emerging 
ATV and lamivudine (3TC) resistance. In particular, the difference in nucleoside/nucleotide 
reverse transcriptase inhibitor (NRTI) resistance was markedly greater in the unboosted ATV 
compared to RTV boosted ATV arm.19 Of note, in this clinical trial (AI468048) NRTIs are not 
used in the experimental Arms 1, 3, and 4. Similar single arm, prospective studies have 
replicated the viral efficacy and immunologic response using unboosted ATV in treatment-naïve 
HIV infected adults.20
Insights from limited data regarding the use of unboosted ATV in treatment-experienced adults 
have demonstrated a viral decay ranging from -1.4 to -2.7 log10 c/mL over 24 weeks of therapy 
in combination with NRTIs (such as TDF, 3TC, and didanosine).21 Also, observational data 
(mean: 24 months of follow-up) has shown similar percentages of subjects with their last HIV 
RNA being undetectable (80% vs 83%) after receiving unboosted and RTV boosted ATV, 
respectively.22
Taking the key findings from studies of ATV in both treatment-naïve and treatment-experienced 
HIV infected adults, Arms 3 and 4 containing unboosted ATV may have the potential for 
increased resistance (relative to Arm 1 containing RTV boosted ATV) and the development of 
virologic failure. However, several other factors must be taken into consideration. First, these 
Arms will use three potent (> 1 log10
c/mL) ARVs in combination. Moreover, 
treatment-experienced subjects who have failed one or two prior regimens are likely to be either 
naïve to ATV treatment (prior NNRTI- and/or INI-class failure) or will need to be fully 
susceptible to approved ARVs (including unboosted ATV, see Section 3.3.2). Second, both the 
combination of ATV and DTG with BMS-955176 independently have demonstrated additivity to 
synergy in-vitro23 (see Section 1.4.1.3 for clinical data on the combination of ATV and 
BMS-955176). Third, unboosted ATV increases the geometric mean ratio of Ctrough for DTG by 
a factor of 2.8.24 Fourth, in normal healthy volunteers, multiple dose administration of 
BMS-955176 40 mg (SDD suspension formulation) with ATV 400 mg for 14 days resulted in an 
approximate 25% increase in the AUC(TAU) of BMS-955176 administration alone25 and 
preliminary PK data from the Phase 2a (AI468002) demonstrated that BMS-955176 AUC(TAU) 
increased approximately 37% and 52% when ATV was combined with BMS-955176 40 and 
80 mg (SDD suspension formulation), respectively, relative to administration of BMS-955176 
alone. It is clinically unclear whether higher exposures of DTG and BMS-955176 would lead to 
a decreased incidence of unboosted ATV resistance in the context of Arms 3 and 4 
(BMS-955176 120 and 180 mg + ATV + DTG). Combined with these factors, BMS proposes to 
mitigate the potential risk of increased resistance by 1) studying two doses of BMS-955176 
(120 and 180 mg) in combination with unboosted ATV and DTG, and 2) using a two stage 
clinical trial design with Stage 2 (Arms 3, 4, and 5) enrolling after the Week 24 analysis of 
Stage 1 (Arms 1 and 2) and AI468038 are completed, and 3) only enrolling subjects who are 
susceptible to study medication (including unboosted ATV) (see Section 1.1.1, Rationale to 
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support study design). This risk mitigation is employed to increase the probability of establishing 
clinical efficacy (number of responders at the Week 24) in treatment-experienced HIV-1 infected 
adults.
BMS expects BMS-955176 120 and 180 mg given with unboosted atazanavir to be generally 
safe and well-tolerated. Subjects in Arms 3 and 4 treated with unboosted ATV would potentially 
benefit from a more favorable lipid profile, fewer gastrointestinal (GI) side effects, and 
decreased indirect hyperbilirubinemia. In total, the potential clinical risks for subjects 
randomized to Arms 3 and 4 in Stage 2 do not outweigh the potential benefits of a Nucleoside-
and Booster-sparing cART regimen that may offer both efficacy and long-term safety (including 
but not limited to improved bone mineral density, improved renal function, and improved lipid 
profile). Please see Section 1.5 for further details on the overall risk/benefit assessment.
1.2
Research Hypothesis 
This Phase 2b study will evaluate whether the combination of BMS-955176 with ATV (with or 
without RTV)
and DTG
is efficacious, safe, and well-tolerated
in HIV-1 infected 
treatment-experienced adults.
1.3
Objectives(s)
1.3.1
Primary Objective
Primary Objective Stage 1

To assess the antiviral efficacy of BMS-955176 120 mg, and a TDF 300 mg-containing arm,
each when given in combination with ATV/r 300/100 mg and DTG 50 mg by determining 
the proportion of treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at 
Week 24 in Stage 1.
Primary Objective Stage 2

To assess the antiviral efficacy of two doses (120 and 180 mg) of BMS-955176, each when 
given in combination with unboosted ATV 400 mg and DTG 50 mg, and to assess the 
antiviral efficacy of TDF 300 mg when given in combination with ATV/r 300/100 mg and 
DTG 50 mg by determining the proportion of treatment-experienced subjects with plasma 
HIV-1 RNA < 40 c/mL at Week 24 in Stage 2. 
1.3.2
Secondary Objectives

To assess the antiviral efficacy of BMS-955176 Arms, and the TDF-containing Arms (TDF + 
ATV/r + DTG), by determining the proportion of treatment-experienced subjects with plasma 
HIV-1 RNA < 40 c/mL at Weeks 48 and 96

To assess the antiviral efficacy of BMS-955176 Arms, and the TDF-containing Arms, by 
determining the proportion of treatment-experienced subjects with plasma HIV-1 RNA 
< 200 c/mL at Weeks 24, 48, 96

To assess the emergence of HIV drug resistance in samples selected for drug resistance 
testing (according to criteria outlined in Section 5.4.1)
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
To assess efficacy of BMS-955176 Arms, and the TDF-containing Arms, by using the mean 
changes from baseline in log10 HIV-1 RNA, CD4+ T-cell counts, and percentage of CD4+ 
T-cells

To assess the safety and tolerability of BMS-955176 in treatment-experienced subjects by 
measuring frequency of SAEs and AEs leading to discontinuation

To assess disease progression as measured by the occurrence of new AIDS defining events 
(CDC Class C events)

To characterize the pharmacokinetics of BMS-955176 when co-administered with ATV 
(with or without ritonavir) and DTG in treatment-experienced HIV-1 infected subjects
1.3.3
Exploratory Objectives

To determine the effect of BMS-955176 Arms, and the TDF-containing Arms, on renal 
clinical parameters and biomarkers through Weeks 48 and 96

To determine the effect of BMS-955176 Arms, and the TDF-containing Arms, on bone 
biomarkers through Weeks 12 and 24

To assess the impact of baseline (pre-therapy) Gag polymorphisms on the efficacy of 
BMS-955176 Arms by determining the proportion of treatment-experienced subjects with 
plasma HIV-1 RNA < 40 c/mL, HIV-1 RNA < 200 c/mL, and the changes from baseline in 
log10 HIV-1 RNA at Weeks 24, 48 and 96, by baseline polymorphisms

To characterize the steady-state plasma PK of DTG when co-administered with BMS-955176 
and ATV (with or without RTV) in treatment-experienced subjects. The effect of 
BMS-955176 on DTG PK in the presence of ATV (without RTV) may be assessed relative to 
historical data

To compare steady-state exposures of DTG when co-administered with BMS-955176 and 
ATV/RTV to DTG when co-administered with TDF and ATV/RTV

To characterize the PK of ATV when co-administered with DTG and BMS-955176, with or 
without RTV

To explore PK/PD and PK/viral kinetic (VK) relationships between BMS-955176, ATV, 
and/or DTG exposure and both efficacy and safety endpoints

To assess the impact of the study therapies on health-related quality of life measures
1.4
Product Development Background
1.4.1
Background Information BMS-955176
1.4.1.1
Mechanism of Action
BMS-955176 is an HIV-1 maturation inhibitor (MI), a novel class of anti-HIV-1 drugs that 
prevents the maturation of HIV-1 virions by binding near a key structural element within the Gag 
polyprotein that is required for virion maturation and assembly. Maturation inhibitors block the 
last protease cleavage event between Gag protein segments designated as capsid (CA) protein 
p24 (p24) and spacer peptide 1 (SP1), resulting in the release of immature noninfectious virus 
particles. BMS-955176 has excellent potency and broad spectrum activity, and mechanism of 
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action studies indicate that BMS-955176 is a true MI, with a mechanism of action distinct from 
current antiretroviral agents.26 Development of BMS-955176 could potentially lead to novel 
HIV-1 treatment regimens in treatment-experienced HIV-1 patients.
1.4.1.2
Nonclinical studies
Nonclinical Pharmacology and Microbiology
BMS-955176 specifically inhibits HIV-1 protease cleavage at the CA(p24)/SP1 junction within 
the Gag protein in both HIV-1-infected cells and purified HIV-1 Gag virus-like particles (VLPs). 
Radiolabeled BMS-955176 specifically binds to purified HIV-1 Gag VLPs, and its binding is 
dose-dependently inhibited by related MIs and is reversible. BMS-955176 does not directly 
inhibit HIV-1 protease nor bind to a small HIV-1 protease peptide substrate. These results 
indicate that BMS-955176 inhibits late in the HIV-1 life cycle by specific binding to immature 
capsid structures at or near the CA(p24)/SP1 junction, thereby inhibiting cleavage at that 
particular site. In cell culture, the range of values for the concentration producing 50% effect 
(EC50) of BMS-955176 against 7 common laboratory strains of HIV-1 was 1.6 to 10.5 nM 
(mean = 6.0 3.5 nM). Using a reverse transcriptase readout, a phenotyping analysis of 
93 subtype B viruses whose genotypes are representative of 96% of the diversity (found in the 
Los Alamos National Laboratory [LANL] database) in Gag sequences indicates that the mean 
EC50 of this cohort was 2.7 1.9 nM, with a median value of 2.2 nM and a range between 0.6 to 
12 nM. A similar analysis of 23 isolates of subtype C viruses found a mean EC50 of 
6.1 3.1 nM, a median value of 5.6 nM, and a range from 2.5 to 16 nM. When evaluated against 
clinical isolates in peripheral blood mononuclear cells (PBMCs), BMS-955176 exhibited a mean 
EC50 of 24 24 nM against a cohort (N = 22) of subtype B viruses. Activity was also observed 
against viruses from subtypes A, C, D, F, and G, with average EC50 values for 96% of tested 
isolates (N = 41) between 5.9 and 87 nM. Clinical isolates from the CRF01_AE subtype were 
approximately 2- to 3-fold less susceptible to BMS-955176 (average EC50 77 nM, N = 7) 
viruses. BMS-955176 was active against 1 of 3 human immunodeficiency virus type-2 (HIV-2)
isolates (EC50 = 15 nM). BMS-955176 retains complete activity against reverse transcriptase 
(RT), protease, and integrase inhibitor-resistant viruses, with EC50 values similar to wild-type 
(wt) viruses, while the potency of currently approved nucleotide/nucleoside reverse transcriptase 
inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors 
(PIs), and integrase inhibitors (INIs) was undiminished when tested against viruses with reduced 
susceptibility to BMS-955176. BMS-955176 maintained activity against a panel of PI-resistant 
isolates from PI-treated subjects harboring a variety of major and minor PI-resistance
determinants in both protease and Gag.27,28 Protein binding to 100% human serum (HS) was 
86%, and in the presence of 40% HS supplemented with additional human serum albumin 
(HuSA) to match physiologic concentrations, BMS-955176 exhibited an approximately 4-fold 
reduction of antiviral activity. Selection for resistance to BMS-955176 in cell culture identified
changes that map to amino acids adjacent to the CA(p24)/SP1 cleavage site. These include an 
amino acid substitution of A364V or a combination of V362I with secondary changes (V370A, 
A374P or I376V). In vitro, virus with the A364V change exhibited a drastic loss of susceptibility 
to BMS-955176 (>100-fold), while the V362I plus secondary change-containing viruses were 
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generally less sensitive to BMS-955176 (median EC50 25 nM, range 7.1 to 167 nM). In 2-drug 
combination studies with representative drugs from NRTI, NNRTI, PI, and INI classes, all 
combinations produced additive to synergistic effects, suggesting that BMS-955176 should be 
amenable for use in combination with any of these agents.
Bevirimat (BVM), a first-generation MI, demonstrated proof of concept and dose-dependent 
anti-HIV-1 potency in both Phase 1 and Phase 2 clinical studies. Patients infected with HIV-1 
sensitive to BVM demonstrated an approximate 1.2 log10 decline in HIV-1 RNA. However, 
approximately 50% of patients harboring naturally occurring polymorphisms located close to the 
CA(p24)/SP1 cleavage site showed a significantly reduced response to BVM treatment. In 
addition, BVM exhibited a large reduction in antiretroviral activity in the presence of human 
serum. BMS-955176 was developed to address the key flaws of BVM by providing improved 
coverage of BVM-resistant polymorphic variants and improved potency in serum. BMS-955176 
has been shown to be active against viruses with resistance from all marketed ARVs, and to 
possess a low serum effect. Development of BMS-955176 could potentially lead to novel HIV-1 
treatment regimens in treatment-experienced HIV-1 patients.
Nonclinical Pharmacokinetics
The absolute oral bioavailability of BMS-955176 was low (3.89% to 26.8%) in all preclinical 
species (mice, rats, dogs, and monkeys). In the dog, though there was a positive food effect and 
no pH dependent absorption, upon repeat dosing a less than dose-proportional increase in 
exposure was observed. BMS-955176 distributed preferentially into the duodenum, liver, and 
lymph nodes with little penetration into the brain. Protein binding was 86.1% in human serum 
and 78% to 94% in animal sera
In human in vitro systems, the metabolism of BMS-955176 was primarily mediated via 
cytochrome P450 (CYP)3A4. In vivo in rats, dogs, and monkeys, BMS-955176 was the 
predominant drug-related component in plasma following a single oral dose of BMS-955176. 
BMS-955176 was eliminated principally via metabolism followed by excretion in bile with little 
renal excretion. 
In vitro, BMS-955176 was an inhibitor of CYP2C8 (concentration at which 50% inhibition 
observed [IC50] = 28.5 M), CYP3A4 (IC50 = 32 M), and uridine diphosphate 
glucuronosyltransferase (UGT)1A1 (IC50 = 20 M) enzymes. No P-gp inhibition or 
time-dependent inhibition of CYPs was observed. BMS-955176 was not an inducer of CYP1A2, 
CYP2B6, or CYP3A4. The steady state Cmax of BMS-955176 180 mg tablet in HIV-infected 
patients with food is projected to be approximately 5.2 M. Thus, the potential exists for 
BMS-955176 to inhibit CYP2C8, CYP3A4, and/or UGT1A1 in vivo and increase exposures to 
co-administered drugs that are metabolized by these enzymes. Furthermore the potential exists 
for drug-drug interactions (DDI) if BMS-955176 is co-administered either with an inhibitor or 
inducer of CYP3A4 or P-gp.
BMS-955176 was a substrate of mouse P-glycoprotein (P-gp) based on higher bioavailability in 
P-gp knock-out mice when BMS-955176 was co-administered with elacridar, a potent inhibitor
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of P-gp and breast cancer resistance protein (BCRP). BMS-955176 could not be reliably assessed 
as a substrate for human P-gp due to nonspecific binding and low solubility. In vitro, 
BMS-955176 inhibited organic anion transporting polypeptide (OATP)1B1 and OATP1B3 
(IC50 5.3 and 4 M, respectively), but was not an inhibitor of P gp, sodium taurocholate 
cotransporting polypeptide (NTCP), organic anion transporter (OAT)1, OAT3, multiple 
drug-resistance protein (MRP)2, and bile salt export pump (BSEP). These findings suggest a 
potential for DDI between BMS-955176 (as the perpetrator) and substrates of OATP1B1 and 
OATP1B3, but not with those of P-gp, NTCP, OAT1, OAT3, MRP2, and BSEP. Furthermore, 
the potential exists for drug-drug interactions (DDI) if BMS-955176 is co-administered either 
with an inhibitor or inducer of CYP3A4 or P-gp. Preliminary data indicate that BMS-955176 
does not inhibit OCT2, a transporter that is inhibited by dolutegravir (DTG), a drug with which 
BMS-955176 is planned to be co-administered.
Nonclinical Toxicology
The toxicity profile of BMS-955176 was evaluated in single- and repeat-dose toxicity, 
genotoxicity, phototoxicity, safety pharmacology, sensitization, reproductive toxicity and 
embryo-fetal development studies. The scope of the toxicologic evaluation for BMS-955176
supports its proposed clinical use for HIV-1 infection. Unless otherwise mentioned, all animal 
studies were dosed by the oral route with an aqueous methylcellulose suspension of a 
BMS-955176 spray-dried dispersion (SDD). 
BMS-955176 was not phototoxic, mutagenic, or clastogenic in vitro and was not genotoxic in a 
rat micronucleus assay at 300 mg/kg/day (AUC 279 g·h/mL). BMS-955176 was not a skin 
sensitizer in the local lymph node assay in the mouse. BMS-955176 had a low potential (IC50 or 
EC50 > 5 M [> 3.45 µg/mL]) for in vitro off-target interactions on a broad range of enzymes, 
transporters, and receptors, including cardiac ion channels. 
In safety pharmacology evaluations in rats, there were no respiratory findings and no direct 
central nervous system (CNS) findings. Decreases in motor activity, arousal, and rearing were 
considered secondary to general toxicity (ie, body weight decreases).
Cardiovascular safety pharmacology evaluations were conducted in rabbits, rats, and dogs. In the 
definitive oral single-dose cardiovascular safety study in conscious telemeterized dogs, blood 
pressure and electrocardiogram were was unaffected at 20 mg/kg; however, increases in heart 
rate (mean 33% to 57% of pretest vehicle) were observed at 8 and 20 mg/kg. The increase in 
heart rate at these doses was primarily due to increases in 2 dogs at each dose that had higher 
plasma concentrations (12.83 g/mL) relative to the dogs without effects on heart rate 
(6.81 g/mL). The no-observed-effect level (NOEL) for cardiovascular effects in dogs was 
2 mg/kg (plasma concentration of 1.93 µg/mL). Importantly, there was no change in heart rate at 
20 mg/kg/day at higher plasma concentrations (Cmax 17.8 µg/mL) in the 1-month study in 
dogs (below). 
Taken together, BMS-955176 has low potential for respiratory, CNS, and cardiovascular effects 
and no cardiovascular effects have been observed in humans to date.
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Two-week, 1-month, and 6-month studies were conducted in rats. As the 2-week study was of 
limited scope, only the 1-month and 6-month studies are presented in this summary. 
BMS-955176 was administered for 1 month at doses of 30, 100, or 300 mg/kg/day. While there
was no mortality at 100 mg/kg/day, the high dose of 300 mg/kg/day was associated with 
pronounced signs of clinical toxicity and early euthanasia of all the rats at that dose level on 
Days 8 to 9. The dose of 30 mg/kg/day was tolerated. The intermediate dose of 100 mg/kg/day 
(AUC 357 g·h/mL) resulted in dose-limiting toxicity including persistent reduction in food 
consumption and body weights. A number of minor hematology (including red cell parameter 
changes with no consistent effect on the erythron) and serum chemistry changes (including 
increased alkaline phosphatase and alanine aminotransferase) without correlating histologic liver 
findings) occurred at 30 and 100 mg/kg/day; these changes were considered not adverse due to 
small magnitude, occurrence only in 1 sex, and lack of microscopic correlates, and most were 
secondary to decreases in food consumption and body weight. Dose-related gastrointestinal 
toxicity was primarily characterized by morphologic changes in the stomach at 100 mg/kg/day 
and the stomach and small and large intestines at 300 mg/kg/day. At the end of the 2-week 
postdose recovery period, there was complete recovery of all BMS-955176-related findings at 
30 mg/kg/day. At 100 mg/kg/day, all findings recovered with the exception of increased red cell 
distribution width in females, minimally higher (1.94×) ALT activity in 1 male without any 
histologic correlates, and decreased mean prostate gland (with seminal vesicles) weights. The 
low dose of 30 mg/kg/day (AUC 113.5 g·h/mL) was considered the no-observed-adverse-effect 
level (NOAEL) because the body weight and food consumption changes were minimal and 
transient and there were no BMS-955176-related morphologic changes.
In a 6-month oral toxicity study in rats with 1-month recovery period, BMS-955176 was 
administered at doses of 10, 25, or 50 mg/kg/day. BMS-955176-related effects were similar to 
those observed in the 1-month rat study and occurred at all doses (10 mg/kg/day; 
AUC 71 gh/mL). Findings included decreased body weight, food consumption, and in the 
stomach, minimal to marked atrophy involving both parietal and chief cells, minimal to mild 
single-cell necrosis and minimal regeneration in the glandular mucosa, which were partially 
reversible at the end of the 1-month recovery period. A NOAEL was not established in this 
study.
Five-day, 1-month, and 9-month repeat-dose studies were conducted in dogs. As the 5-day 
toxicokinetics and tolerability studies were of limited scope, only the 1-month and 9-month
studies are presented here. In the 1-month study, BMS-955176 was administered at doses of 2, 8, 
or 20 mg/kg/day. Increased incidences of sporadic vomiting and liquid, yellow, and/or mucoid 
feces occurred at all doses, but had no apparent effect on the overall health of these animals. 
At 20 mg/kg/day, additional findings included occasional decreases in food consumption in a 
few animals, loss of body weight (up to 8%) in 2 females, a minimal increase in serum ALT 
activity (2.10× pretest) in 1 female with no microscopic correlates, and minimal single-cell 
necrosis of stomach glandular epithelium. All BMS-955176-related changes were fully 
reversible by the end of the 2-week recovery period. The dose of 8 mg/kg/day was considered a 
NOAEL (AUC 219.5 g·h/mL) since the sporadic clinical observations had no adverse effects 
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on the general health of the animals and there were no BMS-955176-related morphologic 
changes. 
In a 9-month oral toxicity study in dogs with 1-month recovery period, BMS-955176 was 
administered at 0 (vehicle), 1, 3, or 10 mg/kg/day. BMS-955176-related effects were similar to 
those observed in the 1-month dog
study
and
occurred at doses 3 mg/kg/day 
(AUC 135 gh/mL). Findings included salivation (only males at 10 mg/kg/day), fur thinness 
(males), thin appearance, and abnormal feces (yellow, liquid, pale and/or mucoid) that occurred 
sporadically throughout the study; increases in mean food consumption; minimal to marked chief 
cell depletion in the glandular stomach. Additional findings at 10 mg/kg/day included thin 
appearance that correlated with decreases in body weight in food consumption; occasional 
vomitus in males; in the stomach, minimal to moderate mucous cell hyperplasia (often associated 
with glandular dilatation) correlating with increased thickness macroscopically (males only) and 
minimal to marked parietal cell depletion and single-cell necrosis of glandular epithelial cells; 
and increases in serum gastrin values (1.31 to 4.56× highest control value) for several dogs that
may have reflected the reductions in gastric parietal cells. The NOAEL was 1 mg/kg/day 
(AUC 64.9 gh/mL).
The embryo-fetal development (EFD) studies were conducted in 3 species (rabbits, rats, and 
mice) instead of the standard 2 species due to poor maternal tolerability and inability to achieve 
adequate systemic exposures in rabbits.
In a definitive EFD study in pregnant mice, BMS-955176 was administered at doses of 15, 45, or 
150 mg/kg/day from gestation day (GD) 6 through 15. BMS-955176 was a selective 
developmental toxicant in mice. Dose of 100 mg/kg/day was associated with an increase in 
embryo-fetal lethality (cumulative postimplantation losses of 11.5%, relative to 3.9% in control 
litters, attributed to increased incidences of dead fetuses, early resorptions and late resorptions). 
Cleft palate and exencephaly were observed in a few fetuses; additionally, marginal reductions in 
fetal body weight (5% relative to control values) were observed. There was no maternal toxicity 
at any dose tested. The developmental NOAEL was 45 mg/kg/day (AUC 213 g·h/mL).
In a definitive EFD study in pregnant rats, BMS-955176 was administered at doses of 10, 30, or 
100 mg/kg/day from GD 6 through 15. BMS-955176 was not a selective developmental toxicant. 
Developmental toxicity (reduced fetal body weights, increases in fetal alterations, and reduced 
fetal ossification) occurred only at 100 mg/kg/day; whereas, maternal toxicity (clinical 
observations, reduced body weights, and reduced food consumption) was observed at 
30 mg/kg/day. The developmental NOAEL was 30 mg/kg/day (AUC 114 gh/mL). 
In an EFD study in pregnant rabbits, BMS-955176 was administered at a dose of 80 mg/kg/day 
from GD 7 through 19. BMS-955176 was not a developmental toxicant in rabbits at 
80 mg/kg/day (AUC 3.26 gh/mL), at which reductions in maternal food consumption and 
weight gain were observed.
In the fertility and early embryonic development study in rats, BMS-955176 was evaluated at 
doses of 10, 30, or 100/60 mg/kg/day in males and females. BMS-955176 did not affect 
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reproduction or early embryonic development at doses 100 mg/kg/day that produced overt 
toxicity. The reproductive NOAEL was 100/60 mg/kg/day (AUC 210 g•h/mL) in male rats and
100 mg/kg/day (AUC 458 g•h/mL) in female rats.
Overall, results from the nonclinical toxicology studies demonstrate that BMS-955176 has a low 
potential for cardiovascular effects, is toxic to the gastrointestinal tract, and is a selective 
developmental toxicant. Clinical monitoring of vital signs (heart rate, systolic and diastolic blood 
pressure) and for gastrointestinal adverse events (AEs) (eg, nausea, vomiting, diarrhea, or fecal 
changes), along with screening for potential renal tubular injury, have not indicated any potential 
for these AEs in Phase 1 or proof of concept (POC) studies in humans. Clinical protocols will 
ensure that appropriate contraceptive measures will be followed to minimize the risk of 
pregnancy while enrolling women of child-bearing potential (WOCBP) males subjects who are 
sexually active with (see Section 3.3.1 Inclusion Criteria).
1.4.1.3
Clinical studies
Phase 1
The safety, tolerability, and PK of BMS-955176 were evaluated in a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD, 10-120 mg) and multiple ascending 
dose (MAD, 10-80 mg QD for 14-28 days) study in healthy subjects (AI468001). No SAEs, 
deaths, or discontinuations related to study drug occurred. No clinically meaningful trends were 
observed in vital signs, physical exam findings, laboratory values, or ECGs. Following 
single-dose and multiple-dose administration of BMS-955176, a slightly less than 
dose-proportional increase in Cmax and AUC(INF) was observed over the dose ranges studied. 
Steady state was reached in approximately 7 days following multiple-dose once daily 
administration of BMS-955176. The half life (T-HALF) of BMS-955176 is approximately 
35 hours. 
Study AI468034 assessed the relative bioavailability and dose proportionality of BMS-955176 
MC tablet - the formulation that will be used in the current study. Relative to 80 mg SDD 
suspension, the bioavailability of BMS-955176 120 mg MC tablet was approximately 23% 
lower. Furthermore, consistent with the low solubility of BMS-955176, considerable overlap in 
exposures was observed between 60 mg, 120 mg and 180 mg MC tablet, when given under 
fasted conditions. The impact of food on exposures to BMS-955176 120 mg MC tablet was
assessed in Study AI468034 as well; a high fat meal increased BMS-955176 AUC approximately 
50% with negligible impact on BMS-955176 Cmax.
Study AI468049 assessed the impact of a light meal, a standard meal, and a high fat meal on the 
PK of BMS-955176 180 mg MC tablet. Preliminary results demonstrate that, relative to fasted 
conditions, BMS-955176 Cmax is increased approximately 2-fold with all three meal types, while 
BMS-955176 AUC increased approximately 1.8-, 2.1-, and 2.5-fold with a light meal, a standard 
meal, and a high fat meal, respectively. These results, taken together with those from AI468034 
described above, demonstrate that the impact of food on exposures to BMS-955176 is 
dose-dependent with the degree of impact increasing with increasing dose. Preliminary safety 
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results from AI468049 indicate that GI adverse events (eg, nausea, vomiting, loose stools) only 
occurred in the fed arms (where the BMS-955176 exposures were higher) relative to the fasted 
arms.
Study AI468049 assessed the impact of a light meal, a standard meal, and a high fat meal on the 
PK of BMS-955176 180 mg MC tablet. Preliminary results demonstrate that, relative to fasted 
conditions, BMS-955176 Cmax is increased approximately 2-fold with all three meal types, while 
BMS-955176 AUC increased approximately 1.8-, 2.1-, and 2.5-fold with a light meal, a standard 
meal, and a high fat meal, respectively. These results, taken together with those from AI468034 
described above, demonstrate that the impact of food on exposures to BMS-955176 is 
dose-dependent with the degree of impact increasing with increasing dose.
Phase 2a
A randomized, double-blind, placebo-controlled proof of concept study in HIV subjects has 
completed enrollment and is undergoing analysis (AI468002). The three parts of this study were: 
1) Part A evaluated doses of 5, 10, 20, 40, 80, and 120 mg of BMS-955176 (SDD suspension) 
given for 10 days in HIV-1 clade B infected subjects, 2) Part B compared the antiviral activity of 
BMS-955176 (SDD suspension) administered with ATV (with or without RTV) against standard 
of care (TDF + FTC + ATV/r) for 28 days in HIV-1 clade B infected subjects, and 3) Part C 
evaluated BMS-955176 40 and 120 mg (SDD suspension) given for 10 days in HIV-1 clade C 
infected subjects. See Table 1.4.1.3-1 for baseline demographics. 
Preliminary results from the Phase 2a study (AI468002) in HIV-1 (clade B and C only) infected 
adults showed that at effective doses, a maximum median reduction in HIV-1 RNA ranging from 
1.3 to 1.7 log10 was observed. In the Phase 2b study BMS-955176 doses estimated to provide 
similar exposure to effective doses in the Phase 2a study will be used. Moreover, when 
BMS-955176 was combined with ATV RTV, these combinations resulted in maximum median 
declines in HIV-1 RNA ranging from 1.9 to 2.2 log10 (see Table 1.4.1.3-2). These results are 
generally similar to the antiviral effect demonstrated by other classes of ARVs in short-term
monotherapy trials, and thus BMS-955176 should contribute substantially with other ARVs to 
form an effective cART regimen. Lastly, preliminary safety data show acceptable safety and 
tolerability across all Phase 2a arms. Most AEs were Grade 1-2 and were most frequently due to 
an indirect hyperbilirubinemia; the levels seen with BMS-955176 and ATV/r were similar to 
those seen with ATV/r combined with TDF/FTC. The arms containing BMS-955176 and 
unboosted ATV had bilirubin levels that were approximately half of those observed in the arms
containing ATV/r. Last, arms containing BMS-955176 alone did not show elevated bilirubin
levels. Many of these events occurred in subjects who were randomized to an arm containing 
BMS-955176 and ATV. Of the Grade 2-4 related AEs, many were due to headache and an 
increase in hyperbilirubinemia. Many of the AEs of hyperbilirubinemia occurred in subjects also 
receiving ATV.
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Table 1.4.1.3-1:
Phase 2a Baseline Demographics and Characteristics of Subjects 
(Preliminary Results)
Treatment Arm
Subjects
(n)
Median 
age
Male
White
Median 
HIV RNA 
(log10 c/ml)
Median 
CD4 
(cells/mm3)
Part A (Clade B, 10 days monotherapy)
BMS-955176 5 mg
8
43.5
8 (100)
6 (75.0)
4.09
437
BMS-955176 10 mg
8
39
7 (87.5)
7 (87.5)
4.02
539
BMS-955176 20 mg
8
33
8 (100)
8 (100)
3.59
512
BMS-955176 40 mg
8
38
8 (100)
8 (100)
4.03
536
BMS-955176 80 mg
8
31.5
8 (100)
8 (100)
3.82
504
BMS-955176 120 mg
8
37.5
8 (100)
8 (100)
3.84
498
Placebo
12
36
12 (100)
12 (100)
3.98
458
Part B (Clade B, 28 days therapy)
BMS-955176 40 mg + ATV 400 mg
8
32.5
8 (100)
6 (75)
4.04
581
BMS-955176 40 mg + ATV 300 mg + 
RTV 100 mg
8
34
8 (100)
8 (100)
4.45
480
BMS-955176 80 mg + ATV 400 mg
8
31.5
8 (100)
7 (87.5)
4.15
549
Truvada® + ATV 300 mg + RTV 100 mg
4
32.5
4 (100)
4 (100)
4.12
427.5
Part C (Clade C, 10 days monotherapy)
BMS-955176 40 mg
7
35
4 (57.1)
2 (28.6)
4.53
554
Placebo
2
38.5
2 (100)
0 (0)
3.78
304
Table 1.4.1.3-2:
Maximum Decline Log10 HIV-1 RNA (Preliminary Results)
Treatment
Mean
S.D.
Median
Max
Min
Part A (Clade B, 10 days monotherapy)
BMS-955176 5 mg
-0.49
0.217
-0.498
-0.78
-0.22
BMS-955176 10 mg
-1.05
0.351
-0.976
-1.76
-0.64
BMS-955176 20 mg
-1.17
0.645
-1.115
-2.12
-0.13
BMS-955176 40 mg
-1.55
0.352
-1.701
-1.88
-0.93
BMS-955176 80 mg
-1.52
0.257
-1.555
-1.82
-1.04
BMS-955176 120 mg
-1.53
0.478
-1.654
-2.07
-0.83
Placebo
-0.48
0.581
-0.381
-1.46
0.56
Part B (Clade B, 28 days therapy)
BMS-955176 40 mg + ATV 400 mg
-1.89
0.273
-1.858
-2.37
-1.49
BMS-955176 40 mg + ATV 300 mg + RTV 100 mg
-2.22
0.676
-2.202
-3.52
-1.24
BMS-955176 80 mg + ATV 400 mg
-2.3
0.307
-2.228
-2.68
-1.87
Truvada® + ATV 300 mg + RTV 100 mg
-2.41
0.495
-2.39
-3.04
-1.83
Part C (Clade C, 10 days monotherapy)
BMS-955176 40 mg
-1.5
0.439
-1.285
-2.03
-1.04
Placebo
0.12
0.141
0.12
0.02
0.22
The pharmacokinetics of BMS-955176 were assessed in HIV-1 infected subjects in AI468002. 
Overall, exposures to BMS-955176 are approximately 30% to 35% lower in HIV-1-infected 
subjects compared to healthy subjects administered the same doses and formulation of 
BMS-955176. Furthermore, exposures to BMS-955176 increased in a generally linear fashion up 
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to 40 mg, with a less than dose proportional increase in exposures between 40 mg and 80 mg, 
and considerable overlap in exposures between 80 mg and 120 mg.
1.4.2
Background Information on TDF
Tenofovir disoproxil fumarate (TDF) is an analog of the nucleotide adenosine 
5’-monophosphate. TDF inhibits HIV-1 reverse transcriptase and is indicated in combination 
with other ARVs for the treatment of HIV-1 infection. The most common adverse reactions 
include rash, diarrhea, headache, pain, depression, asthenia, and nausea. Clinicians are warned 
about new onset or worsening renal impairment, decreases in bone density, and immune 
reconstitution syndrome. For more information
concerning TDF, please refer to the 
TDF/Viread® SmPC or TDF/Viread® USPI.29
1.4.3
Background Information on DTG
Dolutegravir (DTG) is a HIV-1 integrase strand transfer inhibitor indicated in combination with 
other ARVs for the treatment of HIV-1 infection. The most common adverse reactions of 
moderate to severe intensity include insomnia, fatigue, and headache. Clinicians are warned 
about immune reconstitution syndrome. For more information concerning DTG, please refer to 
the DTG/Tivicay SmPC or the DTG/Tivicay USPI.30
1.4.4
Background Information on ATV 
Atazanavir is a protease inhibitor indicated for use in combination with other ARVs for the 
treatment of HIV-1 infection. The most common adverse reactions include nausea, 
jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral 
neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. Clinicians are warned 
about hyperbilirubinemia, nephrolithiasis, and cholelithiasis. For more information concerning 
ATV please refer to the ATV/Reyataz® SmPC or ATV/Reyataz® USPI.31
1.4.5
Background Information on RTV
Ritonavir is a protease inhibitor indicated in combination with other ARVs for the treatment of 
HIV-1 infection. The most frequently reported adverse drug reactions with RTV alone or in 
combination with other ARVs include diarrhea, nausea, vomiting, abdominal pain, paresthesia, 
rash, and fatigue/asthenia. Clinicians are warned about total cholesterol and triglyceride 
elevations. For more information concerning RTV please refer to the RTV/Norvir® SmPC or 
RTV/Norvir® USPI.32
1.4.6
Drug-Drug Interactions
In AI468001, coadministration of BMS-955176 as a single dose following two doses of 100 mg 
RTV resulted in an approximate 48% increase in BMS-955176 AUC(INF), consistent with 
inhibition of CYP3A4 and/or P-gp. Multiple-dose administration of BMS-955176 with daily 
400 mg ATV and a standard meal for 14 days resulted in a modest (~25%) increase in the 
BMS-955176 AUC(TAU).
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Study AI468005 assessed the two-way interaction between BMS-955176 40 mg (administered as 
an SDD suspension) and TDF at steady state in healthy subjects. Relative to administration of 
each drug alone, neither BMS-955176 nor TDF exposures were meaningfully impacted upon 
coadministration.
Study AI468041 assessed the impact of BMS-955176 80 mg (administered as an SDD 
suspension) on the pharmacokinetics of the components of a combined oral contraceptive 
containing ethinyl estradiol (EE) and norgestimate (NGM). Exposures to both EE and 
norelgestromin (NGMN), the active metabolite of NGM were reduced in the presence of 
BMS-955176. Furthermore, one subject had a serum progesterone level > 300 ng/dL while 
BMS-955176 and the oral contraceptive were concomitantly administered, indicative of 
ovulation and contraceptive failure.
Finally, in vitro data suggest that BMS-955176 may inhibit OATP1B1 and OATP1B3 and 
exposures to substrates of these transporters, such as HMG-CoA reductase inhibitors, may 
increase when co-administered with BMS-955176.
1.5
Overall Risk/Benefit Assessment
The preclinical and clinical safety data demonstrate that BMS-955176 administered at doses in 
this Phase 2b study (120, and 180 mg) should be well tolerated without a major clinically 
relevant impact on safety. Moreover, there have been no identified safety risks from 
completed/ongoing clinical studies to date.
The preclinical toxicology studies demonstrate two potential risks to subjects:
First, BMS-955176 is a selective developmental toxicant. Developmental toxicity (skeletal 
alterations in rats; cleft palate and reduced fetal body weights in mice) were observed in 
embryofetal development studies. In order to address this concern, subjects will be required to 
use two methods of contraception (as described in Section 3.3.1 Inclusion Criteria) and undergo 
routine urine pregnancy testing (as described in the T&E Tables in Section 5.1). Furthermore, 
due to results from Study AI468041 that demonstrates reduced exposures to the components of a 
combination oral hormonal contraceptive containing ethinyl estradiol and norgestimate when 
given concomitantly with BMS-955176, oral hormonal contraceptives cannot be used as a 
method of contraception by WOCBP in this study.
Second, single or repeat oral doses of BMS-955176 were associated with sporadic vomiting in 
dogs and unformed and/or liquid feces in rats and dogs. In rats at 10 mg/kg/day there were 
decreases in body weight and food consumption; in the stomach there was atrophy involving 
both parietal and chief cells, single-cell necrosis and regeneration in the glandular mucosa, and 
modest increases in serum gastrin values. At higher doses (100 mg/kg/day) in rats there were 
additional findings in the intestines (distended jejunum, ileum, and cecum; hyperplasia of the 
crypt epithelium in the jejunum; ulcers and erosions in the cecum; and decreased mucosal cell 
extrusion and increased mucus in the colon). 
Similar gastric changes were seen in dogs. At 20 mg/kg/day there was single-cell necrosis of the 
stomach glandular epithelium. At 3 mg/kg/day gastric changes showed chief cell depletion. 
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At 10 mg/kg/day changes in the stomach included: mucous cell hyperplasia correlating with 
increased thickness macroscopically, parietal cell depletion, single-cell necrosis of glandular 
epithelial cells, and modest increases in serum gastrin values. Unlike the rats, no changes were 
observed elsewhere in the alimentary canal including the gastroesophageal junction and the 
duodenum. There was no evidence of macrocytosis. Measurement of Total Protein and Albumin 
revealed no clinically relevant changes. The stomach histologic findings were BMS-955176 
dose- and duration dependent. In the 1-month studies, vomiting and fecal changes stopped soon 
after dosing cessation, and microscopic lesions in the stomach and/or intestines reversed 
completely within a 2-week treatment-free period. In the 6 month study in rats and the 9-month 
study in dogs, microscopic lesions in the stomach partially recovered after a 1 month treatment 
free period. The NOAEL was 1 mg/kg/day (AUC 64.9 mg•h/mL) in the 9-month study in dogs, 
and was not established in the 6-month study in rats. Investigative studies for gastric toxicity in 
rats and dogs indicated similar findings with both SDD and MC forms, and with no clear 
evidence that the gastric toxicity is a direct local effect of BMS-955176. The mechanism and 
clinical relevance of these gastrointestinal findings is unknown at present (see below).
A Phase 1 study (AI468001) in healthy volunteers evaluated single and multiple doses of 
BMS-955176 for 14-28 days both alone and in certain arms, in combination with ATV or RTV. 
Overall the safety data demonstrated that BMS-955176 was generally safe and well tolerated. 
A Phase 2a (AI468002) study in HIV-1 infected adults evaluated several doses of BMS-955176 
given alone or in combination with ATV RTV for 10-28 days. The preliminary results show 
acceptable safety and tolerability across all arms. There were no deaths, SAEs, or AEs leading to 
discontinuation. There were no clinically relevant changes in vital signs, lab parameters, or 
EKGs. Most of the AEs were Grade 1-2 and were most frequently due to hyperbilirubinemia 
(primarily observed in treatment arms with ATV). Of the GI AEs, most were attributable to 
diarrhea or loose/watery stools. Many of these events occurred in subjects who were randomized 
to an arm containing BMS-955176 and ATV. Of the Grade 2-4 related AEs, many were due to 
headache and an increase in hyperbilirubinemia. Many of the AEs of hyperbilirubinemia 
occurred in subjects also receiving ATV; moreover, the three arms with the highest average total 
bilirubin occurred in subjects receiving both BMS-955176 and ATV. Clinical changes/symptoms 
consistent with the GI findings from dogs and rats (described above) were not seen in the 
preliminary data set from short-term therapy with BMS-955176 in HIV-1 infected adults. 
In this treatment-experienced study population, we estimate GI safety multiples of 2× and 1×, 
(based on NOAEL in 9-month dog study), corresponding to projected human exposures at 
BMS-955176 doses of 120 and 180 mg.
While no clinically relevant GI safety signals have been observed in AI468001 or AI468002, in 
this clinical trial, subjects will undergo routine targeted and complete history/physical exams in 
addition to regular laboratory measurements (including CBC and chemistries). This will initially 
occur more frequently than in standard clinical practice and allow for increased vigilance for any 
potential GI toxicity. Guidance on the evaluation and management of potential GI toxicity is 
outlined in Section 6.7.1.4.
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Subjects in this clinical study will benefit from receiving cART potentially containing 
BMS-955176. Preliminary data from the Phase 2a (Part A, B and C) study show a maximum 
median reduction in HIV-1 RNA (clades B and C) ranging from 1.3 to 1.7 log10 in the dose arms 
estimated to provide similar exposure to those in this current study. When BMS-955716 was 
combined with ATV RTV (Part B) this resulted in maximum median declines in HIV-1 RNA 
ranging from 1.9 to 2.2 log10. These results are generally similar to the antiviral effect 
demonstrated by other classes of ARVs. Thus, BMS-955176 should contribute with other ARVs 
substantially to form an effective cART regimen.
As with any antiretroviral study in HIV-1-infected subjects, there is a risk for the development of 
treatment failure and the development of drug resistance associated mutations to BMS-955176 
and/or other antiretrovirals. However, drug resistance to the maturation inhibitor would not be 
anticipated to result in cross-resistance to any other ARV class, including protease inhibitors.33
Ongoing analysis of preliminary data from the Phase 2a study is evaluating both emergent 
genotypic and phenotypic changes after short term monotherapy with BMS-955176. The use of 
three fully susceptible agents as a part of cART is expected to decrease the probability of 
virologic failure and drug resistance. Initially in this clinical trial, measurement of HIV-1 RNA 
will occur more frequently than in standard clinical practice which will allow for increased 
vigilance for the development of lack of efficacy/resistance. Finally, an analysis for virologic 
futility will occur at Week 24 (see Section 8.4.7).
As described earlier, treatment-experienced adults enrolled in Arms 3-4 may be exposed to a 
subtherapeutic regimen and may be at higher risk for virologic failure and the development of 
resistance. In order to decrease this probability, this clinical trial uses a two-stage design 
whereby enrollment in Arms 3-5 will be dependent upon the results of the Week 24 analyses in 
Stage 1 (whose two Arms contain ATV/r) and Study AI468038. This will minimize the risk of 
virologic failure and resistance to subjects enrolled in Arms 3-4 because clinical data will already 
have been generated using BMS-955176 with ATV/r (Arm 1) in Stage 1.
In-vitro studies show that BMS-955176 is expected to be active against a variety of HIV-1 clades 
albeit with EC50s 2-3 fold less toward HIV-1 clade AE compare to clade B (see Section 1.4.1). 
As described in Section 1.1.1, the only clinical data for BMS-955176 exists in HIV-1 clade B 
and C. The efficacy profile of BMS-955176 in other HIV-1 clades encountered in other 
geographical regions where this multinational Phase 2b trial will be conducted (eg, clae AE in
Thailand) is unknown. To mitigate the risk of randomizing subjects infected with HIV-1 with an 
unknown efficacy profile, the number of subjects with HIV-1 Clade AE will be stratified to 
ensure each treatment are has approximately the same number of HIV-1 clade AE infected 
subjects in their respective Stages and the maximum number of subjects with HIV-1 clade AE 
will be capped at approximately 3 per treatment arm.
Of note, the other ARVs used in this clinical trial have a known and acceptable risk benefit ratio 
and are frequently prescribed to HIV-1 infected adults as a part of standard of care.
Taken together, the clinical data to date show that BMS-955176 has potent antiretroviral activity 
and is generally safe and well tolerated in healthy volunteers and HIV-1 infected adults. These 
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factors should allow subjects to benefit from achieving viral suppression whilst taking a 
generally safe and well-tolerated new antiretroviral; additionally subjects in Arms 1, 3, and 4 
may benefit from a cART regimen that is nucleoside and nucleoside/booster sparing, 
respectively. Specifically, these subjects may benefit from improved bone mineral density, renal 
function, and lipid profiles. The risks, including teratogenicity, GI toxicity, and drug resistance, 
will be appropriately managed by following guidance in the study protocol.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
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BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion.
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented.
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator.
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The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a randomized, active-controlled, staged, open-label clinical trial. Approximately 
200 treatment-experienced HIV-1 subjects will be randomized to one of five treatment arms
(approximately 40 per arm) in a staged fashion.
Randomization will be stratified by HIV-1 Clade (AE versus Other). The number of subjects 
with HIV-1 Clade AE will be capped at a maximum of approximately 3 per treatment arm.
The totality of the data from the Week 24 analysis of Stage 1 and AI468038, including safety, 
efficacy and resistance, will be examined in conjunction with PK/PD modeling to determine if 
Stage 2 of the study will be initiated, and confirm the two doses of BMS-955176 for study in 
Stage 2.
Stage 1:
In Stage 1, subjects will be randomly assigned 1:1 to one of two treatment arms and on Day 1 
will begin dosing with:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:
In Stage 2, subjects will be randomly assigned 1:1:1 to one of three treatment arms and on Day 1 
will begin dosing with: 

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
3.1.1
Screening
The screening period begins with the subject’s signature on the informed consent form (ICF).
The subject is then enrolled via the Interactive Voice Response System IVRS (or its web-based 
equivalent) See Section 4.4.
If the subject meets all eligibility criteria, the subject must be randomized within the 42 day 
screening period.
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3.1.2
Day 1/Baseline Visit
3.1.2.1
Day 1/Baseline Visit for Arms 1 and 2 - Stage 1
In Stage 1, approximately 80 subjects will be randomized 1:1 (approximately 40 per arm) to 
either of the treatment arms containing boosted atazanavir (ATV/r).
On the Day 1 Visit, subjects in Arms 1 and 2 will begin QD dosing with BMS-955176 or TDF, 
each in combination with ATV/r and DTG (see Section 4.5 for additional details of Selection and 
Timing of Dose).

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
3.1.2.2
Day 1/Baseline Visit for Arms 3, 4 and 5 - Stage 2
In Stage 2, approximately 120 subjects will be randomized 1:1:1 (approximately 40 per arm) to 
either of the two BMS-955176 treatment arms containing ATV, or to the TDF Arm.
On the Day 1 Visit, subjects will begin QD dosing with BMS-955176 in combination with ATV 
and DTG, or TDF in combination with ATV/r and DTG (see Section 4.5 for additional details of 
Selection and Timing of Dose).

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r QD 300/100 mg + DTG 50 mg QD
3.1.3
Week 2 Intensive PK Visit
Subjects with anemia, defined as Hemoglobin < 11.0 g/dL, should be excluded from 
participation in the Week 2 Intensive PK Substudy.
Subjects in all arms will have the opportunity to participate in an elective Intensive PK Substudy 
visit at Week 2 (window for visit: Day 12-16). Approximately 60 subjects, 12 subjects from each 
arm, are expected to participate in the substudy; BMS may allow the substudy to over-enroll in 
an effort to have a sufficient number of complete datasets.
The series of 12 blood draws begins with pre-dose (0-hour) blood samples to be collected
approximately 24 hours (20-28 hrs) after the morning doses of study drugs that were taken on the 
day before. Ten more samplings are drawn through the 12-hr time point, with one final sampling 
collected at the 24-hr time point, requiring the subject to either remain overnight in the clinic, or 
to return the next morning; the final 24-hr sample will be collected prior to administration of the 
morning doses of study drugs (See Section 5.5.1).
PK Tools/Job Aids will be provided to assist with the proper sequencing of dosing and blood 
sample collections, as well as the collection of required data.
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3.1.4
Visits Week 4 - 96
Subjects are expected to be treated for the duration of 96 weeks. In each Stage, after Day 1 and 
the optional Intensive PK visit at Week 2, subjects will be required to attend 12 more in-clinic 
study visits over the 96-week treatment period, as follows:

Visits are conducted every 4 weeks from Week 4 through Week 16

Visits are conducted every 8 weeks from Week 24 through Week 48

Visits are conducted every 12 weeks from Week 60 through Week 96
Visits should be scheduled as an interval from the Day 1/Randomizaton date, and within a 
window of 5 days earlier or later.
Visits Week 4 - 24 should be conducted in the morning so that the blood is drawn as a 
pre-morning (pre-AM) dose collection, in order to meet the requirement for Sparse PK 
(see Section 5.5.2). One of these visits should meet the very specific timing requirements as 
outlined in Section 5.5.2.
Telephonic visits will be conducted with each subject at visit Weeks 20, 28, 36, 44, 54, 66, 78,
and 90 to conduct an adherence assessment and to continue retention efforts
3.1.5
Selection of the Continuation Dose of BMS-955176
3.1.5.1
Selection of the Continuation Dose, and the Switch for Stage 1
Once all subjects in Stage 1 have reached Week 24*, BMS will conduct an analysis of efficacy, 
safety, and resistance.
As described in Section 8.4.7, an analysis of Virologic Futility will also occur. If Arm 1 meets 
criteria for Virologic Futility at Week 24, the clinical trial will be terminated.
The Week 24 analysis of Arms 1 and 2, combined with the Week 24 analysis of all Arms in the 
AI468038 study, will be used to select a Continuation Dose of BMS-955176 for Arm 1 in this 
study. Subjects in the BMS-955176 Treatment Arm 1 may subsequently be transitioned to a
selected Continuation Dose.
Subjects in the Arm containing TDF will continue with the TDF treatment regimen.
The assigned backbone will not change.
The result of the analyses from Stage 1 and Week 24 analysis from AI468038 will also trigger 
the start of Stage 2.
* If the Continuation Dose cannot be clearly identified using the Week 24 data, the study 
will continue in original fashion until an analysis of the Week 48 data can be performed 
and the Continuation Dose is selected. If a Continuation Dose cannot be selected based 
upon the Week 24 data, this does not preclude the ability to start recruitment of Stage 2.
After the Continuation Dose is selected, and once all of the logistics (eg, distribution of clinical 
drug supplies, activation of the new portion of the IVRS) have been completed globally, the 
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transition of the subjects in Arm 1 to the Continuation Dose will occur. It is anticipated that this 
transition will occur on or after all subjects have reached Week 48 (the earliest subjects to begin 
study treatment could be well beyond Week 48 when the switch to the Continuation Dose 
occurs).
3.1.5.2
Selection of the Continuation Dose, and the Switch for Stage 2
Once all subjects in Stage 2 have reached Week 24, BMS will conduct an analysis of efficacy, 
safety, and resistance.
As described in Section 8.4.7, an analysis of Virologic Futility will also occur. If a BMS-955176 
dose arm meets criteria for Virologic Futility at Week 24, subjects in said arm will begin dosing 
with the next highest available remaining dose of BMS-955176.
The totality of data from AI468038 and AI468048 (Stages 1 and 2) will be used to select a 
Continuation Dose of BMS-955176 for Arms 3 and 4. Subjects in the BMS-955176 Treatment 
Arms 3 and 4 will subsequently be transitioned to a selected Continuation Dose. It is anticipated 
that this transition may occur on or after all subjects have reached Week 48, or it could occur 
sooner after Week 24.
The assigned backbone will not change.
Subjects in the arm containing TDF will continue with this assigned treatment regimen.
3.1.6
End of the study
The end of the study will occur when the last study visit has been completed, defined as the final 
subject completing their final study visit (expected to be a Week 96 or Early Termination visit).
The study design schematic is presented in Figure 3.1.6-1.
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Figure 3.1.6-1:
Study Design Schematic
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3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug. Study drug will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee 
or through another mechanism at the discretion of BMS. BMS reserves the right to terminate 
access to BMS supplied study drug if any of the following occur: a) the marketing application is 
rejected by responsible health authority; b) the study is terminated due to safety concerns; c) the 
subject can obtain medication from a government sponsored or private health program; or 
d) therapeutic alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Ability to understand and sign a written informed consent form
2. Target Population
a) Antiretroviral treatment-experienced, defined as having documented evidence of having
failed, 1 or 2 regimens that include 2 or 3 classes of ARV (with or without documented 
resistance)
b) Confirmed Plasma HIV-1 RNA 400 copies/mL (First value from investigator; second 
value from screening test)
c) CD4+ T-cell count > 50 cells/mm3
d) Screening genotype/phenotype indicating susceptibility to study drugs (unboosted ATV, 
FC < 2.2; DTG; TDF)
e) Estimated Life expectancy 1 year
f)
Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / 
has not been treated). If re-enrolled, the subject must be re-consented and assigned a new 
PID.
3. Age and Reproductive Status
a) Males and non-pregnant females
b) At least 18 years of age, (or minimum age as determined by local regulatory or as legal 
requirements dictate)
c) Willingness to use approved highly effective methods of contraception (see below) to 
avoid pregnancy (female subjects who are WOCBP and male subjects who are sexually 
active with WOCBP)
d) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
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e) Women must not be breastfeeding
f)
WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug BMS-955176 plus 5 half-lives of study drug BMS-955176
(8 days) plus 30 days (duration of ovulatory cycle) for a total of 38 days post-treatment 
completion.
g) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug BMS-955176
plus 5 half-lives of the study drug BMS-955176 (8 days) plus 90 days (duration of sperm 
turnover) for a total of 98 days post-treatment completion.
h) Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However WOCBP must still undergo 
pregnancy testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as 
listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Male condoms with spermicide34,35

Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirena

For female study subjects who are WOCBP:
Study subjects who are WOCBP cannot use hormonal methods of contraception as 
one of the two methods of contraception because there are data that show a lack of 
effectiveness of systemic hormonal contraceptives in women taking BMS-955176
However, WOCBP can continue to use hormonal contraceptives, if necessary, in 
addition to 2 other non-hormonal methods of contraception (one of which must be 
highly effective)

For female partners of male study subjects (if they are WOCBP):
Hormonal methods of contraception may be used by male subject’s WOCBP partner. 
Female partners of male subjects participating in the study may use hormone based 
contraceptives as one of the acceptable methods of contraception since they will not 
be receiving BMS-955176

Nonhormonal IUDs, such as ParaGard

Tubal ligation
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
Vasectomy

Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence.
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge

Male Condom without spermicide 

Progestin only pills by male subject’s WOCBP partner

Female Condom*
* A male and female condom must not be used together
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Antiretroviral treatment-experienced adults who have failed > 2 ARV regimens
b) Resistance or partial resistance to any study drug
c) Three or more of the following PI mutations, historical or documented: M36I/V, 
M46I/L/T, G48M/V, I54V/L/T/M/A, G73S/A/C/T, V82A/F/T/S/I, or L90M
d) Any major ATV mutations, historical or documented: I50L, I84V/A, N88D/S
e) Any major TDF mutation, historical or documented: K65R or T69ins
f)
Three or more of the following non-accessory thymidine analogue mutations (TAMs): 
M41L, D67N, K70R, L210W, T215Y/F, K219Q/E
g) Any major mutations for raltegravir (RAL), elvitegravir (or clinically suspected INI 
resistance), historical or documented: T66IAK, E92Q, S147G, N155H, Q148H/K/R, 
Y143C/H/R, E157Q
2. Medical History and Concurrent Diseases
a) A new AIDS defining condition diagnosed within the 30 days prior to screening
(see Appendix 2)
b) Any other clinical condition (including but not limited to active substance use) or prior 
therapy that, in the opinion of the Investigator, would make the subject unsuitable for the 
study; unable to comply with dosing requirements; or unable to comply with study visits; 
or a condition that could affect the absorption, distribution, metabolism or excretion of 
the drug.
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3. Physical and Laboratory Test Findings
a) Chronic HBV/HCV (Positive blood screen for HBsAg; Positive blood screen for HCV 
Ab and HCV RNA)
b) ALT or AST > 3 × ULN
c) Alkaline Phosphatase > 5 × ULN
d) Bilirubin ≥ 1.5 × ULN
e) History of decompensated cirrhosis or active decompensated cirrhosis
f)
Hemoglobin < 8.0 g/dL
g) Platelets < 50,000 cells/mm3
h) Estimated eGFR < 60 mL/min (CKD-EPI formula)
i)
Confirmed QT value > 500 msec at Screening or Day 1
j)
Confirmed QTcF value > 470 msec for women and > 450 msec for men at Screening or 
Day 1
k) Confirmed PR Interval > 260 msec (severe first degree AV block) at Screening or Day 1
l)
Confirmed second or third degree heart block at Screening or Day 1
4. Allergies and Adverse Drug Reaction
a) Medications contraindicated for use with investigational/non-investigational study drugs 
(ATV, RTV, DTG, TDF);
or subjects with any known allergies to the 
investigational/non-investigational study drugs (ATV, RTV, DTG, TDF)
b) Current or anticipated treatment with any of the medications listed in Appendix 1, in 
addition to any medications that are contraindicated with ATV, RTV, DTG or TDF
c) Participation in an experimental drug and/or HIV-1 vaccine trial(s) within 30 days prior 
to Screening
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A woman of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/mL to confirm menopause.
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Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is > 40 mIU/mL at any time 
during the washout period, the woman can be considered postmenopausal:

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
Refer to Appendix 1 which details prohibited and precautionary therapies during the study, 
including specifics about the use of antacids and hormonal methods of contraception.
3.4.2
Other Restrictions and Precautions
None.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Repeat non-adherence by the subject with the requirements of the protocol or treatment
(as determined by Investigator in consultation with the BMS Medical Monitor)

Evidence of Hepatitis B or C infection

Confirmed plasma HIV-1 RNA 1000 c/mL after Week 24

Confirmed plasma HIV-1 RNA 200 c/mL after Week 48

Emergence of genotypic and/or phenotypic resistance to any component of the study 
treatment regimen at any time after Screening

Subject requires switching to any other ARV

Development of pDILI (potential drug induced liver injury)
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
Confirmed QTcB or QTcF value > 500 msec

Confirmed second degree (Type II) or third degree AV block at any time during the study
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5 (ie, perform an Early Termination [ET] visit). The only 
exception to this requirement is when a subject withdraws consent for all study procedures 
including post-treatment study follow-up (no such period exists in this study) or loses the ability 
to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
Subjects who discontinue study drug may continue to be followed.
Subject’s contact information will be collected/confirmed throughout the study so that subjects 
who discontinue study drug may continue to be followed for resolution of a pregnancy or SAE.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
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All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for AI468048:
Product Description / 
Class and Dosage Form
Potency
IMP/Non-IMP
Blinded or 
Open Label
Packaging/ Appearance
Storage Conditions
(per label)
BMS-955176 
60 mga
IMP
Open Label
Bottle/
A white to off-white, biconvex, 
oval shaped film coated tablet
Store at 2 - 30°C
Protect from light.
Store in a tightly closed container.
BMS-955176
120 mga
IMP 
Open Label
Bottle/
A white to off-white, biconvex, 
capsule shaped tablet
Store at 2 - 30°C
Protect from light.
Store in a tightly closed container.
Tenofovir (TDF)
300 mg
Non-IMP
Open Label
Various packaging configurations
Refer to label on
container or package insert.
Atazanavir (ATV)
200 mg
IMP
Open Label
Bottle/
Blue cap and blue body
printed with white ink
Store at 15 - 30°C
Store in a tightly closed container.
Atazanavir (ATV)
300 mg
IMP
Open Label
Bottle/
Red cap and blue body,
printed with white ink
Store at 15 - 30°C
Store in a tightly closed container.
Ritonavir (RTV)
100 mg
Non-IMP
Open Label
Various packaging configurations
Refer to label on
container or package insert.
Dolutegravir (DTG)
50 mg
Non-IMP or 
IMP,
depending on 
country 
approval status.
Open Label
Various packaging configurations
Refer to label on
container or package insert.
a The 180 mg dose of BMS-955176 will be constructed with BMS-955176 60 mg + BMS-955176 120 mg
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, investigational product(s) is/are: BMS-955176, ATV, and DTG (in countries 
where DTG has not been approved for use). These products will be supplied.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products.
In this protocol, noninvestigational product(s) is/are: TDF, RTV, and DTG (in countries where 
DTG is approved for use). These products will be supplied.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
4.4
Method of Assigning Subject Identification
At the start of the screening period, the investigative staff will call the Assignment Center via an 
Interactive Voice Response System ([IVRS], or its web-based equivalent) designated by the 
sponsor to enroll the subject and to obtain a subject patient identification number (PID).
For subjects who meet the protocol eligibility criteria, the investigative staff will call the IVRS 
and subjects will start treatment.
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Subjects will be randomly assigned in the staged fashion to one of the treatment arms, and 
stratified by HIV-1 Clade (AE versus Other), as described in Section 3 and as outlined in the 
AI468048 Study Schematic Figure 3.1.6-1.
Note: All efforts should be made to limit the possibility of randomizing subjects that do not start 
treatment. If a subject is randomized but does not receive study medication, the BMS study team 
must be notified immediately.
4.5
Selection and Timing of Dose for Each Subject
Subjects will be randomized into the treatment arms in a staged fashion described in Section 3.1.
Stage 1:
In Stage 1, subjects will be randomly assigned 1:1 to one of two treatment arms and on Day 1 
will begin dosing with:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:
In Stage 2, subjects will be randomly assigned 1:1:1 to one of three treatment arms and on Day 1 
will begin dosing with:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
4.5.1
Instructions for Dose Administration
4.5.1.1
General Instructions

Subjects should administer doses of each drug from only one bottle at a time, until that bottle 
is empty, before another bottle may be opened. 

Subjects will be required to complete Dosing Diaries so that drug administration can be 
accurately accounted. It is important that sites provide instructions to subjects for completion 
and obtain their acknowledgment that doing so provides critical information for the clinical 
trial.

Dosing times (and study appointment times) must be carefully considered through Week 24 
due to the requirements of the PK collection outlined in Section 5.5.
4.5.1.2
Specific Dosing Instructions for Initial Treatment Arm Assignment
In the morning, with a meal, subjects will take the following:

Arm 1: One pill each from bottles BMS-955176 120 mg, ATV, RTV, and DTG

Arm 2: One pill each from bottles TDF, ATV, RTV and DTG
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
Arm 3: One pill each from bottles BMS-955176 120 mg, DTG, and two pills from bottle
ATV (the unboosted dose of ATV is 400 mg, achieved by 200 mg x 2)

Arm 4: One pill each from bottles BMS-955176 60 mg, BMS-955176 120 mg and DTG, and 
two pills from bottle ATV (the unboosted dose of ATV is 400 mg, achieved by 200 mg x 2)

Arm 5: One pill each from bottles TDF, ATV, RTV and DTG
4.5.2
Dose Modifications
No dose adjustments or changes in intake frequency are allowed for any of the assigned study 
drugs in the protocol, except for the unique case of treatment-limiting renal toxicity which limits 
the use of the TDF. In the event of treatment-limiting renal toxicity, dose interval adjustments for 
TDF are permitted according to the local package insert/label, and only after the completion of 
the Week 2 Intensive PK optional Visit, if the subject is inclined to participate.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment Adherence to the treatment regimen will be critical to the conduct of this study. 
Adherence will be evaluated by the investigative staff at every treatment visit (including 
telephone contact visits) through interviews with the subjects and through examination of 
returned medication. It is expected that site staff attempt to have subjects maintain 90% 
treatment compliance or greater. Subjects should be instructed to bring all unused study 
medication back in the original container to each visit. Site staff are required to review Dosing 
Diaries completed by the subject, and to reinforce their use.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request
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
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (AI468048)
Procedure
Screening Visit
(42-day screening period)
Notes
Eligibility Assessments
Informed Consent
X
Call IVRS to Enroll the subject; PID assigned
X
Inclusion/Exclusion Criteria
X
Medical History
X
Includes historical CDC Class C Events
Non-Laboratory Safety Assessments
Full Physical Examination
X
See Section 5.3.1 for requirements
Vital Signs & Physical Measurements
X
See Section 5.3.1 for requirements
Pre-treatment events
X
Only CDC Class C events with onset during the Screening period
Serious Adverse Events Assessment
X
All SAEs that occur after the ICF has been signed should be reported
ECG
X
See Section 5.3.4 for requirements
Pregnancy Test
X
WOCBP
For females under age 55, an FSH level must be on record to confirm she 
is not a WOCBP if pregnancy testing is not being performed.
If positive urine, request serum hCG quant. on lab requisition.
Laboratory Assessments
Fasting Chemistry and Lipid Panel
X
Fasting overnight
Hematology
X
Urinalysis
X
Plasma HIV-1 RNA
X
This is the confirmatory HIV-1 RNA
(The first value is provided by the PI)
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Table 5.1-1:
Screening Procedural Outline (AI468048)
Procedure
Screening Visit
(42-day screening period)
Notes
CD4+ and CD8+ T-cell count
X
HBV Surface Antigen
X
HCV Serology
X
Urine toxicology (drugs of abuse)
X
Could aid in the selection of appropriate study candidates.
Pharmacodiagnostic (PDx) samplea
X
Plasma collection to be banked for potential future use in development of 
novel predictive assay(s)
Resistance Testing
(HIV-1 Drug Resistance)
PhenoSense GT Plus Integrase
X
Complete set of test results may take up to 4 weeks.
PhenoSense Gag
X
Next Generation Seq. - Qs Gag
X
Exploratory Resistance
(HIV-1 Drug Resistance)
X
Molecular analysis at BMS WFD Discovery of baseline resistant samples 
and baseline sensitive controls in cases of subsequent on-treatment 
virologic failure
a By definition, a pharmacodiagnostic sample (PDx) is a pre-treatment test to determine whether or not a patient is likely to respond to a drug (ie, a predictive 
test). Based on the results of clinical studies with BMS-955176, BMS may have to develop a PDx assay. Thus, PDx samples obtained at Screening in this 
study would be used for that sole purpose.
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Eligibility Assessments
Inclusion/Exclusion Criteria
X
Non-Laboratory Safety Assessments
Full Physical Examination
WK 12, 24, 48, 96/ET
See Section 5.3.1 for requirements
Targeted Physical Examination
X
WK 4, 8, 16, 32, 40, 60, 72, 84
See Section 5.3.1 for requirements
Vital Signs & Physical 
Measurements
X
X
See Section 5.3.1 for requirements
Adherence Assessments
X
X
Including review of Dosing Diaries
Pre-treatment Events
X
See Table 5.1-1
Adverse Events Assessments
X
X
X
Serious and Non-serious AEs
Concomitant Medications
X
X
X
See Section 5.3.3
ECG
X
WK 4, 12, 24, 48, 96/ET
See Section 5.3.4 for requirements
Pregnancy Test
X
X
X
For females under age 55, an FSH 
level must be on record to confirm 
she is not a WOCBP if pregnancy 
testing is not being performed.
If positive urine, request serum 
hCG quant. on lab requisition.
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Provide WOCBP with Home 
Pregnancy test kit(s) to be used 
during the in-clinic visit interval
WK 16, 24, 32, 40,
48, 60, 72, 84
Provide One Kit at Weeks 16 - 40
Provide Two Kits at Weeks 48 - 84
WOCBP subjects perform test Q4 
weeks at home and report results to 
site.
Laboratory Assessments for Safety and Efficacy and Other Endpoints
Fasting Chemistry
X
X
Fasting overnight
Fasting Lipid Panel
X
WK 4, 12, 24, 48, 96/ET
Fasting overnight
Hematology
X
X
Urinalysis
X
X
Fractional Excretion of Phosphorous 
(FePO4)
(Urine creatinine and phosphorus, 
Plasma creatinine and phosphorus)
X
WK 48 and 96/ET
Plasma HIV-1 RNA
X
X
X
If collecting an HIV-1 RNA at an 
UNSCHEDULED visit, also collect 
samples for Resistance and 
Exploratory Resistance Testing
CD4 and CD8 T-cell counts
X
X
HBV Surface Antigen
WK 48 and 96/ET
HCV Serology
WK 48 and 96/ET
Positive HCV Ab will reflex to 
HCV RNA
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Resistance Testing
(HIV-1 Drug Resistance)
PhenoSense GT Plus Integrase
X
X
Samples stored and tested if needed
(ie, analyses of subjects if deemed 
clinically relevant)
See Section 5.4.2.2
PhenoSense Gag
X
X
Next Generation Seq. - Qs Gag
X
X
Exploratory Resistance
(HIV-1 Drug Resistance)
X
X
Samples stored and tested
retrospectively if needed (ie,
exploratory analyses for subjects if 
deemed clinically relevant)
Intensive PK sample collection
X
Use of PK Tools for data collection 
recommended.
See Section 5.5.1 for requirements
Sparse PK sample collection
WK 4, 8, 12, 16, 24
See Section 5.5.2 for requirements
Bone Biomarkers
(P1NP and CTX)
X
WK 12 and 24/ET
Serum collection
Renal Biomarkers
(2-microglobulin and creatinine)
X
WK 48 and 96/ET
Urine collection
Backup Serum and Plasma Sample
X
X
Samples stored and tested if needed
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Outcomes Measures
EQ-5D-3L Form
X
WK 12, 24, 32, 40, 48,
60, 72, 84, 96
Health Outcomes Questionnaire
FAHI Form
X
WK 12, 24, 32, 40, 48,
60, 72, 84, 96
Functional Assessment of HIV 
Infection
Clinical Drug Supply
Call IVRS to Randomize
X
Dispense Study Drug
X
X
There is no dispensation at Week 96 
or ET.
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value). The Screening Period for this study is 42 days.
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultations 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant (eg, a previously failed inclusion criterion).
Rescreening is different than Retesting. Rescreening is the process of Re-enrollment and requires 
that all procedures be repeated in an entirely new screening period. Rescreening will also be 
allowed. If it is clinically reasonable, and upon Investigator assessment (and in consultation with 
the BMS Medical Monitor, if necessary), a subject may be rescreened multiple times during the 
entire course of the enrollment period. Therefore, subjects may be Rescreened, if, in the opinion 
of the Investigator, a current clinical outlook of the subjects seems favorable for study inclusion 
(and if the patient never received study medication in this trial).
The assigned patient identifier (PID) for the subject must be Screen Failed in the IVRS. A new 
call must be made to the IVRS for the assignment of a new PID for the subject, and all Screening 
parameters must be done again in reference to the new PID (See Section 3.3.1, Inclusion 
Criteria 2f). Subject must also be re-consented with the new PID.
5.2
Study Materials
The sponsor will provide each investigative site with the following:

BMS-955176 Investigator Brochure (IB) and any relevant safety addenda or updates

Protocol and any Amendments to the Protocol

Instructions for completing electronic Case Report Forms (eCRFs)

Laboratory Manual from the central laboratory

ECG Machines and manual

IVRS Worksheets to complete when calling the IVRS center to enroll, randomize, and 
discontinue subjects

Patient-reported Outcomes Questionnaires: EQ-5D-3L Health Outcome Questionnaire, FAHI 
(Functional Assessment of HIV Infection)

PK Tools/Job Aids that may be used for detailed instruction about the PK visits, and as a 
comprehensive source for documents of date/times of dosing and blood sampling

Dosing Diaries

Completion by subjects is required
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
Should include daily dose of study medications administered by subject, modified or 
missed

Site staff should review the diaries with the subject at each visit, and, in combination with 
detailed questioning, should be able to provide comprehensive information in the case 
report form, noting discrepancies in the subject’s file. Dosing Diaries should be 
maintained in the subject’s study file.
5.3
Safety Assessments
The investigative team should follow the protocol-specified scheduled of safety-related 
measurements. Only data for the procedures and assessments specified should be submitted to 
BMS on the case report form. Additional procedures and assessments may be performed as part 
of standard of care, however, data for these assessments should remain in the subject’s medical 
record and should not be submitted to BMS, unless specifically requested (ie, as part of an SAE).
5.3.1
Vital Signs and Physical Examinations
The schedule of vital signs, physical examinations, and targeted physical examinations is 
provided in Section 5.1 (Flow Chart/Time and Events Schedule). Vital signs include heart rate, 
blood pressure, respiration rate, and temperature and should be measured after the subject has 
been sitting/resting for at least 5 minutes. Physical measurements include height and weight. 
Targeted physical examinations will include examination of the heart, lungs, skin, abdomen, any 
symptomatic organ system, and general appearance.
5.3.2
Adverse Events
Subjects will be closely monitored throughout the study for any new or ongoing HIV-related 
diagnoses (Appendix 2) and/or adverse events. CDC Class C events that occur from the 
Screening Visit through Day 1 (prior to dosing), will be recorded as Pre-treatment Events. All 
events that occur after dosing on Day 1 will be recorded on the appropriate Adverse Event eCRF. 
Additional information on Adverse Events is provided in Section 6.
5.3.3
Concomitant Medication Assessment
All medications taken from the Screening Visit throughout the duration of the study will be 
reported. In addition, any prior therapy with antiretroviral drugs will be reported
(See Appendix 1 for Prohibited and Precautionary Therapies).
5.3.4
Electrocardiograms
The schedule of electrocardiograms (ECGs) is provided in Section 5.1 (Flow Chart/Time and 
Events Schedule). ECG machines will be provided by a central vendor who will also perform the
read/interpretation of the output.
5.4
Efficacy Assessments
5.4.1
Primary Efficacy Assessment
The primary assessment for efficacy is HIV-1 RNA through Week 24.
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5.4.1.1
Guidelines for Confirmatory Testing of Plasma HIV-1 RNA and 
Resistance testing
A confirmatory HIV-1 RNA viral load should be obtained when:

HIV-1 RNA 40 c/mL if prior suppression 40 c/mL, or

> 1 log10 c/mL increase in HIV-1 RNA at anytime above nadir level where nadir is 
40 c/mL
All efforts should be made to collect this sample within 2-4 weeks from the collection of the 
original sample.
When collecting a blood sample for HIV-1 RNA testing at an Unscheduled visit, samples should 
also be collected for the sets of Resistance and Exploratory Resistance Tests, so that the samples
are available should resistance testing be required or deemed necessary based on the result of the 
HIV-1 RNA test.
Table 5.4.1.1-1:
Management of Detectable HIV-1 RNA, based on Confirmed 
(2-4 weeks from original sample) or Consecutive HIV-1 RNA Resulta
Day 1 through Week 24
40 - 399 c/mL
Reinforce Adherence
400 c/mL
Consider the need for resistance testing, in consultation with BMS Medical Monitor.
Consider possible discontinuation of subject, in consultation with BMS Medical Monitor, and/or 
reinforce adherence.
After Week 24 through Week 48
40 - 399 c/mL
Reinforce Adherence
400 - 999 c/mL
Resistance testing will be performed.
If resistance has developed, subject must be discontinued.
If resistance has not developed, consider possible discontinuation of subject, in consultation with 
BMS Medical Monitor, and/or reinforce adherence.
1000 c/mL
Resistance testing will be performed.
Regardless of result of resistance tests, subject must be discontinued (see Section 3.5).
After Week 48
< 200 c/mL
Reinforce Adherence
200 c/mL
Subject must be discontinued (see Section 3.5). 
If 400 c/mL, consider the need for resistance testing, in consultation with BMS Medical 
Monitor.
a When discontinuation is required or otherwise warranted and resistance results are needed, subject may continue 
on study medication/on study until resistance testing results are available.
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5.4.1.2
Protocol Defined Virologic Failure
Protocol Defined Virologic Failure (PDVF) is defined by a subject meeting one of the following 
three criteria:
1) Confirmed > 1 log10 c/mL increase in HIV-1 RNA at anytime above nadir level where nadir 
is 40 c/mL
2) Confirmed HIV-1 RNA 400 c/mL after Week 24
3) Failure to suppress last HIV-1 RNA to < 400 c/mL within Week 24, 48, or 96 week snapshot 
window
In addition to the clinical management outlined in section 5.4.1.1, samples meeting criteria for 
PDVF will also be sent for resistance and exploratory resistance testing.
5.4.2
Secondary Efficacy Assessments
5.4.2.1
CD4+ and CD8+ T-Cells
CD4+ and CD8+ T-cells counts and percentages will be assessed using flow cytometry. The 
schedule of assessments is provided in Section 5.1 (Flow Chart/Time and Events Schedule). 
Procedures for samples collection and processing are provided in the central clinical laboratory 
manual.
5.4.2.2
Drug Resistance Testing
Plasma samples for viral drug resistance testing will be collected at Screening for all subjects and 
the HIV-1 drug resistance genotype will be analyzed to rule out resistance to any component of 
the study regimen or specific resistance mutations as outlined in Section 3.3.2, Exclusionary 
Criteria. At subsequent visits, samples for emergent drug resistance testing (both genotypic and 
phenotypic) will be collected and stored to be as outlined in Section 5.4.1.
5.5
Pharmacokinetic Assessments
It is extremely important to record the exact dose and time of the dose(s) taken the day prior to 
the visit/collection, and the exact date and time of the sample collection, even if drawn slightly 
off-schedule.
5.5.1
Intensive Pharmacokinetic Assessment
A subset of subjects (about 12 subjects per treatment group) will participate in an optional 
Intensive PK assessment at Week 2 (window Day 12-16).
Intensive PK samples collection in this study will provide for the assessment of BMS-955176, 
ATV, RTV, and DTG to support the secondary objective (to compare steady-state exposures of 
DTG when co-administered with BMS-955176 and ATV/RTV to DTG when co-administered 
with TDF and ATV/RTV).
Intensive PK sampling begins with a morning pre-dose (0 hour) sampling, ie, prior to the 
administration of the morning doses of the study drugs on the day of the visit. The sampling 
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should also begin 24 hours after the morning doses of the study drugs were taken the day prior to 
the visit.
The subsequent 11 time points include samplings through Hour 12, with the last sample collected 
at Hour 24. The subject will either stay overnight or will return to the clinic so that the final 
sample can be collected at Hour 24.
It is critical to capture the exact date and time of each PK sample collection, even if drawn 
slightly off-schedule. There is no specified collection window end for which any one time point 
should be abandoned as the schedule progresses. If a sample collection time point is missed/late 
and the next collection time point has not yet been reached, collect the missed time point, and 
record the exact time of that collection, then get back on track for the next time point/on-time 
collection.
Table 5.5.1-1 lists the sampling schedule to be followed for the assessment of intensive 
pharmacokinetics. Further details of PK blood collection and sample processing will be provided 
in the central clinical laboratory manual.
Table 5.5.1-1:
AI468048 Intensive Pharmacokinetic Sampling Schedule at Week 2
Time 
(Event)
Time 
(Relative to Dosing)
Hour: Min
PK
Blood Sample
Study Week 2
(window Day 12-16)
0 (morning pre-dose)
00:00
X
1 Hr
01:00
X
2 Hr
02:00
X
2.5 Hr
02:30
X
3 Hr
03:00
X
4 Hr
04:00
X
4.5 Hr
04:30
X
5 Hr
05:00
X
6 Hr
06:00
X
8 Hr
08:00
X
12 Hr
12:00
X
24 hr (morning pre-dose)
24:00
X
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5.5.2
Sparse Pharmacokinetic Assessments
All subjects will provide Sparse PK samples (as part of the regular blood collection) for the 
assessment of BMS-955176, ATV, RTV and DTG at visit Weeks 4- 24.
The visits Week 4 - 24 would need to be performed in the morning: Sparse samples must be 
collected as morning pre-dose (0 hour) samplings, ie, drawn prior to the morning doses taken on 
the day of the visit. 
Table 5.5.2-1:
AI468048 Sparse Pharmacokinetic Sampling Weeks 4 - 24
Time 
(Event)
Time 
(Relative to Dosing)
Hour: Min
PK
Blood Sample
Weeks 4 - 24
0 (morning pre-dose)
00:00
X
Of the five visits (Week 4 - 24), it is requested that the following guidelines are followed:
At any one visit Week 4 through Week 24, perform the blood collection for the visit as a 
pre-AM dose sampling that is 24-hours post-morning dose, ie, 24 hours after the morning 
doses of the study drugs were taken the day prior (20-28 hours) 
At the remaining four visits Week 4 through Week 24, the pre-AM dose blood collections may 
be done without any specific consideration to timing of previous dose administration, though 
it is critical that the exact date and time of the morning doses of study drug taken the day 
prior be accurately reported to the site
PK Samples need to be tested on an ongoing basis prior to the Week 24 database lock and 
analysis.
5.6
Biomarker Assessments
In this study, BMS is confirming the safety of BMS-955176 demonstrated in the Phase 2a study 
to date. The proposed sample population of treatment-experienced adults in Arms 3, 4, and 5, 
will provide a representation of the potential benefits of BMS-955176 on nucleoside and RTV 
based toxicities of interest (ie, renal toxicity, bone mineral density, and dyslipidemia): Arms 3 
and 4 relative to Arms 1, 2, and 5.
Specifically, to evaluate for renal toxicity we will evaluate clinically relevant parameters and 
biomarkers for glomerular and tubular toxicity, which may include but are not limited to: 
fractional excretion of phosphorous and urinary β2-microglobulin/creatinine, in all available 
subjects. To evaluate for bone-related toxicity, clinically relevant bone biomarkers for both 
formation and resorption will be evaluated in all available subjects. These may include but are 
not limited to: N-terminal Propeptide of Type 1 procollagen (P1NP) and Cross-linked 
C-telopeptide of Type 1 collagen (CTX). The bone and renal biomarkers will be collected and 
measured at time points specified in Table 5.1-2 Additionally, back-up plasma and serum 
samples (at Baseline, Week 24, and Week 48) will be obtained for potential future evaluation of 
the safety of BMS-955176.
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Samples will be collected at the screening visit for HIV-1 Gag sequencing, phenotypic 
susceptibility (PhenoSense Gag) and potential pharmacodiagnostic analysis as specified in Table 
5.1-1. These samples may be analyzed, if deemed clinically relevant, as a predictive marker of 
clinical response.
Any remaining blood and urine specimens that are available after completion of the designated 
analyses may be used in the future for identification of potentially predictive or 
pharmacodynamic markers of study drug activity or to enhance the understanding around disease 
biology, except where prohibited by local laws or regulations.
5.7
Outcomes Research Assessments
Increases in CD4 counts and avoidance of opportunistic infections and other AIDS-defining 
illnesses have been shown in many studies to improve health related quality of life (HRQoL). To 
help assess whether use of BMS-955176 will result in a better quality of life outcome, both a 
disease specific quality of life assessment and a generic quality of life assessment will be 
administered. Disease specific instruments are more sensitive to disease specific changes in 
quality of life and are more likely to show improvement with new interventions. The generic 
instruments are needed because Health Technology Authorities often require use of these 
instruments for cost-effectiveness modeling.
The Functional Assessment of HIV (FAHI) is the disease specific instrument that will be used. 
The FAHI evaluates physical well-being, functional and global well-being, emotional 
well-being/living with HIV, social well-being and cognitive functioning. It yields a total score 
and individual subscale scores.
The EQ-5D-3L is the generic instrument that will be used. The EQ-5D-3L includes two parts: the 
EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L 
descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some 
problems, extreme problems. The EQ VAS records the respondents’ self-rated health on a 
100 point, vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable health 
state’ and ‘Worst imaginable health state.’
5.8
Other Assessments 
We will obtain back-up plasma and serum samples for current/future evaluation of the efficacy, 
safety and tolerability of BMS-955176. 
Should any new safety signal develop during the course of the ongoing analysis of the Phase 2a 
trial, appropriate measures for evaluation and management will be incorporated into the design 
of the Phase 2b trial via a protocol amendment.
5.9
Results of Central Assessments
The following describes the centrally assessed parameters and the timing with which they will be 
shared with investigators, if pertinent. Some parameters are relevant to ongoing subject 
management during the study and will be provided to the site for such purpose, while others are 
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not relevant to subject management during the study and results may only be shared in a 
summarized way at the end of the study.

Samples sent to the central lab vendors for safety and efficacy assessments and that are tested 
real time will be provided to the sites as soon as results are available

The results of the read of each ECG will be sent to the site by the central ECG vendor as 
soon as results are available

Samples collected on-treatment for resistance testing will be tested if deemed clinically 
relevant (eg, if the development of resistance is suspected). If tested, results will be reported 
to the site

Other samples (including but not limited to biomarker assessments, exploratory resistance, 
pharmacodiagnostics) may not be tested immediately, and may only be tested if deemed 
clinically relevant. Results may be suppressed from laboratory reports and may not be 
provided to the sites

Individual PK results will not be reported to the site; the overall PK assessments will be 
included in the CSR

Individual assessments of the Outcomes research will not be reported to the site; the overall 
Outcomes assessments will be included in the CSR
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs).
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6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above).
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization). Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must
be handled as
SAEs. 
(See Section 6.1.1 for reporting pregnancies).
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies:

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason)

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
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6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing.
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies, must be reported to BMS 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on 
a Pregnancy Surveillance Form (electronic or paper forms). The preferred method for SAE data 
reporting collection is through the eCRF. The paper SAE/pregnancy surveillance forms are only 
intended as a back-up option when the eCRF system is not functioning. In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
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6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours and in accordance with SAE reporting procedures 
described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
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The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important.
All occurrences of overdose must be reported as an SAE (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury in HIV-1 mono-infected subjects is defined as:
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic
6.7
Other Safety Considerations
Any 
significant 
worsening
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
6.7.1
Toxicity Management
6.7.1.1
Management of Elevations in Liver Transaminases
The following Table 6.7.1.1-1 summarizes the management of elevations in liver transaminases:
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Table 6.7.1.1-1:
Management of Elevations in Liver Transaminases Grade 
Level of AST or ALT Recommendationsa
Grade
Recommendation
Grade1
None
Grade 2
none
Grade 3
Confirm elevation, evaluate for potential causes (including but not limited to alcohol or 
other substance abuse, concomitant medications, reactivation of existing or de novo 
infection with hepatitis viruses) consult with BMS Medical Monitor or designate as soon as 
possible.
Grade 4
Interrupt all study medications, evaluate for potential causes (including but not limited to 
alcohol or other substance abuse, concomitant medications, reactivation of existing or de 
novo infection with hepatitis viruses), monitor values frequently and consult with BMS 
Medical Monitor or designate as soon as possible. If Grade 4 is deemed related to study 
medication the subject must be discontinued from the study. Otherwise, if reinstitution of 
study therapy is considered, please obtain approval from the BMS Medical Monitor or 
designate.
a If persisting (> Grade 1/2), evaluate for alternative etiologies, including alcohol use and viral hepatitis
6.7.1.2
Management of Renal Toxicity
Serum phosphate levels and creatinine clearance (CrCl; CCL: as calculated by the Cockcroft 
Gault Equation [see Appendix 4] or eGFR) should be monitored and managed as described in the 
Viread local package insert/label.29 Dose interval adjustments of TDF (Viread) are permitted, as 
described in Section 4.5.2.
6.7.1.3
Management of Hyperbilirubinemia
Most patients taking ATV experience asymptomatic elevations in indirect (unconjugated) 
bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). Hepatic transaminase 
elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. Dose 
modification of ATV is not permitted. Subjects who experience unacceptable jaundice/scleral 
icterus should be discussed with the BMS Medical Monitor or designate to determine if subjects 
are to be discontinued from study. The investigator must contact the BMS Medical Monitor or 
designate prior to discontinuing any subject due to hyperbilirubinemia.
6.7.1.4
Gastrointestinal Toxicity Evaluation and Management Plan
Pre-clinical toxicology studies in rats and dogs (see Section 1.4.1.2) have suggested a potential 
for GI related toxicity with BMS-955176. This section provides general guidance to the 
Investigator on the evaluation and management of primarily upper gastrointestinal symptoms. 
The Investigator may contact the Medical Monitor to discuss evaluation and management 
(including interruption of ARVs or discontinuation of a subject) of any GI symptoms throughout 
the trial.
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Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the foundation of proper 
evaluation and management. The following are potential manifestations of some GI 
clinical syndromes that may occur (possibly in combination) during the clinical trial. 
Nausea and Vomiting
The investigator should attempt to identify the etiology of these symptoms (and whether it 
is intraperitoneal, extraperitoneal, medication related, infection related, or due to a 
metabolic disorder).36 Medications can cause nausea and vomiting acutely. 
Dyspepsia
The Investigator should identify the presence of red flags (odynophagia, unexplained 
weight loss, recurrent vomiting, GI bleeding, jaundice, palpable mass or adenopathy, or 
family history of GI malignancy). Symptoms of dyspepsia could include early satiety, 
bloating, or belching. Additionally, atypical symptoms of dyspepsia could include: 
pharyngitis, asthma, bronchitis, hoarseness, chest pain, or abdominal pain. 
Ulcerative Disease
Symptoms suggestive of ulceration often are intermittent over a period of weeks to months 
and may be relieved by eating or antacid use;37 penetrating ulcers become more acute 
with localized pain and may not improve with food.38 The development of perforation 
may be indicated by severe diffuse abdominal pain. 
Other Clinical 
Syndromes
Additional diagnostic criteria for other GI disorders potentially encountered in the clinical 
trial are available elsewhere.39
PHYSICAL 
EXAMINATION
Physical examination should complement elements obtained from the history37
Acutely, the investigator may assess for signs of intravascular volume depletion 
(eg, orthostasis) and/or aspiration of vomitus as appropriate. Abdominal tenderness 
and guarding may indicate inflammation. The presence of fecal blood can indicate 
mucosal damage (eg, from an ulcer). Complete evaluation of dyspepsia should 
include an oral examination (poor dentition or pharyngeal erythema) and lungs for 
wheezing. 
DIAGNOSTIC 
EVALUATION AND 
MANAGEMENT
A major goal in the diagnostic evaluation of a subject with upper GI symptoms is to 
quickly arrive at a final diagnosis without exposing the subject to unnecessary 
(invasive) testing; Investigators should exercise good clinical judgment38 in this 
regard. A major goal of therapy is directed at correcting the underlying identifiable 
medical or surgical abnormalities. Consultation (eg, gastroenterologist) is 
recommended as clinically indicated.
Grade 1 symptoms
Subjects may be treated symptomatically. If subjects develop dyspepsia alone, generally 
only limited and direct diagnostic testing should be performed.37 If the subject has 
dyspepsia they should limit alcohol, caffeine, chocolate, tobacco, other contributing 
concomitant medications (eg, NSAIDs) and eating directly before bedtime. A variety of 
OTC medications are available to address constipation and diarrhea as indicated. Please 
refer to Appendix 1 for Prohibited and Precautionary Therapies.
Grade 2 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically indicated):

Serum chemistries and assessment of hemoglobin if not recently performed. 

Testing for Helicobacter pylori

Serologies (eg, celiac disease) 

PCR for viruses (eg, CMV)

Iron panel or Vitamin B12 level
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Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
For subjects who develop dyspepsia or are infected with H. pylori the use of H2 
antagonists, PPIs, Sucralfate, and antacids are prohibited (see Appendix 1 Prohibited 
Medications). If such therapy is required, discontinuation from the trial is necessary. 
The use of antiemetic’s (eg, Prochlorperazine) can be utilized as indicated. Management 
should be targeted at addressing the underlying pathology.
Grade 3 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically indicated):

The testing outlined above in Grade 2

A fasting serum gastrin level can be obtained in cases of known ulcers refractory to 
therapy, a family history of the disease, or when surgery is required; of note, H. pylori
can increase gastrin levels.38

A barium swallow to detect ulcers 

CT to identify gastrointestinal inflammation and a penetrating or perforated ulcer. 

Upper endoscopy with biopsy as indicated in order to evaluate dyspepsia further (eg,
mucosal injury, new onset unexplained dyspepsia in subjects > 55 y/o, or the presence 
of red flags).
Management should be targeted at addressing the underlying pathology.
Grade 4 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically indicated):

The testing outlined above in Grade 2 and Grade 3

An acute abdominal series

If a perforated ulcer is clinically suspected, surgical consultation may be necessary
Initial management can include correction of hemodynamic and electrolyte abnormalities 
as clinically indicated. After stabilization, management should be targeted at addressing 
the underlying pathology.
a For Grade 2-4 symptoms if any ARV is thought to have a direct causal relationship to the patient’s 
gastrointestinal symptoms, the Investigator should consider discontinuing the subject from the study and 
performing an evaluation/management plan incorporating elements above. The Investigator can consider 
interruption of the potential offending ARV(s) but must balance this with the increased probability of 
development of viral resistance/lack of efficacy. As stated above, prior to discontinuing the subject from the 
study, attempts should be made to discuss with the BMS Medical Monitor unless the safety of the subject is 
acutely at risk.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This is an estimation study, without statistical testing, and hence there are no power 
considerations.
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It is expected that response rate for the primary endpoint for all five arms will be somewhere 
around 80%. With this response rate, and 40 subjects per arm, an exact 95% confidence interval 
would run from roughly 64% to 91%.
8.2
Populations for Analyses
The following definitions are used in this document:

Enrolled subjects: Subject who signed an informed consent form and were assigned a 
Patient Identification number (PID);

Randomized subjects: Enrolled subjects who received a treatment assignment from the 
IVRS;

Treated subjects: Randomized subjects who received at least 1 dose of BMS-955176 or 
TDF. 

Modified Intent to Treat Analysis Set: All randomized subjects who received at least 
1 dose of BMS-955176 or TDF (this is the same as all treated subjects)

Observed analysis set: A collection of subjects that have data within an interval of 
interest.
8.3
Endpoints
8.3.1
Primary Endpoint(s)Stage 1 and Stage 2
The primary endpoint for Stage 1 and Stage 2 is the proportion of subjects with plasma HIV-1 
RNA < 40 c/mL at Week 24. This will be assessed with the FDA snapshot algorithm. This uses 
the last on-treatment plasma HIV-1 RNA measurement, within an FDA-specified visit window, 
to determine response. 
8.3.2
Secondary Endpoint(s)

The antiviral efficacy will be determined by the proportion of subjects with plasma HIV-1 
RNA < 40 c/mL at Weeks 48 and 96 using the FDA snapshot algorithm

The antiviral efficacy will also be assessed by the proportion of subjects with plasma HIV-1 
RNA < 200 c/mL at Weeks 24, 48 and 96 using the FDA snapshot algorithm approach with 
positive response defined as HIV-1 RNA < 200 c/mL

The emergence of HIV drug resistance among samples sent for drug resistance testing will be 
assessed using the most recent version of the IAS-USA list of HIV-1 drug resistance 
mutations

Changes from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the 
percentage of CD4+ T-cells will be assessed using on-treatment laboratory results, and 
pre-specified visit windows

The frequency of SAEs and AEs leading to discontinuation (DC) will be tabulated directly 
from the case report forms (CRFs). The summary will count the number of subjects that have 
at least one event
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
The occurrence of new AIDS defining events (CDC Class C events) will be tabulated from 
the CRFs. The summary will count the number of subjects that have at least one event

The steady-state plasma PK of BMS-955176 will be assessed using the intensive PK data, 
collected at Week 2 from a subset of subjects
8.4
Analyses
In general, categorical variables are tabulated with counts and percents. Continuous variables are 
summarized with univariate statistics (eg, mean, median, standard error).
Longitudinal analyses use pre-defined visit week windows. Unless otherwise specified, windows 
around planned measurement times are constructed based on the midpoint between planned 
study visits (ie, half the duration of time between study visits), and data are summarized at each 
scheduled visit. 
For the calculation of descriptive statistics of observed data, subjects must have a baseline 
measurement to be evaluable for longitudinal tabulations of parameter values and changes from 
baseline. 
Tabulations of the following endpoints present the number of unique subjects with an event: 
protocol deviations; interruptions of study therapy; non-study medications; adverse events; and 
laboratory abnormalities. Thus, multiple occurrences of the same event are counted only once 
per subject.
8.4.1
Demographics and Baseline Characteristics
The following demographic and baseline characteristics will be summarized by treatment arm
and overall using the treated subjects:

Demographics: age, race, ethnicity, gender, geographic region;

Disease characteristics at baseline: plasma HIV-1 RNA level, CD4+ T-cell counts and 
percentages, CD8+ T-cell counts, HIV-1 subtype;

Laboratory tests at baseline;

Pre-treatment CDC Class C AIDS events;

Prior medications
8.4.2
Efficacy Analyses
The efficacy analyses will be based on the treated subjects.
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8.4.2.1
Primary Efficacy Analyses
The primary efficacy endpoint is the proportion of subjects with plasma HIV-1 RNA < 40 c/mL 
at the Week 24 snapshot within each stage. This endpoint is assessed with the FDA snapshot 
algorithm. The primary analysis will be based on a modified ITT (mITT) approach. A sensitivity 
analysis will be conducted using an observed values approach. The two approaches will be 
implemented as follows:

Modified ITT: The numerator will be based on subjects with plasma HIV-1 RNA < 40 c/mL 
at Week 24. The denominator will be based on all treated subjects

Observed values: Similar to the mITT approach, the numerator will be based on subjects with 
plasma HIV-1 RNA < 40 c/mL at Week 24. However, the denominator will be based on the 
treated subjects with plasma HIV-1 RNA at Week 24
Response rates will be tabulated by treatment arm (within the stage) with exact binomial 95% 
confidence intervals.
Subgroup summaries will be provided to examine the impact of baseline viral load and HIV-1 
Clade (Clade AE versus Other) for both the mITT and the observed values approach. Other 
subgroup summaries may be provided to examine the impact of other important covariates such 
as CD4+ count, sex, geographic region, etc
8.4.2.2
Secondary Efficacy Analyses
The following secondary endpoints will be summarized by treatment arm:

Proportion of subjects with HIV-1 RNA < 40 c/mL at Week 48 and Week 96 using mITT 
and observed values

Proportion of subjects with HIV-1 RNA < 200 c/mL at Week 24, 48 and 96 using mITT and 
observed values

Change from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the 
percentage of CD4+ T-cells over time

Newly emergent genotypic substitutions (using all on-treatment isolates) will be tabulated by 
treatment arm

The newly emergent phenotypic resistance profile (using all on-treatment isolates) will be 
tabulated by treatment arm
8.4.3
Safety Analyses
The investigators will determine the intensity of adverse events (AEs) and the relationship of 
AEs to study therapy. The investigators’ terms will be coded and grouped by system organ class 
using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) in 
production at BMS. AEs will be presented by system organ class and preferred term. 
Presentations will include both non-serious and serious adverse events, unless specified 
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otherwise. If a subject had an adverse event with different intensities over time, then only the 
greatest intensity will be reported.
Deaths will be listed for enrolled subjects without regard to onset.
In analyses of fasting lipids over time, values will be excluded after the start of serum lipid 
reducing agents.
The frequency of the following safety events will be summarized by treatment arm for treated 
subjects:

SAEs

AEs leading to discontinuation of study therapy

AEs by intensity

CDC Class C AIDS events

Laboratory abnormalities by toxicity grade
8.4.4
Pharmacokinetic Analyses
The following PK parameters will be summarized by treatment arm:

Cmax: maximum observed plasma concentration

Tmax: time of maximum observed plasma concentration

Ctau: observed plasma concentration at the end of a dosing interval (eg, concentration at 
24 hours)

C0: observed pre-dose plasma concentration

AUC(TAU) : area under the concentration-time curve in one dosing interval
8.4.4.1
Sparse Pharmacokinetic Analyses
Sparse pharmacokinetic data will be used in population PK, PK/PD and PK/VK analyses.
8.4.4.2
PK/PD and PK/VK Analyses
PK data obtained from this study will be pooled with data from other studies to perform an 
integrated population PK analysis, exposure-response analyses for selected safety and efficacy 
endpoints, and viral kinetic modeling of BMS-955176 in combination with other ARVs to 
support the on-going development of BMS-955176. These analyses will facilitate optimal dose 
selection for future Phase 3 studies. 
The population PK, exposure-response, and viral kinetic analyses will be reported separately.
8.4.5
Biomarker Analyses
Details about the biomarker analyses will be provided in the Statistical Analysis Plan (SAP).
8.4.6
Outcomes Research Analyses
Details about the outcomes research analyses will be provided in the SAP.
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8.4.7
Other Analyses (including Virologic Futility)
An analysis of virologic futility will be performed at Week 24 when the last randomized subject 
in Stage 1 completes their Week 24 visit. This analysis will be conducted to evaluate whether the 
BMS-955176 arm shows significantly worse antiviral efficacy (HIV-1 RNA < 40 c/mL using the 
FDA snapshot algorithm) than the TDF-containing arm. The comparison of Arms 1 (containing 
BMS-955176) to Arm 2 (containing TDF) will be made with one-sided, Fisher’s exact tests, 
conducted at the 0.01 probability level.
An analysis of virologic futility will be performed at Week 24 when the last randomized subject 
in Stage 2 completes their Week 24 visit. This analysis will be conducted to evaluate whether a 
BMS-955176 arm shows significantly worse antiviral efficacy (HIV-1 RNA < 40 c/mL using the 
FDA snapshot algorithm) than the TDF-containing arm. The comparison of Arms 3-4
(containing BMS-955176) to Arm 5 (containing TDF) will be made with one-sided, Fisher’s 
exact tests, conducted at the 0.01 probability level.
8.5
Interim Analyses
The first two interim analyses are scheduled to support the decision on initiating the second stage 
of this study. This decision will be based on the totality of the data, including: safety, efficacy 
and resistance data from this study; relevant data from other studies in the development program; 
and PK/PD modeling.
The first interim analysis will be conducted after approximately 50% of the randomized subjects
have completed 24 weeks of therapy in Stage 1. This analysis will use the BMS equivalent of 
SDTM (Study Data Tabulation Model) data (“level 1” data) to facilitate the development of 
models for: population pharmacokinetics; exposure-response relationships; and viral kinetics.
A second interim analysis will be conducted after the last subject has completed 24 weeks of 
therapy in Stage 1. This will be a complete analysis of the available efficacy, safety and 
resistance data.
The schedule for additional analyses will depend upon the decision to initiate the Stage 2, as well 
as the recruiting time frame of Arms 1 & 2 relative to the time frame for Arms 3, 4, and 5. If 
Stage 2 is initiated, and recruiting follows projected timelines, then it is anticipated that analyses 
will be conducted when:

The last subject in Arms 3, 4, and 5 completes the Week 24 visit

The last subject in Arms 1 and 2 completes the Week 96 visit

The last subject in Arms 3, 4, and 5 completes the Week 96 visit
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
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deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the 
source documents:
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS.
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
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with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include the investigational product 
and the non-investigational product(s). Records or logs must comply with applicable regulations 
and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted)

amount destroyed at study site, if applicable

amount returned to BMS
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
retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

External Principal Investigator designated at protocol development
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
National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region 
or country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete Abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Female subjects must continue 
to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to 
forego complete abstinence.
If two forms of contraception is required, Complete abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as complete 
avoidance of heterosexual intercourse is an acceptable form of 
contraception for all study drugs. This also means that abstinence is the 
preferred and usual lifestyle of the patient. This does not mean periodic 
abstinence (eg, calendar, ovulation, symptothermal, profession of 
abstinence for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of contraception. Subjects 
who choose complete abstinence are not required to use a second method 
of contraception, but female subjects must continue to have pregnancy 
tests. Acceptable alternate methods of highly effective contraception must 
be discussed in the event that the subject chooses to forego complete 
abstinence
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11
LIST OF ABBREVIATIONS
Term
Definition
3TC
Lamivudine
AE
adverse event
AI
accumulation index
AIDS
Acquired Immunodeficiency Syndrome
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after the 
first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ARV
antiretroviral
AST
aspartate aminotransferase
ATV
atazanavir
ATV/r
atazanavir boosted with ritonavir
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of 
the last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
BID, bid
bis in die, twice daily
BCRP
Breast cancer reactive protein
BDC
Bile duct-cannulated
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BVM
bevirimat
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Term
Definition
c
copies
c/mL
copies per milliliter
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
CA
capsid
cART
Combination antiretroviral therapy
Cavg
average concentration
Cexpected-tau
expected concentration in a dosing interval
CD
Cluster designation (CD4; CD8)
CDC
Centers for Disease Control
CFC
corrected fold change
CFR
Code of Federal Regulations 
CI
confidence interval
CrCl
creatinine clearance
CLR
renal clearance
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CMV
cytomegalovirus
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Css,avg
average steady-state plasma concentration
CSR
Clinical study report
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
Trough observed plasma concentration
CT
Computed tomography
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Term
Definition
CTA
clinical trial agreement
CTX
Cross-linked C-telopeptide of Type 1 collagen
CYP
cytochrome p-450
D/C
discontinue
DDI
drug-drug interaction
DHHS
Department of Health and Human Services
dL
deciliter
DTG
dolutegravir
EC
Ethics committee
EC
effective concentration
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EFV
efavirenz
eg
exempli gratia (for example)
E-R
exposure-response
ESR
Expedited Safety Report
ET
Early termination or End of Treatment
EU
European Union
FAHI
Functional Assessment of HIV Infection
FDA
Food and Drug Administration
FDC
Fixed dose combination
FSH
follicle stimulating hormone
FTC
emtricitabine
g
gram
GFR
glomerular filtration rate
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
GSH
glutathione
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Term
Definition
h; hr
hour
HAART
Highly active antiretroviral therapy
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
hepatitis C virus
HCO3-
bicarbonate
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
HS
Human serum
HuSA
Human serum albumin
IAS
International AIDS Society
IB
Investigator brochure
IC
Inhibitory concentration
ICD
International Classification of Diseases
ICF
informed consent form
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
INI
Integrase inhibitor
IP
investigational product
IRB
Institutional Review Board
IU
International Unit
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
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Term
Definition
GALT
Gut associated lymphoid tissue
GI
gastrointestinal
kg
kilogram
L
liter
MAD
multiple ascending dose
MC
micronized crystalline
mg
milligram
MI
Maturation inhibitor
MIC
minimum inhibitory concentration
min
minute
mITT
Modified Intent to Treat
mL
milliliter
mmHg
millimeters of mercury
msec
millisecond
MOA
mechanism of action
g
microgram
M
micromolar
N
number of subjects or observations
N/A
not applicable
ng
nanogram
nM
nanomolar
NIMP
non-investigational medicinal products 
NNRTI
Non- nucleoside reverse transcriptase inhibitor
NOAEL
No observed adverse effect level
NOEL
No observed effect level
NRTI
nucleoside reverse transcriptase inhibitor
NSAID
nonsteroidal anti-inflammatory drug
pDILI
potential drug induced liver injury
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
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Term
Definition
PD
pharmacodynamics
PI
protease inhibitor
PDVF
Protocol-defined virologic criteria
PK
pharmacokinetics
PPI
proton pump inhibitor
PR
atrial depolarization to ventricular depolarization
PT
prothrombin time
PTT
partial thromboplastin time
QC
quality control
QD, qd
quaque die, once daily
QRS
interval representing the time for ventricular depolarization
QT
Duration of ventricular electrical activity
QTcF
QT corrected for heart rate using Frederica’s formula
RAL
raltegravir
RBC
red blood cell
RNA
ribonucleic acid
RTV
ritonavir
SAD
single ascending dose
SDD
spray-dried dispersion
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDTM
Study Data Tabulation Model
SOP
Standard Operating Procedures
SP1
spacer peptide 1
Subj
subject
STR
single tablet regimen
t
temperature
T
time
TDF
tenofovir
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Term
Definition
TDF/FTC
Truvada (TDF 300 mg + FTC 200 mg)
TAO
Trial Access Online, the BMS implementation of an EDC capability
TAM
Thymidine analogue mutation
T-HALF
Half life
T-HALFeff_AUC
Effective elimination half life that explains the degree of AUC 
accumulation observed
Tmax, TMAX
time of maximum observed concentration
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UGT
UDP-glucuronosyltransferase
ULN
upper limit of normal
US
United States
VF
virologic failure
VK
Viral kinetics
VLP
Virus-like particles
WBC
white blood cell
WFD
Wallingford, Connecticut, USA
WHO
World Health Organization
Wk or WK
week
WOCBP
women of childbearing potential
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12
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1
WHO HIV Department. Global Summary of the AIDS Epidemic 2013. Available at: 
http://www.who.int/hiv/data/epi_core_dec2014.png?ua=1 Accessed 12/29/14
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European AIDS Clinical Society. European Guidelines for treatment of HIV-infected adults 
in Europe (Oct 2013). http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf. 
Accessed Nov 30, 2013.
3
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 
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Services. 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed Nov 
30, 2013.
4
United States Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research. Guidance for Industry Human Immunodeficiency 
Virus-1 Infection: Developing Antiretroviral Drugs for Treatment. (June 2013). Revision 1.
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Gupta S.K., Lombaard J., Echevarria J., et. al. HIV NRTI BMS-986001 in Antiretroviral-
Naive Subjects: Week 24/49 Analyses. ICAAC 2014 Oral Abstract: H-642
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Study AI468001 Randomized, Double-Blinded, Placebo-Controlled, Single and Multiple 
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BMS-955176 in Healthy Subjects. Document Control No. 930071044
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Study AI468002 Randomized, Placebo-Controlled, Multiple-Dose Study to Evaluate the 
Pharmacodynamics, Safety and Pharmacokinetics of BMS-955176 (Double-Blinded) and 
BMS-955176 with Atazanavir +/- Ritonavir (Open-Labelled) in HIV-1 Infected Subjects. 
Draft Document Control No. 930087017
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Min 
S., 
Sloan 
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Walmsley SL., Antela A., Clumeck N., et. al. Dolutegravir plus abacavir-lamivudine for the 
treatment of HIV-1 infection. NEJM 2013 369(19):1807-18.
10
Raffi F., Jaeger H., Quiros-Roland E., et. al. Once-daily dolutegravir versus twice-daily 
raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week 
results from a randomised, double-blind, non-inferiority trial. Lancet ID. 2013 13(11): 
927-35.
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Cahn P., Pozniak AL., Mingrone H,. et. al. Dolutegravir versus raltegravir in antiretroviral-
experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, 
double-blind, non-inferiority SAILING study. Lancet 2013 382(9893):700-8.
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12
Stellbrink HJ., Reynes J., Lazzarin A., Dolutegravir in antiretroviral-naive adults with 
HIV-1: 96-week results from a randomized dose-ranging study. AIDS 2013 27(11):1771-8.
13
Eron JJ., Clotet B., Durant J., Safety and efficacy of dolutegravir in treatment-experienced 
subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING 
Study. JID 2013 207(5): 740-748.
14
Sanne I, Piliero P, Squires K, Thiry A, Schnittman S. Results of a phase 2 clinical trial at 48 
weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at 
three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. 
J Acquir Immune Defic Syndr. Jan 1 2003;32(1):18-29.
15
Bertz RJ, Persson A, Chung E, et al. Pharmacokinetics and pharmacodynamics of atazanavir-
containing antiretroviral regimens, with or without ritonavir, in patients who are 
HIV-positive and treatment-naive. Pharmacotherapy. Mar 2013;33(3):284-294.
16
Molto J, Santos JR, Valle M, et al. Monitoring atazanavir concentrations with boosted or 
unboosted regimens in HIV-infected patients in routine clinical practice. Ther Drug Monit. 
Oct 2007;29(5):648-651.
17
Goutelle S, Baudry T, Gagnieu MC, et al. Pharmacokinetic-pharmacodynamic modeling of 
unboosted Atazanavir in a cohort of stable HIV-infected patients. Antimicrob Agents 
Chemother. Jan 2013;57(1):517-523.
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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. 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed Nov 
30, 2013.
19
Malan DR, Krantz E, David N, Wirtz V, Hammond J, McGrath D. Efficacy and safety of 
atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy 
regimens in antiretroviral-naive patients. J Acquir Immune Defic Syndr. Feb 1 
2008;47(2):161-167.
20
Landman R, Diallo MB, Gueye NF, et al. Efficacy and safety of unboosted atazanavir in 
combination with lamivudine and didanosine in naive HIV type 1 patients in Senegal. AIDS 
Res Hum Retroviruses. May 2010;26(5):519-525.
21
Gianotti N, Seminari E, Guffanti M, et al. Evaluation of atazanavir Ctrough, atazanavir 
genotypic inhibitory quotient, and baseline HIV genotype as predictors of a 24-week 
virological response in highly drug-experienced, HIV-infected patients treated with 
unboosted atazanavir. New Microbiol. Apr 2005;28(2):119-125.
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22
Giuntini R, Martinelli C, Ricci E, et al. Efficacy and safety of boosted and unboosted 
atazanavir-containing antiretroviral regimens in real life: results from a multicentre cohort 
study. HIV Med. Jan 2010;11(1):40-45.
23
Two Drug Combination Studies with BMS-955176 and HIV Antiviral Agents. Version 1.0. 
June 2013. DCN 930071469
24
Song I., Borland J., Chen S. Effect of atazanavir and atazanavir/ritonavir on the 
pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572. Br. J. 
Pharm. 2011 72(1):103-108
25 BMS-955176 Investigator Brochure, Version 2.0, July 2013 DCN 930056146
26 BMS-955176 Investigator Brochure, Version 3.0, April 17, 2014 DCN 930056146
27 Partial response to FDA “May Proceed” Letter dated 27 Sep 2013 for IND 118,936. Bristol-
Myers Squibb Company; Jan 2014. Document Control No. 930076507 2.0. Insert this 
additional reference: “Evaluation of cross-resistance of HIV-1 Maturation Inhibitor 
BMS-955176 toward HIV-1 protease inhibitor resistant viruses. Bristol-Myers Squibb 
Company; 30-Sept-2014. Document Control No. 930083565.”
28 Evaluation of Cross Resistance of HIV-1 Maturation Inhibitor BMS-955176 Toward HIV-1 
Protease Inhibitor Resistant Viruses. Document Control No. 930083565
29 Gilead 
Sciences. 
Prescribing 
Information 
for 
TDF. 
Available 
at: 
http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/viread/viread_pi.pdf.
Accessed Dec 31, 2014
30
ViiV 
Healthcare. 
Prescribing 
Information 
for 
DTG. 
Available 
at: 
https://www.viivhealthcare.com/media/58599/us_tivicay.pdf. Accessed Dec 31, 2014.
31 BMS. 
Prescribing 
Information 
for 
ATV. 
Available 
at: 
http://packageinserts.bms.com/pi/pi_reyataz.pdf. Accessed Dec 31, 2014
32 AbbVie. 
Prescribing 
Information 
for 
RTV. 
Available 
at: 
http://www.rxabbvie.com/pdf/norvirtab_pi.pdf. Accessed Dec 31, 2014
33 Evaluation of Cross-Resistance of HIV-1 Maturation Inhibitor BMS-955176 Toward HIV-1 
Protease Inhibitor Resistant Viruses. DCN 930083565
34
Kestelman P. et. al., Efficacy of the Simultaneous Use of Condoms and Spermicides Family 
Planning Perspectives.Vol 23 (5); October 1991.
35
Gabbay MB, Thomas J, Gibbs A, Hold P. A Randomized Crossover Trial of The Impact of 
Additional Spermicide on Condom Failure Rates. Sex Transm Dis 2008; 35: 862-8.
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Hasler WL Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrisons 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill
37
Hasler WL and Owyang C Approach to the Patient with Gastrointestinal Disease. Chapter 
290. Harrisons Principles of Internal Medicine 18th edition. 2012. McGraw Hill
38
Soll AH and Graham DY. Peptic Ulcer Disease. Chapter 40. Textbook of Gastroenterology. 
5th edition. 2009. Blackwell Publishing
39
Rome Foundation. Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders. 
Available: http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed 
Dec 22 2014
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APPENDIX 1
LISTINGS OF PROHIBITED AND PRECAUTIONARY
THERAPIES
General Notes: 

Guidelines for the use of drugs with established or other potentially significant drug 
interactions listed in the Package Inserts of the marketed ARV agents used by subjects 
participating in this study (Reyataz, Norvir, Viread, Tivicay) should be followed. 

Medications listed in the Package Inserts as contra-indicated with the other marketed ARV 
agents used by subjects participating in this study are not permitted. 

Any immunizations deemed appropriate by the subject’s physician are permitted provided 
that the immunization is given > 4 weeks from any HIV-1 RNA measurement.

A subject may not be co-enrolled in a concomitant trial unless it is approved by the Medical 
Monitor prior to randomization.
Prohibited Therapies
Drugs that should not be administered throughout the duration of the study:
Anticonvulsants: Carbamazepine, 
Phenobarbital, Phenytoin
Use with ATV may result in decreased ATV concentrations. Use 
of Carbamazepine may result in decreased DTG concentrations.
Oral Antifungals: Itraconazole, 
Posaconazole, and Voriconazole
Use with ATV can result in increased ATV concentrations
Antimycobacterials: Rifampin, 
Rifapentine, Rifabutin
These antimycobacterials decrease ATV plasma concentrations
and may decrease BMS-955176 plasma concentrations.
St. John’s wort
Use with ATV or DTG may result in loss of antiviral therapeutic 
effect
GI motility agent: Cisapride
Potential for serious and/or life threatening reactions such as 
cardiac arrhythmias
Pimozide
Potential for serious and/or life threatening reactions such as 
cardiac arrhythmias
Zetia (ezetimibe)
Ezetimibe is a substrate of OATP1B1 (of which BMS-955176 is 
an inhibitor in vitro).
Dofetilide
Use with DTG may result in the potential for increased Dofetilide 
plasma concentrations and the risk for serious and/or life 
threatening events
Alfuzosin
ATV increases Alfuzosin concentrations which can result in 
hypotension
Benzodiazepines: Triazolam and 
Midazolam
ATV can increase the concentration of these Benzodiazepines 
with the potential to increase sedation or respiratory depression
Ergot derivatives: 
Dihydroergotamine, ergotamine, 
ergonovine, methylergonovine
ATV can increase potential for ergot toxicity (e.g. peripheral 
vasospasm)
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HMG-CoA Reductase Inhibitors: 
Lovastatin, Simvastatin, 
Atorvastatin, Pitavastatin, 
Rosuvastatin, Pravastatin
Use with ATV may result in increased levels of HMG-CoA 
Reductase Inhibitors and potential for serious reactions such as 
myopathy
Antacids, H2 receptor angatonists, 
Proton Pump Inhibitors, Sucralfate
Use with ATV may result in decreased plasma concentrations of 
ATV. Use of Antacids containing Aluminium, Magnesium, or 
Calcium may result in decreased levels of DTG.
Macrolides: Clarithromycin
Use with ATV may result in increased Clarithromycin levels and 
QTc prolongation
Buprenorphine
Use with ATV may increase levels of Buprenorphine
Quetiapine
Use with ATV may increase levels of Quetiapine
Salmeterol
Use with ATV may result in increased levels of Salmeterol
Avanafil
Use with ATV may result in increased Avanafil levels
All drugs with antiretroviral 
activity other than those 
considered study therapy
Any drugs with antiretroviral activity not considered study 
therapy may interfere with the assessments of the study.
Precautionary Therapies
Drugs that should be administered with caution during the study:
Hormonal Contraceptives
Hormonal Contraceptives cannot be relied upon as a highly 
effective method of contraception. 
See Protocol Section 3.3.1, for more information on Highly 
Effective Methods of Contraception.
Antidepressants: Trazodone, 
Tricyclic Antidepressants (TCA)
Use with ATV/r may result in increased plasma concentrations of 
trazodone and TCA
Antimalarials: 
Atovaquone/Proguanil, Mefloquine
Use with ATV/r may result in decreased Atovaquone/Proguanil 
levels. The effect of Mefloquine on ATV/r is unknown.
Benzodiazepines: Alprazolam and 
Diazepam
ATV can increase the concentration of these Benzodiazepines 
Calcium Channel Blockers
Use with ATV may result in increased concentrations of CCB’s. 
Non-topical Corticosteroids: 
Budesonide, Fluticasone, 
Prednisone, Methylprednisolone, 
Prednisolone, Triamcinolone
Use with ATV/r may result in increased levels of glucocorticoids 
and adrenal insufficiency
Dexamethasone
Use with ATV may result in reduced levels of ATV.
Colchicine
Use with ATV may result in increased Colchicine levels
Metformin
Use with DTG may result in increased levels of metformin. 
A cation-containing (e.g. 
Magnesium) laxative
If used with DTG the laxative should be taken 2 hours before or 
6 hours after taking concomitant laxatives.
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APPENDIX 2
AIDS-DEFINING DIAGNOSES
I.
PARASITIC INFECTIONS
Pneumocystis carinii (PC)
1011
PC pneumonia histologically proven.
1012
PC pneumonia, clinical diagnosis by the following specifications and confirmed HIV 
infection:
A history of dyspnea on exertion or non-productive cough of recent onset (within the past 
3 months).
AND
Chest X-ray evidence of diffuse bilateral interstitial or gallium scan evidence of diffuse 
bilateral pulmonary disease;
AND
Arterial blood gas analysis showing an arterial pO2 of < 70 mmHg or a low respiratory 
diffusing capacity (< 80% of predicted values) or an increase in the alveolar-arterial 
oxygen tension gradient;
AND
Successful response to appropriate therapy and no evidence of pneumonias of other 
etiologies.
1013
Pneumocystis carinii, histologically proven, at a site other than lungs.
Toxoplasmosis (in patients > 1 month old)
1021
Toxoplasmosis, clinical diagnosis (of brain only) by the following specifications and 
confirmed HIV infection:
Recent onset of a neurologic disease consistent with toxoplasmosis;
AND
Brain imaging evidence of a mass lesion (on computed tomography, nuclear magnetic 
resonance of radiography enhanced by injection of contrast medium);
AND
Serum antibody to toxoplasmosis and successful response to therapy for toxoplasmosis.
1022
Toxoplasmosis, of brain or internal organs other than liver, spleen or lymph nodes. 
Proven by microscopy.
Isosporiasis
1031
Isosporiasis causing chronic diarrhea of > 1 month. Proven by microscopy.
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Cryptosporidiosis
1041
Cryptosporidiosis causing chronic diarrhea of > 1 month. Proven by microscopy.
II.
FUNGAL INFECTIONS
Candidiasis
2011
Candidiasis, Esophageal, definitive diagnosis by the following specifications:
Gross inspection by endoscopy or autopsy or by microscopy (histology or cytology) on a 
specimen obtained directly from the tissues affected (including scrapings from the 
mucosal surface), not from a culture.
2012
Candidiasis, Esophageal, presumptive diagnosis by the following specifications and 
confirmed HIV infection:
Recent onset of retrosternal pain on swallowing:
AND
Oral candidiasis diagnosed by the gross appearance of white patches or plaques on an 
erythematous base OR by the microscopic appearance of fungal mycelial filaments in an 
uncultured specimen scraped from the oral mucosa;
AND
Response to appropriate therapy.
2013
Candidiasis, Bronchial/Pulmonary, definitive diagnosis by the following specifications; 
Gross inspection by endoscopy or autopsy or by microscopy (histology or cytology) on a 
specimen obtained directly from the tissues affected (including scrapings from the 
mucosal surface), not from a culture.
Cryptococcosis
2022
Cryptococcosis, Extra-pulmonary, proven by microscopy (histology or cytology), culture 
or detection of antigen in a specimen obtained directly from the tissues affected or a fluid 
from those tissues.
Histoplasmosis
2031
Histoplasmosis, Disseminated (at a site other than or in addition to lungs or cervical or 
hilar lymph nodes), proven by microscopy (histology or cytology), culture or detection of 
antigen in a specimen obtained directly from the tissues affected or a fluid from those 
tissues.
Coccidioidomycosis
2041
Coccidioidoidomycosis, Disseminated (at a site other than or in addition to lungs or 
cervical or hilar lymph nodes), proven by microscopy (histology or cytology), culture or 
detection of antigen in a specimen obtained directly from the tissues affected or a fluid 
from those tissues.
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Coccidioidomycosis, clear reactivation of prior infection, proven by microscopy 
(histology or cytology), culture or detection of antigen in a specimen obtained directly 
from the tissues affected or a fluid from those tissues.
III.
BACTERIAL INFECTIONS
Mycobacterium
3001
Mycobacterium (unidentified species). Presumptive diagnosis, by the following 
specifications and confirmed HIV infection.
Acid fast bacilli (AFB) positive stain of specimen obtained from endoscopic biopsy or 
from a normal sterile site other than lungs, skin or cervical or hilar lymph nodes. Species 
NOT identified by culture.
Mycobacterium tuberculosis
3011
Mycobacterium tuberculosis, Pulmonary, definitive diagnosis proven by culture, without 
evidence of upper respiratory infection symptoms of Mycobacterium tuberculosis that 
could account for the positive culture.
3012
Mycobacterium tuberculosis, definitive diagnosis proven by culture, of at least one extra 
pulmonary site regardless of concurrent pulmonary involvement.
3013
Mycobacterium tuberculosis, Disseminated, definitive diagnosis proven by culture.
Mycobacterium avium intracellulare
3022
MAI in Blood, proven by culture.
3023
MAI Colitis, proven by histology and culture. (This does not include MAI of the stool 
alone).
3024
MAI, Disseminated, at a site other than or in addition to lungs or cervical or hilar lymph 
nodes, proven by culture.
Mycobacterium Kansasii, Mycobacterium Scrofulaceum and Other Atypical 
Mycobacterium
3032
M. Kansasii, in Blood, proven by culture.
3033
M. Kansasii Colitis, proven by histology and culture. (NOT including positive M. 
Kansasii of stool alone).
3034
M. Kansasii, Disseminated, at a site other than or in addition to lungs, or cervical or hilar 
lymph nodes, proven by culture.
3035
M. Scrofulaceum or other Atypical Mycobacterium, proven by culture.
Salmonella
3041
Salmonella, recurrent Bacteremia (non-typhoid), proven by culture.
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IV.
VIRAL INFECTIONS
Cytomegalovirus
4011
CMV, Pneumonitis, pathologically or histologically confirmed. Serum antibody titer and 
culture alone is not sufficient for the diagnosis.
4012
CMV, Esophagitis, as diagnosed by histology, pathology or culture of an esophageal 
lesion. Serum antibody titer and culture of other than esophageal tissue is not sufficient 
for the diagnosis.
4013
CMV, Retinitis as evidenced by a characteristic appearance on serial ophthalmoscopic 
examinations (eg, discrete patches of retinal whitening with distinct borders, spreading in 
a centrifugal manner, following blood vessels, progressing over several months, 
frequently associated with retinal vasculitis, hemorrhage, and necrosis). Resolution of 
active disease leaves retinal scarring and atrophy with retinal pigment epithelial mottling.
4014
CMV, Colitis, as diagnosed by histology, pathology or culture of a colonic lesion. Serum 
antibody titer and culture of other than colonic tissue is not sufficient for the diagnosis.
4015
CMV, Encephalitis, as diagnosed by histology, pathology or culture of brain tissue or 
CSF. Serum antibody titer and culture of other than brain tissue or CSF is not sufficient 
for the diagnosis.
Herpes Simplex (in patients > 1 month old).
4021
HSV, Disseminated (but not encephalitis alone), proven by microscopy (histology or 
cytology), culture or detection of antigen in a specimen obtained directly from affected 
tissues.
4022
HSV, Esophagitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for the diagnosis.
4023
HSV, Bronchitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for the diagnosis.
4024
HSV, Pneumonitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for diagnosis.
4025
HSV, GI, other than mouth, throat, or peri-rectal, as diagnosed by microscopy (histology 
or cytology), culture or detection of antigen in a biopsy specimen obtained directly from 
affected tissue. Serological measurement and culture from other than the affected tissue is 
not sufficient for diagnosis.
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HSV, Mucocutaneous, ulcers persisting for 1 month despite appropriate therapy, as 
diagnosed by microscopy (histology or cytology), culture or detection of antigen in a 
biopsy specimen obtained directly from affected tissue. Serological measurement and 
culture from other than the affected tissue is not sufficient for the diagnosis.
Progressive Multifocal Leukoencephalopathy
4041
Progressive Multifocal Leukoencephalopathy, proven by microscopy.
VI.
NEOPLASTIC DISEASES
Kaposi’s Sarcoma
6011
Kaposi’s sarcoma, Mucocutaneous, proven by microscopy.
6012
Kaposi’s sarcoma. Mucocutaneous, presumptive diagnosis with characteristic gross 
appearance and confirmed HIV infection.
6013
Kaposi’s sarcoma, Visceral.
6014
Kaposi’s sarcoma, other than above.
Lymphoma of the Brain
6021
Primary Lymphoma of the brain at any age, proven by microscopy.
Non-Hodgkins Lymphoma
6031
Small Non-cleaved lymphoma (either Burkitt or non-Burkitt type).
6032
Immunoblastic sarcoma, equivalent to any of the following, although not necessarily all 
in combination: Immunoblastic lymphoma, large-cell lymphoma, diffuse histocytic 
lymphoma.
Cervical Carcinoma
6041
Histologically proven invasive carcinoma of the cervix.
VII.
OTHER CONDITIONS
HIV Dementia/Motor Defects
7011
HIV Dementia, clinical findings of disabling cognitive and/or motor dysfunction 
interfering with occupation or activities of daily living progressing over weeks to months, 
in the absence of a concurrent illness or condition other than HIV infection that could 
explain the findings. Method to rule out such concurrent illnesses and conditions must 
include cerebrospinal fluid examination and either brain imaging (computed tomography 
or magnetic resonance) or autopsy.
Slim Disease or HIV Wasting Syndrome
7021
HIV Wasting Syndrome, findings of profound involuntary weight loss > 10% of baseline 
body weight plus either chronic diarrhea (at least two loose stools per day for 30 days) 
or chronic weakness and documented fever (for 30 days, intermittent to constant) in the 
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absence of a concurrent illness or condition other than HIV infection that could explain 
the findings (eg, cancer, tuberculosis, cryptosporidiosis, or other specific enteritis).
7061
Recurrent pneumonia, acute onset within 12 months of most recent episode.
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APPENDIX 3
DAIDS TOXICITY GRADES
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APPENDIX 4
COCKCROFT-GAULT EQUATION TO CALCULATE SERUM 
CREATINE CLEARANCE
Online calculator:
http://nephron.com/cgi-bin/CGSI.cgi
Manual calculation:
Male:
Estimated Creatinine Clearance =
(140-age in years) x Body Weight (kg)
72 x Serum Creatinine (mg/dL)
Female:
Estimated Creatinine Clearance =
(140-age in years) x Body Weight (kg) x 0.85
72 x Serum Creatinine (mg/dL)
1 pound = 0.4536 kilograms
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Protocol Number:
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IND Number:
118,936
Ex-US
Non-IND
EUDRACT Number
N/A
Date:
28-Jan-2015
Revised Date:
19-Mar-2015
CLINICAL PROTOCOL AI468048
A Phase 2b Randomized, Active-Controlled, Staged, Open-Label Trial to Investigate Safety and 
Efficacy of BMS-955176 in Combination with Dolutegravir and Atazanavir (with or without 
Ritonavir) in Treatment-Experienced HIV-1 Infected Adults
Revised Protocol Number: 01
Incorporates Amendment(s): 04
Study Director/Central Medical Monitor
 DO, MPH
5 Research Parkway
Office 201D
Wallingford, CT  06492 USA
Telephone (office): 
Fax: 
24-hr Emergency Telephone Number
USA:
International: 
Bristol-Myers Squibb Research and Development
Virology Clinical Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
5 Research Parkway
Wallingford, CT 06492
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
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Date: 19-Mar-2015
2
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 01
19-Mar-2015
Incorporates Amendment 04
Amendment 04
19-Mar-2015
Incorporated information that more clarify the Week 24 data (consisting of 
efficacy, safety, and pharmacokinetic data) to be used to confirm the doses 
for Stage 2 and to trigger the start of Stage 2 of the study relative to other 
analyses conducted under the protocol for other purposes.
Removed the requirement that all Sparse PK samples need to be collected 
as pre-AM dose samplings.  Only one visit Weeks 4- 24 (as opposed to all 
visits Weeks 4 - 24) needs to be performed in the morning and to have the 
blood collected as a pre-AM dose sampling; (includes the deletion of 
Table 5.5.2-1).
Administrative changes.
Original 
Protocol
28-Jan-2015
Not applicable
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SYNOPSIS
Clinical Protocol AI468048
Protocol Title: A Phase 2b Randomized, Active-Controlled, Staged, Open-label Trial to Investigate Safety and 
Efficacy of BMS-955176 in Combination with Dolutegravir and Atazanavir (with or without Ritonavir) in 
Treatment-Experienced HIV-1 Infected Adults
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Subjects in each arm and per stage will begin QD dosing (in the morning, with a meal) with 
BMS-955176 in combination with atazanavir (ATV) [with or without ritonavir (RTV)] and dolutegravir (DTG), or 
tenofovir (TDF) in combination with atazanavir boosted with ritonavir (ATV/r) and DTG, for a duration of 
96 weeks.
Stage 1:

Arm 1: BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, OR

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Study Phase: 2b
Research Hypothesis: This Phase 2b study will evaluate whether the combination of BMS-955176 with ATV (with 
or without RTV) and DTG is efficacious, safe, and well-tolerated in HIV-1 infected treatment-experienced adults.
Objectives:
Primary Objective Stage 1

To assess the antiviral efficacy of BMS-955176 120 mg and a TDF 300 mg-containing arm, each when given in 
combination with ATV/r 300/100 and DTG 50 mg by determining the proportion of treatment-experienced 
subjects with plasma HIV-1 RNA < 40 c/mL at Week 24 in Stage 1.
Primary Objective Stage 2

To assess the antiviral efficacy of two doses (120 and 180 mg) of BMS-955176, each when given in 
combination with unboosted ATV 400 mg and DTG 50 mg, and to assess the antiviral efficacy of TDF 300 mg 
when given in combination with and ATV/r 300/100 mg and DTG 50 mg by determining the proportion of 
treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at Week 24 in Stage 2. 
Secondary Objectives

To assess the antiviral efficacy of BMS-955176 Arms, and the TDF-containing Arms (TDF + ATV/r + DTG), 
by determining the proportion of treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at 
Weeks 48 and 96

To assess the antiviral efficacy of BMS-955176 Arms, and the TDF-containing Arms, by determining the 
proportion of treatment-experienced subjects with plasma HIV-1 RNA < 200 c/mL at Weeks 24, 48, 96
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
To assess the emergence of HIV drug resistance in samples selected for drug resistance testing (according to 
criteria outlined in Protocol Section 5.4.1)

To assess efficacy of BMS-955176 Arms, and the TDF-containing Arms, by using the mean changes from 
baseline in log10 HIV-1 RNA, CD4+ T-cell counts, and percentage of CD4+ T-cells

To assess the safety and tolerability of BMS-955176 in treatment-experienced subjects by measuring frequency 
of SAEs and AEs leading to discontinuation

To assess disease progression as measured
by the occurrence of new AIDS defining events 
(CDC Class C events)

To characterize the pharmacokinetics of BMS-955176 when co-administered with ATV (with or without 
ritonavir) and DTG in treatment-experienced HIV-1 infected subjects
Study Design: This is a randomized, active-controlled, staged, open-label clinical trial. Approximately 
200 treatment-experienced subjects total will be randomized into the study. In Stage 1, approximately 80 subjects 
will be randomized 1:1 (approximately 40 per arm) to either of the treatment arms containing BMS-955176 or TDF 
in combination with boosted atazanavir (ATV/r) and DTG. In Stage 2, approximately 120 subjects will be 
randomized 1:1:1 (approximately 40 per arm) to either of the two BMS-955176 treatment arms containing
unboosted ATV and DTG, or to the TDF-containing Arm containing ATV/r and DTG. The randomization in both 
Stages will be stratified by HIV-1 Clade (AE versus Other). The number of subjects with HIV-1 Clade AE will be 
capped at a maximum of approximately 3 per arm.
Stage 1:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, OR

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
A Continuation Dose of BMS-955176 will be selected based on Week 24 data from Stage 1 and from study 
AI468038 (BMS-955176 in ARV treatment-naive HIV-1 infected subjects) with which subjects in Stage 1, Arm 1 
may transition to for the remainder of the study. The transition may occur on or after Week 48.
The data from the Week 24 analysis for AI468038 and Stage 1, including safety, efficacy and pharmacokinetics, will 
be examined to trigger the start of Stage 2 and confirm the two doses of BMS-955176 for study in Stage 2.
After the Stage 2 Week 24 endpoint, a Continuation Dose of BMS-955176 will be selected based on data from 
Stages 1 and 2, and study AI468-038 with which subjects in Stage 2, Arms 3 and 4 will transition to for the 
remainder of the study. The switch in Stage 2 may occur sooner, between Week 24 and Week 48, or it may be after 
Week 48.
The assigned backbone for each arm, ATV and DTG, or ATV/r and DTG, will remain unaltered throughout the 
study.
All subjects in both stages are expected to receive study treatment for 96 weeks.
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Arm 2
TDF
300 mg QD
+ ATV/r + DTG
Day 1
Begin dosing
Arm 3
BMS-955176 
120 mg QD
+ ATV + DTG
1 Virologic Futility will be evaluated at Week 24 
(see Section 8.4.7).  
Results of Week 24 Stage 1 AI468-048 & AI468-038 
Confirm the Start of Stage 2   
Arm 4
BMS-955176 
180 mg QD
+ ATV + DTG
40
40
Week 2
Week 24
Week 24 Analysis1
Intensive PK subset
4 Based on totality of data from both studies the 
Continuation Dose for Arms 3 & 4 may be 
identified.  
Number
Randomized
STAGE 2
Week 96
Week 96 Analysis/End of Study
Week 48
Week 48 Analysis
The Switch to the Continuation Dose4,3     
is expected to occur on or after Week 48, 
but could occur sooner.
Arm 1
BMS-955176 
120 mg QD
+ ATV/r + DTG
Week 2
Number
Randomized
Week 24
Week 24 Analysis1
Day 1
Begin dosing
Intensive PK subset
40
40
Week 48
Week 96
Week 48 Analysis
Week 96 Analysis/End of Study
The Switch to             
the Continuation Dose2,3
may occur on or after 
Week 48 
STAGE 1
BMS-955176
Continuation Dose QD 
+ ATV/r + DTG
Arm 5
TDF
300 mg QD
+ ATV/r + DTG
40
3 The actual switch of subjects of BMS-955176 
subjects to that Continuation Dose may occur when 
all of the subjects have reached at least Week 48 
(though it could occur sooner in Stage 2).
BMS-955176
Continuation Dose QD
+ ATV + DTG
2 Based on Week 24 data from Arms 1 & 2 and 
from AI468-038, the Continuation Dose for 
Arm 1 may be identified.  
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Study Population:
Key Inclusion Criteria:

Men and non-pregnant women, at least 18 years of age (or minimum age as determined by local regulatory or as 
legal requirements dictate)

Antiretroviral treatment-experienced, defined as having documented evidence of having failed 1 or 2 regimens 
that include 2 or 3 classes of ARV (with or without documented resistance)

Confirmed Plasma HIV-1 RNA 400 copies/mL

CD4+ T-cell count > 50 cells/mm3

Screening genotype/phenotype indicating susceptibility to study drugs (unboosted ATV, FC < 2.2; DTG; TDF)
Key Exclusion Criteria:

Antiretroviral treatment-experienced adults who have failed > 2 ARV regimens

Resistance or partial resistance to any study drug

Three or more of the following PI mutations, historical or documented: M36I/V, M46I/L/T, G48M/V, 
I54V/L/T/M/A, G73S/A/C/T, V82A/F/T/S/I, or L90M

Any major ATV mutations, historical or documented: I50L, I84V/A, N88D/S

Any major TDF mutation, historical or documented: K65R or T69ins

Three or more of the following non-accessory thymidine analogue mutations (TAMs): M41L, D67N, K70R, 
L210W, T215Y/F, K219Q/E

Any major mutations for raltegravir (RAL), elvitegravir (or clinically suspected INI resistance), historical or 
documented: T66IAK, E92Q, S147G, N155H, Q148H/K/R, Y143C/H/R, E157Q

Chronic HBV/HCV (Positive blood screen for HBsAg; Positive blood screen for HCV Ab and HCV RNA)

ALT or AST > 3 × ULN

Alkaline Phosphatase > 5 × ULN

Bilirubin 1.5 × ULN

History of decompensated cirrhosis or active decompensated cirrhosis

Hemoglobin < 8.0 g/dL

Platelets < 50,000 cells/mm3
Study Drug: includes both Investigational
[Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for AI468048
Medication 
Potency 
IMP/Non-IMP 
BMS-955176 
60 mg or 120 mga
IMP
Tenofovir (TDF)
300 mg
Non-IMP
Atazanavir (ATV)
200 mg and 300 mg
IMP
Ritonavir (RTV)
100 mg
Non-IMP
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Study Drug for AI468048
Medication 
Potency 
IMP/Non-IMP 
Dolutegravir (DTG)
50 mg
IMP and Non-IMP, based on 
country approval status
a The 180 mg dose of BMS-955176 will be constructed with BMS-955176 60 mg + BMS-955176 120 mg
Study Assessments: Efficacy assessments will include plasma HIV-1 RNA measurements. Safety Assessments will 
include blood chemistry and hematology, ECGs, Physical Exams and Vital Signs, and assessment of non-serious 
AEs, SAEs and AEs leading to discontinuation.
Statistical Considerations:
Sample Size:
This is an estimation study, without statistical testing, and hence there are no power considerations.
It is expected that response rate for the primary endpoint for all five arms will be somewhere around 80%. With this 
response rate, and 40 subjects per arm, an exact 95% confidence interval would run from roughly 64% to 91%.
Endpoints:
Primary Endpoint(s) for Stage 1 and Stage 2
The primary endpoint for Stage 1 and Stage 2 is the proportion of subjects with plasma HIV-1 RNA < 40 c/mL at 
Week 24. This will be assessed with the FDA snapshot algorithm. This uses the last on-treatment plasma HIV-1 
RNA measurement, within an FDA-specified visit window, to determine response
Secondary Endpoint(s)

The antiviral efficacy will be determined by the proportion of subjects with plasma HIV-1 RNA < 40 c/mL at 
Weeks 48 and 96 using the FDA snapshot algorithm

The antiviral efficacy will also be assessed by the proportion of subjects with plasma HIV-1 RNA < 200 c/mL 
at Weeks 24, 48 and 96 using the FDA snapshot algorithm approach with positive response defined as HIV-1 
RNA < 200 c/mL

The emergence of HIV drug resistance among samples sent for drug resistance testing will be assessed using the 
most recent version of the IAS-USA list of HIV-1 drug resistance mutations

Changes from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the percentage of 
CD4+ T-cells will be assessed using on-treatment laboratory results, and pre-specified visit windows

The frequency of SAEs and AEs leading to discontinuation (DC) will be tabulated directly from the case report 
forms (CRFs). The summary will count the number of subjects that have at least one event.

The occurrence of new AIDS defining events (CDC Class C events) will be tabulated from the CRFs. The 
summary will count the number of subjects that have at least one event.

The steady-state plasma PK of BMS-955176 will be assessed using the intensive PK data, collected at Week 2 
from a subset of subjects.
Analyses:
There are two interim analyses scheduled before the start of Stage 2.
The first interim analysis will be conducted after approximately 50% of the randomized subjects have completed
24 weeks of therapy in Stage 1. This analysis will use the BMS equivalent of SDTM (Study Data Tabulation Model) 
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data (“level 1” data) to facilitate the development of models for: population pharmacokinetics; exposure-response 
relationships; and, as available, viral kinetics.
A second interim analysis will be conducted after the last subject has completed 24 weeks of therapy in Stage 1. 
This will be an analysis of the available efficacy, safety, resistance and pharmacokinetic data.
The schedule for additional analyses will depend upon the decision to initiate the Stage 2, as well as the recruiting 
time frame of Arms 1 & 2 relative to the time frame for Arms 3, 4, and 5. If Stage 2 is initiated, and recruiting 
follows projected timelines, then it is anticipated that analyses will be conducted when:

The last subject in Arms 3, 4 and 5 completes the Week 24 visit

The last subject in Arms 1 and 2 completes the Week 96 visit

The last subject in Arms 3, 4 and 5 completes the Week 96 visit
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale to support study design ............................................................ 
1.1.2 Rationale to support the dose selection ................................................... 
1.1.3 Rationale to support any drug combinations ........................................... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
1.4.1 Background Information BMS-955176 .................................................... 
1.4.1.1 Mechanism of Action....................................................................... 
1.4.1.2 Nonclinical studies .......................................................................... 
1.4.1.3 Clinical studies................................................................................ 
1.4.2 Background Information on TDF ............................................................ 
1.4.3 Background Information on DTG ............................................................ 
1.4.4 Background Information on ATV ............................................................. 
1.4.5 Background Information on RTV ............................................................. 
1.4.6 Drug-Drug Interactions ........................................................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Screening.................................................................................................. 
3.1.2 Day 1/Baseline Visit ................................................................................. 
3.1.2.1 Day 1/Baseline Visit for Arms 1 and 2 - Stage 1 ............................ 
3.1.2.2 Day 1/Baseline Visit for Arms 3, 4 and 5 - Stage 2 ........................ 
3.1.3 Week 2 Intensive PK Visit ........................................................................ 
3.1.4 Visits Week 4 - 96 ..................................................................................... 
3.1.5 Selection of the Continuation Dose of BMS-955176 ............................... 
3.1.5.1 Selection of the Continuation Dose, and the Switch for Stage 1 .... 
3.1.5.2 Selection of the Continuation Dose, and the Switch for Stage 2 .... 
3.1.6 End of the study ........................................................................................ 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
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3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Instructions for Dose Administration ...................................................... 
4.5.1.1 General Instructions ....................................................................... 
4.5.1.2 Specific Dosing Instructions for Initial Treatment Arm Assignment
...............................................................................................................
4.5.2 Dose Modifications .................................................................................. 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Vital Signs and Physical Examinations ................................................... 
5.3.2 Adverse Events ......................................................................................... 
5.3.3 Concomitant Medication Assessment ...................................................... 
5.3.4 Electrocardiograms ................................................................................. 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.1.1 Guidelines for Confirmatory Testing of Plasma HIV-1 RNA and 
Resistance testing .................................................................................. 
5.4.1.2 Protocol Defined Virologic Failure ................................................ 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.4.2.1 CD4+ and CD8+ T-Cells ............................................................... 
5.4.2.2 Drug Resistance Testing ................................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Intensive Pharmacokinetic Assessment .................................................... 
5.5.2 Sparse Pharmacokinetic Assessments ...................................................... 
5.6 Biomarker Assessments .................................................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
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5.8 Other Assessments ............................................................................................ 
5.9 Results of Central Assessments ........................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
6.7.1 Toxicity Management ............................................................................... 
6.7.1.1 Management of Elevations in Liver Transaminases ....................... 
6.7.1.2 Management of Renal Toxicity ....................................................... 
6.7.1.3 Management of Hyperbilirubinemia ............................................... 
6.7.1.4 Gastrointestinal Toxicity Evaluation and Management Plan ......... 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s)Stage 1 and Stage 2 ................................................. 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Efficacy Analyses .............................................................. 
8.4.2.2 Secondary Efficacy Analyses .......................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.4.1 Sparse Pharmacokinetic Analyses .................................................. 
8.4.4.2 PK/PD and PK/VK Analyses .......................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses (including Virologic Futility) ......................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
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9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 LISTINGS OF PROHIBITED AND PRECAUTIONARY 
THERAPIES ........................................................................................................... 
APPENDIX 2 AIDS-DEFINING DIAGNOSES.......................................................... 
APPENDIX 3 DAIDS TOXICITY GRADES .............................................................. 
APPENDIX 4 COCKCROFT-GAULT EQUATION TO CALCULATE SERUM 
CREATINE CLEARANCE .................................................................................... 
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1
INTRODUCTION AND STUDY RATIONALE
1.1
Study Rationale
Despite advances in prevention and care, HIV/AIDS remains a significant epidemic in both the 
US and worldwide. AIDS remains the 6th leading cause of death, internationally. Globally, 
approximately 35 million people were living with HIV infection in 2013.1 A number of these 
patients include those who are treatment-experienced. Note: the use of the term 
“treatment-experienced” herein refers to subjects who have failed at least one or two 
antiretroviral (ARV) regimens and who may be harboring drug resistant virus (current or 
archived) to at least one drug class.
In contrast to current HIV treatment guidelines for treatment-naïve patients, the recommended 
composition of combination
antiretroviral therapy (cART) is far less uniform for 
treatment-experienced subjects.2,3 The level of detail in the DHHS and EACS guidelines leads to 
a lack of uniformity in treatment for patients in later lines of therapy. Moreover, drug related 
toxicities (both short and longer term) in treatment-experienced subjects necessitate vigilance 
and continued monitoring. Thus, there is a need for new and efficacious agents with novel 
mechanisms of action (MOA) and favorable safety/tolerability profiles. Given the aging HIV-1 
infected population and overall fewer number of ARV options for treatment-experienced 
patients, there is a need for a more simplified regimen that may have a better long-term safety 
profile such as that of a nucleoside- and booster-sparing cART regimen. As discussed below, this 
study 
evaluates 
the 
merits 
of 
a 
nucleoside-sparing 
cART 
regimen 
and 
a 
nucleoside/booster-sparing cART regimen in Stage 1 and 2, respectively.
Given the aforementioned challenges with existing treatment in ARV treatment-experienced 
adults, the two primary objectives of this two stage, Phase 2b study are to: 1) To study the 
efficacy of one dose (120 mg) of BMS-955176 (a novel HIV-1 maturation inhibitor) when given 
in combination with atazanavir boosted with ritonavir (ATV/r) 300/100 mg and dolutegravir 
(DTG) 50 mg in Stage 1, and 2) to study the efficacy of two doses (120 and 180 mg) of 
BMS-955176 when given in combination with unboosted ATV 400 mg and dolutegravir (DTG) 
50 mg in Stage 2.
Ultimately this Phase 2b clinical trial will provide supportive data in the context of a therapeutic 
dose of BMS-955176 and the clinical safety/efficacy/resistance of the proposed component(s) of 
a single tablet regimen (STR, that is also a nucleoside/ritonavir sparing ARV strategy) for 
Phase 3 trial development in HIV-1 infected treatment-experienced subjects. Specifically, two 
arms in Stage 2 will contain the individual ARV components of a potential STR: BMS-955176, 
ATV, and DTG.
1.1.1
Rationale to support study design
This Phase 2b open-label clinical trial design is in general agreement with published Food and 
Drug 
Administration 
(FDA)
guidance.4
Initially,
in 
Stage 
1, 
approximately 
80 treatment-experienced HIV-1 infected subjects will be randomized 1:1 (approximately 40 per 
treatment group) to one experimental arm (Arm 1) and a TDF-containing arm (Arm 2) 
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(see Figure 3.1.6-1) to accomplish this study’s Stage 1 primary study objective: to study the 
efficacy of one dose (120 mg) of BMS-955176 when given in combination with ATV/r 
(300/100 mg) and DTG (50 mg). At the Week 24 primary endpoint of Stage 1 and AI468038, 
Bristol-Myers Squibb (BMS) will conduct an analysis of efficacy, safety, and pharmacokinetics; 
this analysis will be used to select a continuation dose for BMS-955176 in Arm 1 of study 
AI468048, trigger the start of Stage 2 of study in AI468048, and confirm the two doses of 
BMS-955176 for study in Stage 2 of study AI468048. Note, AI468038 is a concurrent Phase 2b 
study in HIV-1 infected treatment naive adults; the primary objective is to evaluate three doses 
of BMS-955176 (60, 120, and 180 mg) and EFV when given in combination with TDF/FTC by 
determining the proportion of subjects with HIV-1 RNA < 40 c/mL at Week 24.
To mitigate the clinical concerns of a potential subtherapeutic regimen and the subsequent 
development of virologic failure/resistance, the clinical trial design will contain a second stage. 
Specifically in Stage 2, approximately 120 additional treatment-experienced HIV-1 infected 
subjects will begin randomization 1:1:1 (approximately 40 per treatment group) to Arms 3, 4,
and 5 based upon the results of two concurrent analyses:

Results of the Week 24 analysis in Stage 1, including an analysis for virologic futility (see 
Section 8.4.7)

Results of the Week 24 analysis in AI468038 (treatment-naïve HIV-1 infected adults)
Thus, Stage 2 (Arms 3, 4, and 5) will not enroll if the likelihood of a subtherapeutic regimen 
(in Arms 3 and 4) is high based upon the results of the Week 24 analyses from either AI468038 
or Stage 1 of AI468048. Note, subjects in Arm 5 (Stage 2) will receive the same ARV regimen 
as subjects in Arm 2 (Stage 1); Arm 5 in Stage 2 exists to maintain similar baseline demographic 
and clinical characteristics among subjects who are randomized to the three Arms in Stage 2. 
This staged design allows Stage 2 (Arms 3, 4, and 5) to begin recruitment in a clinically 
de-risked fashion and accomplish this study’s Stage 2 primary study objective: to study the 
efficacy of two doses (120 mg and 180 mg) of BMS-955176 when given in combination with 
unboosted ATV 400 mg and DTG 50 mg. Ultimately, the totality of data from the Week 24 
primary endpoint of Stage 2 (Arms 3, 4, and 5), Stage 1 (Arms 1 and 2), and all arms in the 
AI468038 study will be used to select a continuation dose for BMS-955176 in Arms 3 and 4 of 
study AI468048. Across all five arms of this study, subjects will receive treatment with three 
fully-active ARVs (see Section 1.1.3, Rationale to support any drug combinations). Ultimately, 
subjects in experimental Arms 1, 3, and 4 will be given a continuation dose of BMS-955176 
which has acceptable efficacy, safety, and tolerability (see Figure 3.1.6-1) for subsequent 
development in HIV-1 treatment-experienced adults. 
In a recent clinical trial approximately 95% of randomized subjects were noted to be infected 
with HIV-1 clades B, C, and AE.5 Based on in-vitro studies, BMS-955176 is expected to be 
active against a variety of clades albeit with EC50s approximately 2-3 fold less toward HIV-1 
clade AE compared to clade B (see Section 1.4.1). Since the Phase 2a study AI468002 did not 
include any subjects infected with HIV-1 clade AE (see Section 1.4.1.3), this multinational 
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Phase 2b trial will stratify randomization to ensure each treatment arm has approximately the 
same number of HIV-1 clade AE infected subjects in their respective Stages and cap the number 
of HIV-1 clade AE subjects to a maximum of approximately 3 per treatment arm. The study 
duration is expected to be 96 weeks in length to assess durability of response and longer term 
safety and tolerability.
1.1.2
Rationale to support the dose selection
Phase 1 and Phase 2a clinical trials (AI4680016 and AI4680027) investigating BMS-955176 
utilized a spray-dried dispersion (SDD) suspension. However, this Phase 2b study will utilize a 
micronized crystalline (MC) tablet.
In the concomitant dose-finding Phase 2b study in HIV-1 infected treatment naive adults for 
BMS-955176 (AI468038), doses of BMS-955176 of 60 mg, 120 mg, and 180 mg MC tablet are 
proposed for assessment. These doses are based upon modeling and simulation and formulation 
considerations. A population pharmacokinetic model was developed using single dose 
(10 mg - 120 mg SDD) and multiple dose (10 mg to 80 mg SDD) data in healthy subjects 
(AI468001) as well as multiple dose data in HIV-1 clade B-infected subjects (5 mg to 120 mg
SDD for 10 days, AI468002). An exposure-response analysis was conducted using data from 
Part A of the Phase 2a clinical trial where HIV-1 clade B infected subjects received 
BMS-955176 monotherapy (Dose range: 5 - 120 mg) for 10 days. The exposure-response 
relationship was assessed via an Emax model using observed BMS-955176 steady state Cmin. The 
primary endpoint was predicted maximum viral load decline from baseline.
Steady state BMS-955176 Cmin values in HIV-infected subjects administered MC tablet with 
food were projected according to the following data and assumptions:

Exposures in HIV-infected subjects are 35% less than normal healthy volunteers based on 
observations from AI468001 and AI468002 study

Single dose data projected to multiple dose using accumulation index from AI468001 study

BMS-955176 exposures from the MC tablet formulation with food were projected based on 
studies AI468001 and AI468034. The impact of food on the 60 mg MC tablet dose was 
assumed to be that observed for the 40 mg MC suspension formulation in AI468001. 
Exposures to BMS-955176 120 mg MC tablet with food were determined from observed data 
in Study AI468034, where BMS-955176 C24 increased approximately 70% when 120 mg 
MC tablet was given with a high fat meal, relative to fasted conditions. Finally, exposures to 
BMS-955176 180 mg MC tablet with food were assumed to be 1.5-times that of 120 mg MC 
tablet with food
Figure 1.1.2-1 depicts the simulated maximum viral load decline in HIV-infected subjects 
administered BMS-955176 MC tablet under fed conditions.
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Figure 1.1.2-1:
Simulated Maximum Viral Load Decline from Baseline Under Fed 
Conditions1
1 Solid lines are 10th and 90th percentiles and the median of simulated data, shaded area is the 90% confidence 
interval of simulated data, vertical solid lines are the 25th to 75th percentile of the simulated steady state 
BMS-955176 Cmin for the 60 mg MC tablet dose, vertical dotted lines are the 25th to 75th percentile of the 
simulated steady state BMS-955176 Cmin for the 120 mg MC tablet dose, and vertical dashed and dotted lines 
are the 25th to 75th percentile of the simulated steady state BMS-955176 Cmin for the 180 mg MC tablet dose.
While baseline EC90 was not a covariate included in the model due to the lack of significance; 
this covariate, among others, was considered marginally significant and it is possible this 
covariate will become important with additional data.
Although data from AI468002 Part C (in HIV-1 clade C infected subjects) were not included in 
the exposure-response assessment described above, BMS-955176 doses 40 mg SDD once daily 
demonstrated median maximal reductions in HIV-1 RNA > 1 log10 in both clade B and clade C 
HIV-1-infected subjects (see Section 1.4.1.3); thus, doses of BMS-955176 60 mg, 120 mg, and 
180 mg are expected to yield a similar response in HIV-1 infected subjects of either clade.
Because the lowest dose assessed in AI468038 (BMS-955176 60 mg) has the potential for a 
suboptimal antiviral response and possible development of resistance, BMS-955176 120 mg in 
combination with ATV/r and DTG will be assessed in Stage 1 of this study. Based on previous 
data that demonstrated exposures to BMS-955176 increase approximately 50% when given in 
combination with RTV, exposures to BMS-955176 120 mg given in combination with ATV/r are 
expected to result in exposures similar to BMS-955176 180 mg given without RTV. Finally, 
BMS-955176 180 mg will not be used in Stage 1 because exposures (when administered with 
RTV) are expected to exceed those previously studied in clinical trials.
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Table 1.1.2-1 depicts the projected exposure multiples of BMS-955176 60 mg, 120 mg, and 
180 mg MC tablet with food at the NOAEL for pre-clinical findings of interest.
Table 1.1.2-1:
Exposure Multiples of BMS-955176 at NOAELa
Species/ Study 
NOAEL
Multiples
Dose 
(mg/kg/d)
Exposure
PK 
Parameter
60 mg
120 mg
180 mg
Rat/6-month (stomach 
histologic changes) 
No NOAEL
AUC
---
---
---
Dog/9-month (stomach 
histologic changes) 
1
AUC:
64.9 gh/mL
AUC 
3
2
1
Dog/1-month (heart rate)
20
Cmax:
17.8 g/mL 
Cmax
19
10
5
Dog/ Cardiovascular 
telemetry (heart rate) 
2
Cp:
1.93 g/mL 
Cmax
2
1
0.5
Mouse/EFD 
45
AUC:
197 gh/mL 
AUC
10
6
3
a Exposure multiple = animal value ÷ human value. Projected human Cmax values are 0.94, 1.79, and 3.61 g/mL 
and steady state AUC values are 19.3, 35.8, and 69.2 g•h/mL at 60, 120, and 180 mg in HIV-1 subjects 
receiving BMS-955176 MC tablets with high fat meal, respectively. High fat meal provides the highest exposure 
relative to other meal types or fasted state.
With regard to heart rate and the NOAEL of 1.93 g/mL observed in the cardiovascular 
telemetry study in dogs (N=2), it is noted that the projected exposure multiple is 1 at a dose of 
120 mg MC tablet in HIV-infected subjects. However, to date, there have been no clinically 
meaningful changes in heart rate observed in subjects treated with BMS-955176 up to 28 days
(in Part B of the Phase 2a study). With regard to stomach histologic changes, no NOAEL could 
be established based on the 6-month rat study and the projected exposure multiples from the 
9-month dog study are relatively low (eg, 2-fold at the 120 mg MC tablet dose). Despite these 
preclinical findings, a dose of BMS-955176 120mg MC tablet will provide exposures in this 
study which are expected to be generally safe and well tolerated based on existing clinical data 
(see Section 1.4.1).
Data from Study AI468034 demonstrated that BMS-955176 120 mg MC tablet AUC increased 
53% when given with a high fat meal, relative to fasted conditions. Furthermore, preliminary 
data from Study AI468049 demonstrated that a light meal, a standard meal, and a high fat meal 
increased BMS-955176 180 mg MC tablet AUC 1.8-, 2.1-, and 2.5-fold, respectively, relative to 
fasted conditions. Taken together, these data suggest that exposures to BMS-955176 MC tablet 
at doses up to 180 mg increase in a linear fashion when given with food and that similar 
exposures are observed regardless of meal type.
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In total, BMS-955176 120 mg is expected to be safe, well-tolerated, and efficacious in Stage 1 
and will inform the selection of a Stage 1 continuation dose and aspects of Stage 2 (as described 
in detail within Section 1.1.1).
The doses of BMS-955176 in Stage 2 will be confirmed based upon the Week 24 analyses
(efficacy, safety, and pharmacokinetics) of both Stage 1 and Study AI468038. As described in 
this protocol, the doses in Stage 2 are proposed to be BMS-955176 120 mg and 180 mg in Arms 
3 and 4, respectively.
1.1.3
Rationale to support any drug combinations
This study co-administers BMS-955176, with unboosted ATV 400 mg QD or ATV/r 300/100 mg
QD, and DTG 50 mg. The drug combinations within this clinical trial design will provide 
supportive data in the context of a therapeutic dose of BMS-955176 and the clinical 
safety/efficacy/resistance of the proposed components (Stage 2, Arms 3 and 4) of a single tablet 
regimen (STR) for Phase 3 trial development. Ultimately, BMS will seek approval of
BMS-955176 for use in treatment-experienced HIV-1 infected adults (including either a STR; 
FDC; and/or monoentity). 
The rationale for using a backbone of ATV and DTG in this treatment-experienced patient 
population is based upon established safety, efficacy, and tolerability of the individual 
components. DTG alone provides a 2.46 log10 c/mL reduction in HIV-1 RNA when administered 
as monotherapy for 10 days.8 Furthermore, DTG has been recently approved and is generally 
safe.9,10,11,12,13 Lastly, ATV/r is often used in treatment-experienced adults’ second-line therapies 
or beyond (for example, in individuals who may have failed an non-nucleoside reverse 
transcriptase inhibitor (NNRTI) and/or integrase inhibitor (INI) based regimen).2,4
This Phase 2b design allows treatment-experienced adults in the experimental Arms to be 
exposed to three fully active ARVs (from three classes). Subjects will benefit from each ARV 
(except
RTV) independently providing a > 1 log10
c/mL decrease in HIV-1 RNA
(see Section 1.4.1.3 for details on Phase 2a results [AI468002]). BMS expects the combination of 
two agents (unboosted ATV and DTG) with one investigational agent (BMS-955176) to provide 
a generally improved safety/tolerability profile relative to the respective arm containing ATV/r 
(Arms 3 and 4 relative to Arm 1, respectively) or TDF (Arms 3 and 4 relative to Arm 5, 
respectively).
There is a potential risk of a subtherapeutic regimen to treatment-experienced subjects enrolled 
in Arms 3 and 4 since unboosted ATV is only approved for use in treatment-naïve HIV infected 
adults (within the US) and the therapeutic dose of BMS-955176 has not been established.
Unboosted ATV (400 mg) in treatment-naïve adults results in a 1.41 log10 c/mL reduction in 
HIV-1 RNA after two weeks of monotherapy.14 Despite the monotherapy based reduction in 
HIV-1 RNA, pharmacokinetic data of unboosted ATV in prospective clinical trials,15
cross-sectional,16 and retrospective analyses17 generally supports the finding of DHHS defined 
subtherapeutic ATV levels (< 150 ng/mL) in patients.18
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In a randomized, open-label clinical trial, ATV/r has demonstrated non-inferiority to unboosted 
ATV (TLVOR: 75% vs 70% VR-OC: 87% vs 76%, respectively), similar declines in HIV-1 
RNA (approx -3.1 log10 c/mL), and increase in CD4 cell counts within treatment-naïve adults. 
However, the unboosted ATV arm had an increased number of subjects with emerging ATV and 
lamivudine (3TC) resistance. In particular, the difference in nucleoside/nucleotide reverse 
transcriptase inhibitor (NRTI) resistance was markedly greater in the unboosted ATV compared 
to RTV boosted ATV arm.19 Of note, in this clinical trial (AI468048) NRTIs are not used in the 
experimental Arms 1, 3, and 4. Similar single arm, prospective studies have replicated the viral 
efficacy and immunologic response using unboosted ATV in treatment-naïve HIV infected 
adults.20
Insights from limited data regarding the use of unboosted ATV in treatment-experienced adults 
have demonstrated a viral decay ranging from -1.4 to -2.7 log10 c/mL over 24 weeks of therapy 
in combination with NRTIs (such as TDF, 3TC, and didanosine).21 Also, observational data 
(mean: 24 months of follow-up) has shown similar percentages of subjects with their last HIV 
RNA being undetectable (80% vs 83%) after receiving unboosted and RTV boosted ATV, 
respectively.22
Taking the key findings from studies of ATV in both treatment-naïve and treatment-experienced 
HIV infected adults, Arms 3 and 4 containing unboosted ATV may have the potential for 
increased resistance (relative to Arm 1 containing RTV boosted ATV) and the development of 
virologic failure. However, several other factors must be taken into consideration. First, these 
Arms will use three potent (> 1 log10
c/mL) ARVs in combination. Moreover, 
treatment-experienced subjects who have failed one or two prior regimens are likely to be either 
naïve to ATV treatment (prior NNRTI- and/or INI-class failure) or will need to be fully 
susceptible to approved ARVs (including unboosted ATV, see Section 3.3.2). Second, both the 
combination of ATV and DTG with BMS-955176 independently have demonstrated additivity to 
synergy in-vitro23 (see Section 1.4.1.3 for clinical data on the combination of ATV and 
BMS-955176). Third, unboosted ATV increases the geometric mean ratio of Ctrough for DTG by 
a factor of 2.8.24 Fourth, in normal healthy volunteers, multiple dose administration of 
BMS-955176 40 mg (SDD suspension formulation) with ATV 400 mg for 14 days resulted in an 
approximate 25% increase in the AUC(TAU) of BMS-955176 administration alone25 and 
preliminary PK data from the Phase 2a (AI468002) demonstrated that BMS-955176 AUC(TAU) 
increased approximately 37% and 52% when ATV was combined with BMS-955176 40 and 
80 mg (SDD suspension formulation), respectively, relative to administration of BMS-955176 
alone. It is clinically unclear whether higher exposures of DTG and BMS-955176 would lead to 
a decreased incidence of unboosted ATV resistance in the context of Arms 3 and 4 
(BMS-955176 120 and 180 mg + ATV + DTG). Combined with these factors, BMS proposes to 
mitigate the potential risk of increased resistance by 1) studying two doses of BMS-955176 
(120 and 180 mg) in combination with unboosted ATV and DTG, and 2) using a two stage 
clinical trial design with Stage 2 (Arms 3, 4, and 5) enrolling after the Week 24 analysis
(efficacy, safety, and pharmacokinetics) of Stage 1 (Arms 1 and 2) and AI468038 are completed, 
and 3) only enrolling subjects who are susceptible to study medication (including unboosted 
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ATV) (see Section 1.1.1, Rationale to support study design). This risk mitigation is employed to
increase the probability of establishing clinical efficacy (number of responders at the Week 24) 
in treatment-experienced HIV-1 infected adults.
BMS expects BMS-955176 120 and 180 mg given with unboosted atazanavir to be generally 
safe and well-tolerated. Subjects in Arms 3 and 4 treated with unboosted ATV would potentially 
benefit from a more favorable lipid profile, fewer gastrointestinal (GI) side effects, and 
decreased indirect hyperbilirubinemia. In total, the potential clinical risks for subjects 
randomized to Arms 3 and 4 in Stage 2 do not outweigh the potential benefits of a Nucleoside-
and Booster-sparing cART regimen that may offer both efficacy and long-term safety (including 
but not limited to improved bone mineral density, improved renal function, and improved lipid 
profile). Please see Section 1.5 for further details on the overall risk/benefit assessment.
1.2
Research Hypothesis 
This Phase 2b study will evaluate whether the combination of BMS-955176 with ATV (with or 
without RTV)
and DTG
is efficacious, safe, and well-tolerated
in HIV-1 infected 
treatment-experienced adults.
1.3
Objectives(s)
1.3.1
Primary Objective
Primary Objective Stage 1

To assess the antiviral efficacy of BMS-955176 120 mg, and a TDF 300 mg-containing arm,
each when given in combination with ATV/r 300/100 mg and DTG 50 mg by determining 
the proportion of treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at 
Week 24 in Stage 1.
Primary Objective Stage 2

To assess the antiviral efficacy of two doses (120 and 180 mg) of BMS-955176, each when 
given in combination with unboosted ATV 400 mg and DTG 50 mg, and to assess the 
antiviral efficacy of TDF 300 mg when given in combination with ATV/r 300/100 mg and 
DTG 50 mg by determining the proportion of treatment-experienced subjects with plasma 
HIV-1 RNA < 40 c/mL at Week 24 in Stage 2. 
1.3.2
Secondary Objectives

To assess the antiviral efficacy of BMS-955176 Arms, and the TDF-containing Arms (TDF + 
ATV/r + DTG), by determining the proportion of treatment-experienced subjects with plasma 
HIV-1 RNA < 40 c/mL at Weeks 48 and 96

To assess the antiviral efficacy of BMS-955176 Arms, and the TDF-containing Arms, by 
determining the proportion of treatment-experienced subjects with plasma HIV-1 RNA 
< 200 c/mL at Weeks 24, 48, 96

To assess the emergence of HIV drug resistance in samples selected for drug resistance 
testing (according to criteria outlined in Section 5.4.1)
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
To assess efficacy of BMS-955176 Arms, and the TDF-containing Arms, by using the mean 
changes from baseline in log10 HIV-1 RNA, CD4+ T-cell counts, and percentage of CD4+ 
T-cells

To assess the safety and tolerability of BMS-955176 in treatment-experienced subjects by 
measuring frequency of SAEs and AEs leading to discontinuation

To assess disease progression as measured by the occurrence of new AIDS defining events 
(CDC Class C events)

To characterize the pharmacokinetics of BMS-955176 when co-administered with ATV 
(with or without ritonavir) and DTG in treatment-experienced HIV-1 infected subjects
1.3.3
Exploratory Objectives

To determine the effect of BMS-955176 Arms, and the TDF-containing Arms, on renal 
clinical parameters and biomarkers through Weeks 48 and 96

To determine the effect of BMS-955176 Arms, and the TDF-containing Arms, on bone 
biomarkers through Weeks 12 and 24

To assess the impact of baseline (pre-therapy) Gag polymorphisms on the efficacy of 
BMS-955176 Arms by determining the proportion of treatment-experienced subjects with 
plasma HIV-1 RNA < 40 c/mL, HIV-1 RNA < 200 c/mL, and the changes from baseline in 
log10 HIV-1 RNA at Weeks 24, 48 and 96, by baseline polymorphisms

To characterize the steady-state plasma PK of DTG when co-administered with BMS-955176 
and ATV (with or without RTV) in treatment-experienced subjects. The effect of 
BMS-955176 on DTG PK in the presence of ATV (without RTV) may be assessed relative to 
historical data

To compare steady-state exposures of DTG when co-administered with BMS-955176 and 
ATV/RTV to DTG when co-administered with TDF and ATV/RTV

To characterize the PK of ATV when co-administered with DTG and BMS-955176, with or 
without RTV

To explore PK/PD and PK/viral kinetic (VK) relationships between BMS-955176, ATV, 
and/or DTG exposure and both efficacy and safety endpoints

To assess the impact of the study therapies on health-related quality of life measures
1.4
Product Development Background
1.4.1
Background Information BMS-955176
1.4.1.1
Mechanism of Action
BMS-955176 is an HIV-1 maturation inhibitor (MI), a novel class of anti-HIV-1 drugs that 
prevents the maturation of HIV-1 virions by binding near a key structural element within the Gag 
polyprotein that is required for virion maturation and assembly. Maturation inhibitors block the 
last protease cleavage event between Gag protein segments designated as capsid (CA) protein 
p24 (p24) and spacer peptide 1 (SP1), resulting in the release of immature noninfectious virus 
particles. BMS-955176 has excellent potency and broad spectrum activity, and mechanism of 
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action studies indicate that BMS-955176 is a true MI, with a mechanism of action distinct from 
current antiretroviral agents.26 Development of BMS-955176 could potentially lead to novel 
HIV-1 treatment regimens in treatment-experienced HIV-1 patients.
1.4.1.2
Nonclinical studies
Nonclinical Pharmacology and Microbiology
BMS-955176 specifically inhibits HIV-1 protease cleavage at the CA(p24)/SP1 junction within 
the Gag protein in both HIV-1-infected cells and purified HIV-1 Gag virus-like particles (VLPs). 
Radiolabeled BMS-955176 specifically binds to purified HIV-1 Gag VLPs, and its binding is 
dose-dependently inhibited by related MIs and is reversible. BMS-955176 does not directly 
inhibit HIV-1 protease nor bind to a small HIV-1 protease peptide substrate. These results 
indicate that BMS-955176 inhibits late in the HIV-1 life cycle by specific binding to immature 
capsid structures at or near the CA(p24)/SP1 junction, thereby inhibiting cleavage at that 
particular site. In cell culture, the range of values for the concentration producing 50% effect 
(EC50) of BMS-955176 against 7 common laboratory strains of HIV-1 was 1.6 to 10.5 nM 
(mean = 6.0 3.5 nM). Using a reverse transcriptase readout, a phenotyping analysis of 
93 subtype B viruses whose genotypes are representative of 96% of the diversity (found in the 
Los Alamos National Laboratory [LANL] database) in Gag sequences indicates that the mean 
EC50 of this cohort was 2.7 1.9 nM, with a median value of 2.2 nM and a range between 0.6 to 
12 nM. A similar analysis of 23 isolates of subtype C viruses found a mean EC50 of 
6.1 3.1 nM, a median value of 5.6 nM, and a range from 2.5 to 16 nM. When evaluated against 
clinical isolates in peripheral blood mononuclear cells (PBMCs), BMS-955176 exhibited a mean 
EC50 of 24 24 nM against a cohort (N = 22) of subtype B viruses. Activity was also observed 
against viruses from subtypes A, C, D, F, and G, with average EC50 values for 96% of tested 
isolates (N = 41) between 5.9 and 87 nM. Clinical isolates from the CRF01_AE subtype were 
approximately 2- to 3-fold less susceptible to BMS-955176 (average EC50 77 nM, N = 7) 
viruses. BMS-955176 was active against 1 of 3 human immunodeficiency virus type-2 (HIV-2)
isolates (EC50 = 15 nM). BMS-955176 retains complete activity against reverse transcriptase 
(RT), protease, and integrase inhibitor-resistant viruses, with EC50 values similar to wild-type 
(wt) viruses, while the potency of currently approved nucleotide/nucleoside reverse transcriptase 
inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors 
(PIs), and integrase inhibitors (INIs) was undiminished when tested against viruses with reduced 
susceptibility to BMS-955176. BMS-955176 maintained activity against a panel of PI-resistant 
isolates from PI-treated subjects harboring a variety of major and minor PI-resistance
determinants in both protease and Gag.27,28 Protein binding to 100% human serum (HS) was 
86%, and in the presence of 40% HS supplemented with additional human serum albumin 
(HuSA) to match physiologic concentrations, BMS-955176 exhibited an approximately 4-fold 
reduction of antiviral activity. Selection for resistance to BMS-955176 in cell culture identified
changes that map to amino acids adjacent to the CA(p24)/SP1 cleavage site. These include an 
amino acid substitution of A364V or a combination of V362I with secondary changes (V370A, 
A374P or I376V). In vitro, virus with the A364V change exhibited a drastic loss of susceptibility 
to BMS-955176 (>100-fold), while the V362I plus secondary change-containing viruses were 
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generally less sensitive to BMS-955176 (median EC50 25 nM, range 7.1 to 167 nM). In 2-drug 
combination studies with representative drugs from NRTI, NNRTI, PI, and INI classes, all 
combinations produced additive to synergistic effects, suggesting that BMS-955176 should be 
amenable for use in combination with any of these agents.
Bevirimat (BVM), a first-generation MI, demonstrated proof of concept and dose-dependent 
anti-HIV-1 potency in both Phase 1 and Phase 2 clinical studies. Patients infected with HIV-1 
sensitive to BVM demonstrated an approximate 1.2 log10 decline in HIV-1 RNA. However, 
approximately 50% of patients harboring naturally occurring polymorphisms located close to the 
CA(p24)/SP1 cleavage site showed a significantly reduced response to BVM treatment. In 
addition, BVM exhibited a large reduction in antiretroviral activity in the presence of human 
serum. BMS-955176 was developed to address the key flaws of BVM by providing improved 
coverage of BVM-resistant polymorphic variants and improved potency in serum. BMS-955176 
has been shown to be active against viruses with resistance from all marketed ARVs, and to 
possess a low serum effect. Development of BMS-955176 could potentially lead to novel HIV-1 
treatment regimens in treatment-experienced HIV-1 patients.
Nonclinical Pharmacokinetics
The absolute oral bioavailability of BMS-955176 was low (3.89% to 26.8%) in all preclinical 
species (mice, rats, dogs, and monkeys). In the dog, though there was a positive food effect and 
no pH dependent absorption, upon repeat dosing a less than dose-proportional increase in 
exposure was observed. BMS-955176 distributed preferentially into the duodenum, liver, and 
lymph nodes with little penetration into the brain. Protein binding was 86.1% in human serum 
and 78% to 94% in animal sera
In human in vitro systems, the metabolism of BMS-955176 was primarily mediated via 
cytochrome P450 (CYP)3A4. In vivo in rats, dogs, and monkeys, BMS-955176 was the 
predominant drug-related component in plasma following a single oral dose of BMS-955176. 
BMS-955176 was eliminated principally via metabolism followed by excretion in bile with little 
renal excretion. 
In vitro, BMS-955176 was an inhibitor of CYP2C8 (concentration at which 50% inhibition 
observed [IC50] = 28.5 M), CYP3A4 (IC50 = 32 M), and uridine diphosphate 
glucuronosyltransferase (UGT)1A1 (IC50 = 20 M) enzymes. No P-gp inhibition or 
time-dependent inhibition of CYPs was observed. BMS-955176 was not an inducer of CYP1A2, 
CYP2B6, or CYP3A4. The steady state Cmax of BMS-955176 180 mg tablet in HIV-infected 
patients with food is projected to be approximately 5.2 M. Thus, the potential exists for 
BMS-955176 to inhibit CYP2C8, CYP3A4, and/or UGT1A1 in vivo and increase exposures to 
co-administered drugs that are metabolized by these enzymes. Furthermore the potential exists 
for drug-drug interactions (DDI) if BMS-955176 is co-administered either with an inhibitor or 
inducer of CYP3A4 or P-gp.
BMS-955176 was a substrate of mouse P-glycoprotein (P-gp) based on higher bioavailability in 
P-gp knock-out mice when BMS-955176 was co-administered with elacridar, a potent inhibitor
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of P-gp and breast cancer resistance protein (BCRP). BMS-955176 could not be reliably assessed 
as a substrate for human P-gp due to nonspecific binding and low solubility. In vitro, 
BMS-955176 inhibited organic anion transporting polypeptide (OATP)1B1 and OATP1B3 
(IC50 5.3 and 4 M, respectively), but was not an inhibitor of P gp, sodium taurocholate 
cotransporting polypeptide (NTCP), organic anion transporter (OAT)1, OAT3, multiple 
drug-resistance protein (MRP)2, and bile salt export pump (BSEP). These findings suggest a 
potential for DDI between BMS-955176 (as the perpetrator) and substrates of OATP1B1 and 
OATP1B3, but not with those of P-gp, NTCP, OAT1, OAT3, MRP2, and BSEP. Furthermore, 
the potential exists for drug-drug interactions (DDI) if BMS-955176 is co-administered either 
with an inhibitor or inducer of CYP3A4 or P-gp. Preliminary data indicate that BMS-955176 
does not inhibit OCT2, a transporter that is inhibited by dolutegravir (DTG), a drug with which 
BMS-955176 is planned to be co-administered.
Nonclinical Toxicology
The toxicity profile of BMS-955176 was evaluated in single- and repeat-dose toxicity, 
genotoxicity, phototoxicity, safety pharmacology, sensitization, reproductive toxicity and 
embryo-fetal development studies. The scope of the toxicologic evaluation for BMS-955176
supports its proposed clinical use for HIV-1 infection. Unless otherwise mentioned, all animal 
studies were dosed by the oral route with an aqueous methylcellulose suspension of a 
BMS-955176 spray-dried dispersion (SDD). 
BMS-955176 was not phototoxic, mutagenic, or clastogenic in vitro and was not genotoxic in a 
rat micronucleus assay at 300 mg/kg/day (AUC 279 g·h/mL). BMS-955176 was not a skin 
sensitizer in the local lymph node assay in the mouse. BMS-955176 had a low potential (IC50 or 
EC50 > 5 M [> 3.45 µg/mL]) for in vitro off-target interactions on a broad range of enzymes, 
transporters, and receptors, including cardiac ion channels. 
In safety pharmacology evaluations in rats, there were no respiratory findings and no direct 
central nervous system (CNS) findings. Decreases in motor activity, arousal, and rearing were 
considered secondary to general toxicity (ie, body weight decreases).
Cardiovascular safety pharmacology evaluations were conducted in rabbits, rats, and dogs. In the 
definitive oral single-dose cardiovascular safety study in conscious telemeterized dogs, blood 
pressure and electrocardiogram were was unaffected at 20 mg/kg; however, increases in heart 
rate (mean 33% to 57% of pretest vehicle) were observed at 8 and 20 mg/kg. The increase in 
heart rate at these doses was primarily due to increases in 2 dogs at each dose that had higher 
plasma concentrations (12.83 g/mL) relative to the dogs without effects on heart rate 
(6.81 g/mL). The no-observed-effect level (NOEL) for cardiovascular effects in dogs was 
2 mg/kg (plasma concentration of 1.93 µg/mL). Importantly, there was no change in heart rate at 
20 mg/kg/day at higher plasma concentrations (Cmax 17.8 µg/mL) in the 1-month study in 
dogs (below). 
Taken together, BMS-955176 has low potential for respiratory, CNS, and cardiovascular effects 
and no cardiovascular effects have been observed in humans to date.
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Two-week, 1-month, and 6-month studies were conducted in rats. As the 2-week study was of 
limited scope, only the 1-month and 6-month studies are presented in this summary. 
BMS-955176 was administered for 1 month at doses of 30, 100, or 300 mg/kg/day. While there
was no mortality at 100 mg/kg/day, the high dose of 300 mg/kg/day was associated with 
pronounced signs of clinical toxicity and early euthanasia of all the rats at that dose level on 
Days 8 to 9. The dose of 30 mg/kg/day was tolerated. The intermediate dose of 100 mg/kg/day 
(AUC 357 g·h/mL) resulted in dose-limiting toxicity including persistent reduction in food 
consumption and body weights. A number of minor hematology (including red cell parameter 
changes with no consistent effect on the erythron) and serum chemistry changes (including 
increased alkaline phosphatase and alanine aminotransferase) without correlating histologic liver 
findings) occurred at 30 and 100 mg/kg/day; these changes were considered not adverse due to 
small magnitude, occurrence only in 1 sex, and lack of microscopic correlates, and most were 
secondary to decreases in food consumption and body weight. Dose-related gastrointestinal 
toxicity was primarily characterized by morphologic changes in the stomach at 100 mg/kg/day 
and the stomach and small and large intestines at 300 mg/kg/day. At the end of the 2-week 
postdose recovery period, there was complete recovery of all BMS-955176-related findings at 
30 mg/kg/day. At 100 mg/kg/day, all findings recovered with the exception of increased red cell 
distribution width in females, minimally higher (1.94×) ALT activity in 1 male without any 
histologic correlates, and decreased mean prostate gland (with seminal vesicles) weights. The 
low dose of 30 mg/kg/day (AUC 113.5 g·h/mL) was considered the no-observed-adverse-effect 
level (NOAEL) because the body weight and food consumption changes were minimal and 
transient and there were no BMS-955176-related morphologic changes.
In a 6-month oral toxicity study in rats with 1-month recovery period, BMS-955176 was 
administered at doses of 10, 25, or 50 mg/kg/day. BMS-955176-related effects were similar to 
those observed in the 1-month rat study and occurred at all doses (10 mg/kg/day; 
AUC 71 gh/mL). Findings included decreased body weight, food consumption, and in the 
stomach, minimal to marked atrophy involving both parietal and chief cells, minimal to mild 
single-cell necrosis and minimal regeneration in the glandular mucosa, which were partially 
reversible at the end of the 1-month recovery period. A NOAEL was not established in this 
study.
Five-day, 1-month, and 9-month repeat-dose studies were conducted in dogs. As the 5-day 
toxicokinetics and tolerability studies were of limited scope, only the 1-month and 9-month
studies are presented here. In the 1-month study, BMS-955176 was administered at doses of 2, 8, 
or 20 mg/kg/day. Increased incidences of sporadic vomiting and liquid, yellow, and/or mucoid 
feces occurred at all doses, but had no apparent effect on the overall health of these animals. 
At 20 mg/kg/day, additional findings included occasional decreases in food consumption in a 
few animals, loss of body weight (up to 8%) in 2 females, a minimal increase in serum ALT 
activity (2.10× pretest) in 1 female with no microscopic correlates, and minimal single-cell 
necrosis of stomach glandular epithelium. All BMS-955176-related changes were fully 
reversible by the end of the 2-week recovery period. The dose of 8 mg/kg/day was considered a 
NOAEL (AUC 219.5 g·h/mL) since the sporadic clinical observations had no adverse effects 
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on the general health of the animals and there were no BMS-955176-related morphologic 
changes. 
In a 9-month oral toxicity study in dogs with 1-month recovery period, BMS-955176 was 
administered at 0 (vehicle), 1, 3, or 10 mg/kg/day. BMS-955176-related effects were similar to 
those observed in the 1-month dog
study
and
occurred at doses 3 mg/kg/day 
(AUC 135 gh/mL). Findings included salivation (only males at 10 mg/kg/day), fur thinness 
(males), thin appearance, and abnormal feces (yellow, liquid, pale and/or mucoid) that occurred 
sporadically throughout the study; increases in mean food consumption; minimal to marked chief 
cell depletion in the glandular stomach. Additional findings at 10 mg/kg/day included thin 
appearance that correlated with decreases in body weight in food consumption; occasional 
vomitus in males; in the stomach, minimal to moderate mucous cell hyperplasia (often associated 
with glandular dilatation) correlating with increased thickness macroscopically (males only) and 
minimal to marked parietal cell depletion and single-cell necrosis of glandular epithelial cells; 
and increases in serum gastrin values (1.31 to 4.56× highest control value) for several dogs that
may have reflected the reductions in gastric parietal cells. The NOAEL was 1 mg/kg/day 
(AUC 64.9 gh/mL).
The embryo-fetal development (EFD) studies were conducted in 3 species (rabbits, rats, and 
mice) instead of the standard 2 species due to poor maternal tolerability and inability to achieve 
adequate systemic exposures in rabbits.
In a definitive EFD study in pregnant mice, BMS-955176 was administered at doses of 15, 45, or 
150 mg/kg/day from gestation day (GD) 6 through 15. BMS-955176 was a selective 
developmental toxicant in mice. Dose of 100 mg/kg/day was associated with an increase in 
embryo-fetal lethality (cumulative postimplantation losses of 11.5%, relative to 3.9% in control 
litters, attributed to increased incidences of dead fetuses, early resorptions and late resorptions). 
Cleft palate and exencephaly were observed in a few fetuses; additionally, marginal reductions in 
fetal body weight (5% relative to control values) were observed. There was no maternal toxicity 
at any dose tested. The developmental NOAEL was 45 mg/kg/day (AUC 213 g·h/mL).
In a definitive EFD study in pregnant rats, BMS-955176 was administered at doses of 10, 30, or 
100 mg/kg/day from GD 6 through 15. BMS-955176 was not a selective developmental toxicant. 
Developmental toxicity (reduced fetal body weights, increases in fetal alterations, and reduced 
fetal ossification) occurred only at 100 mg/kg/day; whereas, maternal toxicity (clinical 
observations, reduced body weights, and reduced food consumption) was observed at 
30 mg/kg/day. The developmental NOAEL was 30 mg/kg/day (AUC 114 gh/mL). 
In an EFD study in pregnant rabbits, BMS-955176 was administered at a dose of 80 mg/kg/day 
from GD 7 through 19. BMS-955176 was not a developmental toxicant in rabbits at 
80 mg/kg/day (AUC 3.26 gh/mL), at which reductions in maternal food consumption and 
weight gain were observed.
In the fertility and early embryonic development study in rats, BMS-955176 was evaluated at 
doses of 10, 30, or 100/60 mg/kg/day in males and females. BMS-955176 did not affect 
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reproduction or early embryonic development at doses 100 mg/kg/day that produced overt 
toxicity. The reproductive NOAEL was 100/60 mg/kg/day (AUC 210 g•h/mL) in male rats and
100 mg/kg/day (AUC 458 g•h/mL) in female rats.
Overall, results from the nonclinical toxicology studies demonstrate that BMS-955176 has a low 
potential for cardiovascular effects, is toxic to the gastrointestinal tract, and is a selective 
developmental toxicant. Clinical monitoring of vital signs (heart rate, systolic and diastolic blood 
pressure) and for gastrointestinal adverse events (AEs) (eg, nausea, vomiting, diarrhea, or fecal 
changes), along with screening for potential renal tubular injury, have not indicated any potential 
for these AEs in Phase 1 or proof of concept (POC) studies in humans. Clinical protocols will 
ensure that appropriate contraceptive measures will be followed to minimize the risk of 
pregnancy while enrolling women of child-bearing potential (WOCBP) males subjects who are 
sexually active with (see Section 3.3.1 Inclusion Criteria).
1.4.1.3
Clinical studies
Phase 1
The safety, tolerability, and PK of BMS-955176 were evaluated in a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD, 10-120 mg) and multiple ascending 
dose (MAD, 10-80 mg QD for 14-28 days) study in healthy subjects (AI468001). No SAEs, 
deaths, or discontinuations related to study drug occurred. No clinically meaningful trends were 
observed in vital signs, physical exam findings, laboratory values, or ECGs. Following 
single-dose and multiple-dose administration of BMS-955176, a slightly less than 
dose-proportional increase in Cmax and AUC(INF) was observed over the dose ranges studied. 
Steady state was reached in approximately 7 days following multiple-dose once daily 
administration of BMS-955176. The half life (T-HALF) of BMS-955176 is approximately 
35 hours. 
Study AI468034 assessed the relative bioavailability and dose proportionality of BMS-955176 
MC tablet - the formulation that will be used in the current study. Relative to 80 mg SDD 
suspension, the bioavailability of BMS-955176 120 mg MC tablet was approximately 23% 
lower. Furthermore, consistent with the low solubility of BMS-955176, considerable overlap in 
exposures was observed between 60 mg, 120 mg and 180 mg MC tablet, when given under 
fasted conditions. The impact of food on exposures to BMS-955176 120 mg MC tablet was 
assessed in Study AI468034 as well; a high fat meal increased BMS-955176 AUC approximately 
50% with negligible impact on BMS-955176 Cmax.
Study AI468049 assessed the impact of a light meal, a standard meal, and a high fat meal on the 
PK of BMS-955176 180 mg MC tablet. Preliminary results demonstrate that, relative to fasted 
conditions, BMS-955176 Cmax is increased approximately 2-fold with all three meal types, while 
BMS-955176 AUC increased approximately 1.8-, 2.1-, and 2.5-fold with a light meal, a standard 
meal, and a high fat meal, respectively. These results, taken together with those from AI468034 
described above, demonstrate that the impact of food on exposures to BMS-955176 is 
dose-dependent with the degree of impact increasing with increasing dose. Preliminary safety 
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results from AI468049 indicate that GI adverse events (eg, nausea, vomiting, loose stools) only 
occurred in the fed arms (where the BMS-955176 exposures were higher) relative to the fasted 
arms.
Study AI468049 assessed the impact of a light meal, a standard meal, and a high fat meal on the 
PK of BMS-955176 180 mg MC tablet. Preliminary results demonstrate that, relative to fasted 
conditions, BMS-955176 Cmax is increased approximately 2-fold with all three meal types, while 
BMS-955176 AUC increased approximately 1.8-, 2.1-, and 2.5-fold with a light meal, a standard 
meal, and a high fat meal, respectively. These results, taken together with those from AI468034 
described above, demonstrate that the impact of food on exposures to BMS-955176 is 
dose-dependent with the degree of impact increasing with increasing dose.
Phase 2a
A randomized, double-blind, placebo-controlled proof of concept study in HIV subjects has 
completed enrollment and is undergoing analysis (AI468002). The three parts of this study were: 
1) Part A evaluated doses of 5, 10, 20, 40, 80, and 120 mg of BMS-955176 (SDD suspension) 
given for 10 days in HIV-1 clade B infected subjects, 2) Part B compared the antiviral activity of 
BMS-955176 (SDD suspension) administered with ATV (with or without RTV) against standard 
of care (TDF + FTC + ATV/r) for 28 days in HIV-1 clade B infected subjects, and 3) Part C 
evaluated BMS-955176 40 and 120 mg (SDD suspension) given for 10 days in HIV-1 clade C 
infected subjects. See Table 1.4.1.3-1 for baseline demographics. 
Preliminary results from the Phase 2a study (AI468002) in HIV-1 (clade B and C only) infected 
adults showed that at effective doses, a maximum median reduction in HIV-1 RNA ranging from 
1.3 to 1.7 log10 was observed. In the Phase 2b study BMS-955176 doses estimated to provide 
similar exposure to effective doses in the Phase 2a study will be used. Moreover, when 
BMS-955176 was combined with ATV RTV, these combinations resulted in maximum median 
declines in HIV-1 RNA ranging from 1.9 to 2.2 log10 (see Table 1.4.1.3-2). These results are 
generally similar to the antiviral effect demonstrated by other classes of ARVs in short-term
monotherapy trials, and thus BMS-955176 should contribute substantially with other ARVs to 
form an effective cART regimen. Lastly, preliminary safety data show acceptable safety and 
tolerability across all Phase 2a arms. Most AEs were Grade 1-2 and were most frequently due to 
an indirect hyperbilirubinemia; the levels seen with BMS-955176 and ATV/r were similar to 
those seen with ATV/r combined with TDF/FTC. The arms containing BMS-955176 and 
unboosted ATV had bilirubin levels that were approximately half of those observed in the arms
containing ATV/r. Last, arms containing BMS-955176 alone did not show elevated bilirubin
levels. Many of these events occurred in subjects who were randomized to an arm containing 
BMS-955176 and ATV. Of the Grade 2-4 related AEs, many were due to headache and an 
increase in hyperbilirubinemia. Many of the AEs of hyperbilirubinemia occurred in subjects also 
receiving ATV.
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Table 1.4.1.3-1:
Phase 2a Baseline Demographics and Characteristics of Subjects 
(Preliminary Results)
Treatment Arm
Subjects
(n)
Median 
age
Male
White
Median 
HIV 
RNA 
(log10
c/ml)
Median 
CD4 
(cells/mm3)
Part A (Clade B, 10 days 
monotherapy)
BMS-955176 5 mg
8
43.5
8 (100)
6 (75.0)
4.09
437
BMS-955176 10 mg
8
39
7 (87.5)
7 (87.5)
4.02
539
BMS-955176 20 mg
8
33
8 (100)
8 (100)
3.59
512
BMS-955176 40 mg
8
38
8 (100)
8 (100)
4.03
536
BMS-955176 80 mg
8
31.5
8 (100)
8 (100)
3.82
504
BMS-955176 120 mg
8
37.5
8 (100)
8 (100)
3.84
498
Placebo
12
36
12 
(100)
12 
(100)
3.98
458
Part B (Clade B, 28 days therapy)
BMS-955176 40 mg + ATV 400 mg
8
32.5
8 (100)
6 (75)
4.04
581
BMS-955176 40 mg + ATV 300 mg + 
RTV 100 mg
8
34
8 (100)
8 (100)
4.45
480
BMS-955176 80 mg + ATV 400 mg
8
31.5
8 (100)
7 (87.5)
4.15
549
Truvada® + ATV 300 mg + RTV 
100 mg
4
32.5
4 (100)
4 (100)
4.12
427.5
Part C (Clade C, 10 days 
monotherapy)
BMS-955176 40 mg
7
35
4 (57.1)
2 (28.6)
4.53
554
Placebo
2
38.5
2 (100)
0 (0)
3.78
304
Table 1.4.1.3-2:
Maximum Decline Log10 HIV-1 RNA (Preliminary Results)
Treatment 
Mean 
S.D. 
Median 
Max
Min
Part A (Clade B, 10 days monotherapy)
BMS-955176 5 mg
-0.49
0.217
-0.498
-0.78
-0.22
BMS-955176 10 mg
-1.05
0.351
-0.976
-1.76
-0.64
BMS-955176 20 mg
-1.17
0.645
-1.115
-2.12
-0.13
BMS-955176 40 mg
-1.55
0.352
-1.701
-1.88
-0.93
BMS-955176 80 mg
-1.52
0.257
-1.555
-1.82
-1.04
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Table 1.4.1.3-2:
Maximum Decline Log10 HIV-1 RNA (Preliminary Results)
Treatment 
Mean 
S.D. 
Median 
Max
Min
BMS-955176 120 mg
-1.53
0.478
-1.654
-2.07
-0.83
Placebo
-0.48
0.581
-0.381
-1.46
0.56
Part B (Clade B, 28 days therapy)
BMS-955176 40 mg + ATV 400 mg
-1.89
0.273
-1.858
-2.37
-1.49
BMS-955176 40 mg + ATV 300 mg + RTV 100 
mg
-2.22
0.676
-2.202
-3.52
-1.24
BMS-955176 80 mg + ATV 400 mg
-2.3
0.307
-2.228
-2.68
-1.87
Truvada® + ATV 300 mg + RTV 100 mg
-2.41
0.495
-2.39
-3.04
-1.83
Part C (Clade C, 10 days monotherapy)
BMS-955176 40 mg
-1.5
0.439
-1.285
-2.03
-1.04
Placebo
0.12
0.141
0.12
0.02
0.22
The pharmacokinetics of BMS-955176 were assessed in HIV-1 infected subjects in AI468002. 
Overall, exposures to BMS-955176 are approximately 30% to 35% lower in HIV-1-infected 
subjects compared to healthy subjects administered the same doses and formulation of 
BMS-955176. Furthermore, exposures to BMS-955176 increased in a generally linear fashion up 
to 40 mg, with a less than dose proportional increase in exposures between 40 mg and 80 mg, 
and considerable overlap in exposures between 80 mg and 120 mg.
1.4.2
Background Information on TDF
Tenofovir disoproxil fumarate (TDF) is an analog of the nucleotide adenosine 
5’-monophosphate. TDF inhibits HIV-1 reverse transcriptase and is indicated in combination 
with other ARVs for the treatment of HIV-1 infection. The most common adverse reactions 
include rash, diarrhea, headache, pain, depression, asthenia, and nausea. Clinicians are warned 
about new onset or worsening renal impairment, decreases in bone density, and immune 
reconstitution syndrome. For more information concerning TDF, please refer to the 
TDF/Viread® SmPC or TDF/Viread® USPI.29
1.4.3
Background Information on DTG
Dolutegravir (DTG) is a HIV-1 integrase strand transfer inhibitor indicated in combination with 
other ARVs for the treatment of HIV-1 infection. The most common adverse reactions of 
moderate to severe intensity include insomnia, fatigue, and headache. Clinicians are warned 
about immune reconstitution syndrome. For more information concerning DTG, please refer to 
the DTG/Tivicay SmPC or the DTG/Tivicay USPI.30
1.4.4
Background Information on ATV 
Atazanavir is a protease inhibitor indicated for use in combination with other ARVs for the 
treatment of HIV-1 infection. The
most common adverse reactions include nausea, 
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jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral 
neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. Clinicians are warned 
about hyperbilirubinemia, nephrolithiasis, and cholelithiasis. For more information concerning 
ATV please refer to the ATV/Reyataz® SmPC or ATV/Reyataz® USPI.31
1.4.5
Background Information on RTV
Ritonavir is a protease inhibitor indicated in combination with other ARVs for the treatment of 
HIV-1 infection. The most frequently reported adverse drug reactions with RTV alone or in 
combination with other ARVs include diarrhea, nausea, vomiting, abdominal pain, paresthesia, 
rash, and fatigue/asthenia. Clinicians are warned about total cholesterol and triglyceride 
elevations. For more information concerning RTV please refer to the RTV/Norvir® SmPC or 
RTV/Norvir® USPI.32
1.4.6
Drug-Drug Interactions
In AI468001, coadministration of BMS-955176 as a single dose following two doses of 100 mg 
RTV resulted in an approximate 48% increase in BMS-955176 AUC(INF), consistent with 
inhibition of CYP3A4 and/or P-gp. Multiple-dose administration of BMS-955176 with daily 
400 mg ATV and a standard meal for 14 days resulted in a modest (~25%) increase in the 
BMS-955176 AUC(TAU).
Study AI468005 assessed the two-way interaction between BMS-955176 40 mg (administered as 
an SDD suspension) and TDF at steady state in healthy subjects. Relative to administration of 
each drug alone, neither BMS-955176 nor TDF exposures were meaningfully impacted upon 
coadministration.
Study AI468041 assessed the impact of BMS-955176 80 mg (administered as an SDD 
suspension) on the pharmacokinetics of the components of a combined oral contraceptive 
containing ethinyl estradiol (EE) and norgestimate (NGM). Exposures to both EE and 
norelgestromin (NGMN), the active metabolite of NGM were reduced in the presence of 
BMS-955176. Furthermore, one subject had a serum progesterone level > 300 ng/dL while 
BMS-955176 and the oral contraceptive were concomitantly administered, indicative of 
ovulation and contraceptive failure.
Finally, in vitro data suggest that BMS-955176 may inhibit OATP1B1 and OATP1B3 and 
exposures to substrates of these transporters, such as HMG-CoA reductase inhibitors, may 
increase when co-administered with BMS-955176.
1.5
Overall Risk/Benefit Assessment
The preclinical and clinical safety data demonstrate that BMS-955176 administered at doses in 
this Phase 2b study (120, and 180 mg) should be well tolerated without a major clinically 
relevant impact on safety. Moreover, there have been no identified safety risks from 
completed/ongoing clinical studies to date.
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The preclinical toxicology studies demonstrate two potential risks to subjects:
First, BMS-955176 is a selective developmental toxicant. Developmental toxicity (skeletal 
alterations in rats; cleft palate and reduced fetal body weights in mice) were observed in 
embryofetal development studies. In order to address this concern, subjects will be required to 
use two methods of contraception (as described in Section 3.3.1 Inclusion Criteria) and undergo 
routine urine pregnancy testing (as described in the T&E Tables in Section 5.1). Furthermore, 
due to results from Study AI468041 that demonstrates reduced exposures to the components of a 
combination oral hormonal contraceptive containing ethinyl estradiol and norgestimate when 
given concomitantly with BMS-955176, oral hormonal contraceptives cannot be used as a 
method of contraception by WOCBP in this study.
Second, single or repeat oral doses of BMS-955176 were associated with sporadic vomiting in 
dogs and unformed and/or liquid feces in rats and dogs. In rats at 10 mg/kg/day there were 
decreases in body weight and food consumption; in the stomach there was atrophy involving 
both parietal and chief cells, single-cell necrosis and regeneration in the glandular mucosa, and 
modest increases in serum gastrin values. At higher doses (100 mg/kg/day) in rats there were 
additional findings in the intestines (distended jejunum, ileum, and cecum; hyperplasia of the 
crypt epithelium in the jejunum; ulcers and erosions in the cecum; and decreased mucosal cell 
extrusion and increased mucus in the colon). 
Similar gastric changes were seen in dogs. At 20 mg/kg/day there was single-cell necrosis of the
stomach glandular epithelium. At 3 mg/kg/day gastric changes showed chief cell depletion. 
At 10 mg/kg/day changes in the stomach included: mucous cell hyperplasia correlating with 
increased thickness macroscopically, parietal cell depletion, single-cell necrosis of glandular 
epithelial cells, and modest increases in serum gastrin values. Unlike the rats, no changes were 
observed elsewhere in the alimentary canal including the gastroesophageal junction and the 
duodenum. There was no evidence of macrocytosis. Measurement of Total Protein and Albumin 
revealed no clinically relevant changes. The stomach histologic findings were BMS-955176 
dose- and duration dependent. In the 1-month studies, vomiting and fecal changes stopped soon 
after dosing cessation, and microscopic lesions in the stomach and/or intestines reversed 
completely within a 2-week treatment-free period. In the 6 month study in rats and the 9-month 
study in dogs, microscopic lesions in the stomach partially recovered after a 1 month treatment 
free period. The NOAEL was 1 mg/kg/day (AUC 64.9 mg•h/mL) in the 9-month study in dogs, 
and was not established in the 6-month study in rats. Investigative studies for gastric toxicity in 
rats and dogs indicated similar findings with both SDD and MC forms, and with no clear 
evidence that the gastric toxicity is a direct local effect of BMS-955176. The mechanism and 
clinical relevance of these gastrointestinal findings is unknown at present (see below).
A Phase 1 study (AI468001) in healthy volunteers evaluated single and multiple doses of 
BMS-955176 for 14-28 days both alone and in certain arms, in combination with ATV or RTV. 
Overall the safety data demonstrated that BMS-955176 was generally safe and well tolerated. 
A Phase 2a (AI468002) study in HIV-1 infected adults evaluated several doses of BMS-955176 
given alone or in combination with ATV RTV for 10-28 days. The preliminary results show 
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acceptable safety and tolerability across all arms. There were no deaths, SAEs, or AEs leading to 
discontinuation. There were no clinically relevant changes in vital signs, lab parameters, or 
EKGs. Most of the AEs were Grade 1-2 and were most frequently due to hyperbilirubinemia 
(primarily observed in treatment arms with ATV). Of the GI AEs, most were attributable to 
diarrhea or loose/watery stools. Many of these events occurred in subjects who were randomized 
to an arm containing BMS-955176 and ATV. Of the Grade 2-4 related AEs, many were due to 
headache and an increase in hyperbilirubinemia. Many of the AEs of hyperbilirubinemia 
occurred in subjects also receiving ATV; moreover, the three arms with the highest average total 
bilirubin occurred in subjects receiving both BMS-955176 and ATV. Clinical changes/symptoms 
consistent with the GI findings from dogs and rats (described above) were not seen in the 
preliminary data set from short-term therapy with BMS-955176 in HIV-1 infected adults. 
In this treatment-experienced study population, we estimate GI safety multiples of 2× and 1×, 
(based on NOAEL in 9-month dog study), corresponding to projected human exposures at 
BMS-955176 doses of 120 and 180 mg.
While no clinically relevant GI safety signals have been observed in AI468001 or AI468002, in 
this clinical trial, subjects will undergo routine targeted and complete history/physical exams in 
addition to regular laboratory measurements (including CBC and chemistries). This will initially 
occur more frequently than in standard clinical practice and allow for increased vigilance for any 
potential GI toxicity. Guidance on the evaluation and management of potential GI toxicity is 
outlined in Section 6.7.1.4.
Subjects in this clinical study will benefit from receiving cART potentially containing 
BMS-955176. Preliminary data from the Phase 2a (Part A, B and C) study show a maximum 
median reduction in HIV-1 RNA (clades B and C) ranging from 1.3 to 1.7 log10 in the dose arms 
estimated to provide similar exposure to those in this current study. When BMS-955716 was 
combined with ATV RTV (Part B) this resulted in maximum median declines in HIV-1 RNA 
ranging from 1.9 to 2.2 log10. These results are generally similar to the antiviral effect 
demonstrated by other classes of ARVs. Thus, BMS-955176 should contribute with other ARVs 
substantially to form an effective cART regimen.
As with any antiretroviral study in HIV-1-infected subjects, there is a risk for the development of 
treatment failure and the development of drug resistance associated mutations to BMS-955176 
and/or other antiretrovirals. However, drug resistance to the maturation inhibitor would not be 
anticipated to result in cross-resistance to any other ARV class, including protease inhibitors.33
Ongoing analysis of preliminary data from the Phase 2a study is evaluating both emergent 
genotypic and phenotypic changes after short term monotherapy with BMS-955176. The use of 
three fully susceptible agents as a part of cART is expected to decrease the probability of 
virologic failure and drug resistance. Initially in this clinical trial, measurement of HIV-1 RNA 
will occur more frequently than in standard clinical practice which will allow for increased 
vigilance for the development of lack of efficacy/resistance. Finally, an analysis for virologic 
futility will occur at Week 24 (see Section 8.4.7).
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As described earlier, treatment-experienced adults enrolled in Arms 3-4 may be exposed to a 
subtherapeutic regimen and may be at higher risk for virologic failure and the development of 
resistance. In order to decrease this probability, this clinical trial uses a two-stage design 
whereby enrollment in Arms 3-5 will be dependent upon the results of the Week 24 analyses
(efficacy, safety, and pharmacokinetics) in Stage 1 and Study AI468038. This will minimize the 
risk of virologic failure and resistance to subjects enrolled in Arms 3-4 because clinical data will 
already have been generated using BMS-955176 with ATV/r (Arm 1) in Stage 1.
In-vitro studies show that BMS-955176 is expected to be active against a variety of HIV-1 clades 
albeit with EC50s 2-3 fold less toward HIV-1 clade AE compare to clade B (see Section 1.4.1). 
As described in Section 1.1.1, the only clinical data for BMS-955176 exists in HIV-1 clade B 
and C. The efficacy profile of BMS-955176 in other HIV-1 clades encountered in other 
geographical regions where this multinational Phase 2b trial will be conducted (eg, clade AE in 
Thailand) is unknown. To mitigate the risk of randomizing subjects infected with HIV-1 with an 
unknown efficacy profile, the number of subjects with HIV-1 Clade AE will be stratified to 
ensure each treatment are has approximately the same number of HIV-1 clade AE infected 
subjects in their respective Stages and the maximum number of subjects with HIV-1 clade AE 
will be capped at approximately 3 per treatment arm.
Of note, the other ARVs used in this clinical trial have a known and acceptable risk benefit ratio 
and are frequently prescribed to HIV-1 infected adults as a part of standard of care.
Taken together, the clinical data to date show that BMS-955176 has potent antiretroviral activity 
and is generally safe and well tolerated in healthy volunteers and HIV-1 infected adults. These 
factors should allow subjects to benefit from achieving viral suppression whilst taking a 
generally safe and well-tolerated new antiretroviral; additionally subjects in Arms 1, 3, and 4 
may benefit from a cART regimen that is nucleoside and nucleoside/booster sparing, 
respectively. Specifically, these subjects may benefit from improved bone mineral density, renal 
function, and lipid profiles. The risks, including teratogenicity, GI toxicity, and drug resistance, 
will be appropriately managed by following guidance in the study protocol.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
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which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion.
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
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5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented.
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a randomized, active-controlled, staged, open-label clinical trial. Approximately 
200 treatment-experienced HIV-1 subjects will be randomized to one of five treatment arms
(approximately 40 per arm) in a staged fashion.
Randomization will be stratified by HIV-1 Clade (AE versus Other). The number of subjects 
with HIV-1 Clade AE will be capped at a maximum of approximately 3 per treatment arm.
The data from the Week 24 analysis of Stage 1 and AI468038, including safety, efficacy and 
pharmacokinetics, will be examined to trigger the start of Stage 2 and confirm the two doses of 
BMS-955176 for study in Stage 2.
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Stage 1:
In Stage 1, subjects will be randomly assigned 1:1 to one of two treatment arms and on Day 1 
will begin dosing with:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:
In Stage 2, subjects will be randomly assigned 1:1:1 to one of three treatment arms and on Day 1 
will begin dosing with: 

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
3.1.1
Screening
The screening period begins with the subject’s signature on the informed consent form (ICF).
The subject is then enrolled via the Interactive Voice Response System IVRS (or its web-based 
equivalent) See Section 4.4.
If the subject meets all eligibility criteria, the subject must be randomized within the 42 day 
screening period.
3.1.2
Day 1/Baseline Visit
3.1.2.1
Day 1/Baseline Visit for Arms 1 and 2 - Stage 1
In Stage 1, approximately 80 subjects will be randomized 1:1 (approximately 40 per arm) to 
either of the treatment arms containing boosted atazanavir (ATV/r).
On the Day 1 Visit, subjects in Arms 1 and 2 will begin QD dosing with BMS-955176 or TDF, 
each in combination with ATV/r and DTG (see Section 4.5 for additional details of Selection and 
Timing of Dose).

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
3.1.2.2
Day 1/Baseline Visit for Arms 3, 4 and 5 - Stage 2
In Stage 2, approximately 120 subjects will be randomized 1:1:1 (approximately 40 per arm) to 
either of the two BMS-955176 treatment arms containing ATV, or to the TDF Arm.
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On the Day 1 Visit, subjects will begin QD dosing with BMS-955176 in combination with ATV 
and DTG, or TDF in combination with ATV/r and DTG (see Section 4.5 for additional details of 
Selection and Timing of Dose).

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r QD 300/100 mg + DTG 50 mg QD
3.1.3
Week 2 Intensive PK Visit
Subjects with anemia, defined as Hemoglobin < 11.0 g/dL, should be excluded from 
participation in the Week 2 Intensive PK Substudy.
Subjects in all arms will have the opportunity to participate in an elective Intensive PK Substudy 
visit at Week 2 (window for visit: Day 12-16). Approximately 60 subjects, 12 subjects from each 
arm, are expected to participate in the substudy; BMS may allow the substudy to over-enroll in 
an effort to have a sufficient number of complete datasets.
The series of 12 blood draws begins with pre-dose (0-hour) blood samples to be collected
approximately 24 hours (20-28 hrs) after the morning doses of study drugs that were taken on the 
day before. Ten more samplings are drawn through the 12-hr time point, with one final sampling 
collected at the 24-hr time point, requiring the subject to either remain overnight in the clinic, or 
to return the next morning; the final 24-hr sample will be collected prior to administration of the 
morning doses of study drugs (See Section 5.5.1).
PK Tools/Job Aids will be provided to assist with the proper sequencing of dosing and blood 
sample collections, as well as the collection of required data.
3.1.4
Visits Week 4 - 96
Subjects are expected to be treated for the duration of 96 weeks. In each Stage, after Day 1 and 
the optional Intensive PK visit at Week 2, subjects will be required to attend 12 more in-clinic 
study visits over the 96-week treatment period, as follows:

Visits are conducted every 4 weeks from Week 4 through Week 16

Visits are conducted every 8 weeks from Week 24 through Week 48

Visits are conducted every 12 weeks from Week 60 through Week 96
Visits should be scheduled as an interval from the Day 1/Randomization date, and within a 
window of 5 days earlier or later.
One of the visits Week 4 - 24 should meet the very specific timing requirements as outlined in 
Section 5.5.2 for a pre-AM dose blood collection.
Telephonic visits will be conducted with each subject at visit Weeks 20, 28, 36, 44, 54, 66, 78,
and 90 to conduct an adherence assessment and to continue retention efforts
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3.1.5
Selection of the Continuation Dose of BMS-955176
3.1.5.1
Selection of the Continuation Dose, and the Switch for Stage 1
Once all subjects in Stage 1 have reached Week 24*, BMS will conduct an interim analysis of 
efficacy, safety, resistance and pharmacokinetics.
As described in Section 8.4.7, an analysis of Virologic Futility will also occur. If Arm 1 meets 
criteria for Virologic Futility at Week 24, the clinical trial will be terminated.
The Week 24 analysis of Arms 1 and 2, combined with the Week 24 analysis of all Arms in the 
AI468038 study, will be used to select a Continuation Dose of BMS-955176 for Arm 1 in this 
study. Subjects in the BMS-955176 Treatment Arm 1 may subsequently be transitioned to a
selected Continuation Dose.
Subjects in the Arm containing TDF will continue with the TDF treatment regimen.
The assigned backbone will not change.
The Week 24 efficacy, safety, and pharmacokinetic analyses from Stage 1 and study AI468038 
will also trigger the start of Stage 2.
* If the Continuation Dose cannot be clearly identified using the Week 24 data, the study 
will continue in original fashion until an analysis of the Week 48 data can be performed 
and the Continuation Dose is selected. If a Continuation Dose cannot be selected based 
upon the Week 24 data, this does not preclude the ability to start recruitment of Stage 2.
After the Continuation Dose is selected, and once all of the logistics (eg, distribution of clinical 
drug supplies, activation of the new portion of the IVRS) have been completed globally, the 
transition of the subjects in Arm 1 to the Continuation Dose will occur. It is anticipated that this 
transition will occur on or after all subjects have reached Week 48 (the earliest subjects to begin 
study treatment could be well beyond Week 48 when the switch to the Continuation Dose 
occurs).
3.1.5.2
Selection of the Continuation Dose, and the Switch for Stage 2
Once all subjects in Stage 2 have reached Week 24, BMS will conduct an analysis of efficacy, 
safety, resistance and pharmacokinetics.
As described in Section 8.4.7, an analysis of Virologic Futility will also occur. If a BMS-955176 
dose arm meets criteria for Virologic Futility at Week 24, subjects in said arm will begin dosing 
with the next highest available remaining dose of BMS-955176.
The data from AI468038 and AI468048 (Stages 1 and 2) will be used to select a Continuation 
Dose of BMS-955176 for Arms 3 and 4. Subjects in the BMS-955176 Treatment Arms 3 and 4 
will subsequently be transitioned to a selected Continuation Dose. It is anticipated that this 
transition may occur on or after all subjects have reached Week 48, or it could occur sooner after 
Week 24.
The assigned backbone will not change.
Subjects in the arm containing TDF will continue with this assigned treatment regimen.
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3.1.6
End of the study
The end of the study will occur when the last study visit has been completed, defined as the final 
subject completing their final study visit (expected to be a Week 96 or Early Termination visit).
The study design schematic is presented in Figure 3.1.6-1.
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Figure 3.1.6-1:
Study Design Schematic
Arm 2
TDF
300 mg QD
+ ATV/r + DTG
Day 1
Begin dosing
Arm 3
BMS-955176 
120 mg QD
+ ATV + DTG
1 Virologic Futility will be evaluated at Week 24 
(see Section 8.4.7).  
Results of Week 24 Stage 1 AI468-048 & AI468-038 
Confirm the Start of Stage 2   
Arm 4
BMS-955176 
180 mg QD
+ ATV + DTG
40
40
Week 2
Week 24
Week 24 Analysis1
Intensive PK subset
4 Based on totality of data from both studies the 
Continuation Dose for Arms 3 & 4 may be 
identified.  
Number
Randomized
STAGE 2
Week 96
Week 96 Analysis/End of Study
Week 48
Week 48 Analysis
The Switch to the Continuation Dose4,3     
is expected to occur on or after Week 48, 
but could occur sooner.
Arm 1
BMS-955176 
120 mg QD
+ ATV/r + DTG
Week 2
Number
Randomized
Week 24
Week 24 Analysis1
Day 1
Begin dosing
Intensive PK subset
40
40
Week 48
Week 96
Week 48 Analysis
Week 96 Analysis/End of Study
The Switch to             
the Continuation Dose2,3
may occur on or after 
Week 48 
STAGE 1
BMS-955176
Continuation Dose QD 
+ ATV/r + DTG
Arm 5
TDF
300 mg QD
+ ATV/r + DTG
40
3 The actual switch of subjects of BMS-955176 
subjects to that Continuation Dose may occur when 
all of the subjects have reached at least Week 48 
(though it could occur sooner in Stage 2).
BMS-955176
Continuation Dose QD
+ ATV + DTG
2 Based on Week 24 data from Arms 1 & 2 and 
from AI468-038, the Continuation Dose for 
Arm 1 may be identified.  
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3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug. Study drug will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee 
or through another mechanism at the discretion of BMS. BMS reserves the right to terminate 
access to BMS supplied study drug if any of the following occur: a) the marketing application is 
rejected by responsible health authority; b) the study is terminated due to safety concerns; c) the 
subject can obtain medication from a government sponsored or private health program; or 
d) therapeutic alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Ability to understand and sign a written informed consent form
2. Target Population
a) Antiretroviral treatment-experienced, defined as having documented evidence of having
failed, 1 or 2 regimens that include 2 or 3 classes of ARV (with or without documented 
resistance)
b) Confirmed Plasma HIV-1 RNA 400 copies/mL (First value from investigator; second 
value from screening test)
c) CD4+ T-cell count > 50 cells/mm3
d) Screening genotype/phenotype indicating susceptibility to study drugs (unboosted ATV, 
FC < 2.2; DTG; TDF)
e) Estimated Life expectancy 1 year
f)
Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / 
has not been treated). If re-enrolled, the subject must be re-consented and assigned a new 
PID.
3. Age and Reproductive Status
a) Males and non-pregnant females
b) At least 18 years of age, (or minimum age as determined by local regulatory or as legal 
requirements dictate)
c) Willingness to use approved highly effective methods of contraception (see below) to 
avoid pregnancy (female subjects who are WOCBP and male subjects who are sexually 
active with WOCBP)
d) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
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e) Women must not be breastfeeding
f)
WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug BMS-955176 plus 5 half-lives of study drug BMS-955176
(8 days) plus 30 days (duration of ovulatory cycle) for a total of 38 days post-treatment 
completion.
g) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug BMS-955176
plus 5 half-lives of the study drug BMS-955176 (8 days) plus 90 days (duration of sperm 
turnover) for a total of 98 days post-treatment completion.
h) Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However WOCBP must still undergo 
pregnancy testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as 
listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Male condoms with spermicide34,35

Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirena

For female study subjects who are WOCBP:
Study subjects who are WOCBP cannot use hormonal methods of contraception as 
one of the two methods of contraception because there are data that show a lack of 
effectiveness of systemic hormonal contraceptives in women taking BMS-955176
However, WOCBP can continue to use hormonal contraceptives, if necessary, in 
addition to 2 other non-hormonal methods of contraception (one of which must be 
highly effective)

For female partners of male study subjects (if they are WOCBP):
Hormonal methods of contraception may be used by male subject’s WOCBP partner. 
Female partners of male subjects participating in the study may use hormone based 
contraceptives as one of the acceptable methods of contraception since they will not 
be receiving BMS-955176

Nonhormonal IUDs, such as ParaGard

Tubal ligation
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
Vasectomy

Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence.
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge

Male Condom without spermicide 

Progestin only pills by male subject’s WOCBP partner

Female Condom*
* A male and female condom must not be used together
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Antiretroviral treatment-experienced adults who have failed > 2 ARV regimens
b) Resistance or partial resistance to any study drug
c) Three or more of the following PI mutations, historical or documented: M36I/V, 
M46I/L/T, G48M/V, I54V/L/T/M/A, G73S/A/C/T, V82A/F/T/S/I, or L90M
d) Any major ATV mutations, historical or documented: I50L, I84V/A, N88D/S
e) Any major TDF mutation, historical or documented: K65R or T69ins
f)
Three or more of the following non-accessory thymidine analogue mutations (TAMs): 
M41L, D67N, K70R, L210W, T215Y/F, K219Q/E
g) Any major mutations for raltegravir (RAL), elvitegravir (or clinically suspected INI 
resistance), historical or documented: T66IAK, E92Q, S147G, N155H, Q148H/K/R, 
Y143C/H/R, E157Q
2. Medical History and Concurrent Diseases
a) A new AIDS defining condition diagnosed within the 30 days prior to screening
(see Appendix 2)
b) Any other clinical condition (including but not limited to active substance use) or prior 
therapy that, in the opinion of the Investigator, would make the subject unsuitable for the 
study; unable to comply with dosing requirements; or unable to comply with study visits; 
or a condition that could affect the absorption, distribution, metabolism or excretion of 
the drug.
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3. Physical and Laboratory Test Findings
a) Chronic HBV/HCV (Positive blood screen for HBsAg; Positive blood screen for HCV 
Ab and HCV RNA)
b) ALT or AST > 3 × ULN
c) Alkaline Phosphatase > 5 × ULN
d) Bilirubin ≥ 1.5 × ULN
e) History of decompensated cirrhosis or active decompensated cirrhosis
f)
Hemoglobin < 8.0 g/dL
g) Platelets < 50,000 cells/mm3
h) Estimated eGFR < 60 mL/min (CKD-EPI formula)
i)
Confirmed QT value > 500 msec at Screening or Day 1
j)
Confirmed QTcF value > 470 msec for women and > 450 msec for men at Screening or 
Day 1
k) Confirmed PR Interval > 260 msec (severe first degree AV block) at Screening or Day 1
l)
Confirmed second or third degree heart block at Screening or Day 1
4. Allergies and Adverse Drug Reaction
a) Medications contraindicated for use with investigational/non-investigational study drugs
(ATV, RTV, DTG, TDF);
or subjects with any known allergies to the 
investigational/non-investigational study drugs (ATV, RTV, DTG, TDF)
b) Current or anticipated treatment with any of the medications listed in Appendix 1, in 
addition to any medications that are contraindicated with ATV, RTV, DTG or TDF
c) Participation in an experimental drug and/or HIV-1 vaccine trial(s) within 30 days prior 
to Screening
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A woman of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/mL to confirm menopause.
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Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is > 40 mIU/mL at any time 
during the washout period, the woman can be considered postmenopausal:

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
Refer to Appendix 1 which details prohibited and precautionary therapies during the study, 
including specifics about the use of antacids and hormonal methods of contraception.
3.4.2
Other Restrictions and Precautions
None.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Repeat non-adherence by the subject with the requirements of the protocol or treatment
(as determined by Investigator in consultation with the BMS Medical Monitor)

Evidence of Hepatitis B or C infection

Confirmed plasma HIV-1 RNA 1000 c/mL after Week 24

Confirmed plasma HIV-1 RNA 200 c/mL after Week 48

Emergence of genotypic and/or phenotypic resistance to any component of the study 
treatment regimen at any time after Screening

Subject requires switching to any other ARV

Development of pDILI (potential drug induced liver injury)
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
Confirmed QTcB or QTcF value > 500 msec

Confirmed second degree (Type II) or third degree AV block at any time during the study
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5 (ie, perform an Early Termination [ET] visit). The only 
exception to this requirement is when a subject withdraws consent for all study procedures 
including post-treatment study follow-up (no such period exists in this study) or loses the ability 
to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
Subjects who discontinue study drug may continue to be followed.
Subject’s contact information will be collected/confirmed throughout the study so that subjects 
who discontinue study drug may continue to be followed for resolution of a pregnancy or SAE.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
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All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for AI468048:
Product Description / 
Class and Dosage Form
Potency
IMP/Non-IMP
Blinded or 
Open Label
Packaging/ Appearance
Storage Conditions
(per label)
BMS-955176 
60 mga
IMP
Open Label
Bottle/
A white to off-white, biconvex, 
oval shaped film coated tablet
Store at 2 - 30°C
Protect from light.
Store in a tightly closed container.
BMS-955176
120 mga
IMP 
Open Label
Bottle/
A white to off-white, biconvex, 
capsule shaped tablet
Store at 2 - 30°C
Protect from light.
Store in a tightly closed container.
Tenofovir (TDF)
300 mg
Non-IMP
Open Label
Various packaging configurations
Refer to label on
container or package insert.
Atazanavir (ATV)
200 mg
IMP
Open Label
Bottle/
Blue cap and blue body
printed with white ink
Store at 15 - 30°C
Store in a tightly closed container.
Atazanavir (ATV)
300 mg
IMP
Open Label
Bottle/
Red cap and blue body,
printed with white ink
Store at 15 - 30°C
Store in a tightly closed container.
Ritonavir (RTV)
100 mg
Non-IMP
Open Label
Various packaging configurations
Refer to label on
container or package insert.
Dolutegravir (DTG)
50 mg
Non-IMP or 
IMP,
depending on 
country 
approval status.
Open Label
Various packaging configurations
Refer to label on
container or package insert.
a The 180 mg dose of BMS-955176 will be constructed with BMS-955176 60 mg + BMS-955176 120 mg
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, investigational product(s) is/are: BMS-955176, ATV, and DTG (in countries 
where DTG has not been approved for use). These products will be supplied.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products.
In this protocol, noninvestigational product(s) is/are: TDF, RTV, and DTG (in countries where 
DTG is approved for use). These products will be supplied.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
4.4
Method of Assigning Subject Identification
At the start of the screening period, the investigative staff will call the Assignment Center via an 
Interactive Voice Response System ([IVRS], or its web-based equivalent) designated by the 
sponsor to enroll the subject and to obtain a subject patient identification number (PID).
For subjects who meet the protocol eligibility criteria, the investigative staff will call the IVRS 
and subjects will start treatment.
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Subjects will be randomly assigned in the staged fashion to one of the treatment arms, and 
stratified by HIV-1 Clade (AE versus Other), as described in Section 3 and as outlined in the 
AI468048 Study Schematic Figure 3.1.6-1.
Note: All efforts should be made to limit the possibility of randomizing subjects that do not start 
treatment. If a subject is randomized but does not receive study medication, the BMS study team 
must be notified immediately.
4.5
Selection and Timing of Dose for Each Subject
Subjects will be randomized into the treatment arms in a staged fashion described in Section 3.1.
Stage 1:
In Stage 1, subjects will be randomly assigned 1:1 to one of two treatment arms and on Day 1 
will begin dosing with:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:
In Stage 2, subjects will be randomly assigned 1:1:1 to one of three treatment arms and on Day 1 
will begin dosing with:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
4.5.1
Instructions for Dose Administration
4.5.1.1
General Instructions

Subjects should administer doses of each drug from only one bottle at a time, until that bottle 
is empty, before another bottle may be opened. 

Subjects will be required to complete Dosing Diaries so that drug administration can be 
accurately accounted. It is important that sites provide instructions to subjects for completion 
and obtain their acknowledgment that doing so provides critical information for the clinical 
trial.

Dosing times (and study appointment times) must be carefully considered through Week 24 
due to the requirements of the PK collection outlined in Section 5.5.
4.5.1.2
Specific Dosing Instructions for Initial Treatment Arm Assignment
In the morning, with a meal, subjects will take the following:

Arm 1: One pill each from bottles BMS-955176 120 mg, ATV, RTV, and DTG

Arm 2: One pill each from bottles TDF, ATV, RTV and DTG
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Arm 3: One pill each from bottles BMS-955176 120 mg, DTG, and two pills from bottle
ATV (the unboosted dose of ATV is 400 mg, achieved by 200 mg x 2)

Arm 4: One pill each from bottles BMS-955176 60 mg, BMS-955176 120 mg and DTG, and 
two pills from bottle ATV (the unboosted dose of ATV is 400 mg, achieved by 200 mg x 2)

Arm 5: One pill each from bottles TDF, ATV, RTV and DTG
4.5.2
Dose Modifications
No dose adjustments or changes in intake frequency are allowed for any of the assigned study 
drugs in the protocol, except for the unique case of treatment-limiting renal toxicity which limits 
the use of the TDF. In the event of treatment-limiting renal toxicity, dose interval adjustments for 
TDF are permitted according to the local package insert/label, and only after the completion of 
the Week 2 Intensive PK optional Visit, if the subject is inclined to participate.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment Adherence to the treatment regimen will be critical to the conduct of this study. 
Adherence will be evaluated by the investigative staff at every treatment visit (including 
telephone contact visits) through interviews with the subjects and through examination of 
returned medication. It is expected that site staff attempt to have subjects maintain 90% 
treatment compliance or greater. Subjects should be instructed to bring all unused study 
medication back in the original container to each visit. Site staff are required to review Dosing 
Diaries completed by the subject, and to reinforce their use.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request
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Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (AI468048)
Procedure
Screening Visit
(42-day screening period)
Notes
Eligibility Assessments
Informed Consent
X
Call IVRS to Enroll the subject; PID assigned
X
Inclusion/Exclusion Criteria
X
Medical History
X
Includes historical CDC Class C Events
Non-Laboratory Safety Assessments
Full Physical Examination
X
See Section 5.3.1 for requirements
Vital Signs & Physical Measurements
X
See Section 5.3.1 for requirements
Pre-treatment events
X
Only CDC Class C events with onset during the Screening period
Serious Adverse Events Assessment
X
All SAEs that occur after the ICF has been signed should be reported
ECG
X
See Section 5.3.4 for requirements
Pregnancy Test
X
WOCBP
For females under age 55, an FSH level must be on record to confirm she 
is not a WOCBP if pregnancy testing is not being performed.
If positive urine, request serum hCG quant. on lab requisition.
Laboratory Assessments
Fasting Chemistry and Lipid Panel
X
Fasting overnight
Hematology
X
Urinalysis
X
Plasma HIV-1 RNA
X
This is the confirmatory HIV-1 RNA
(The first value is provided by the PI)
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Table 5.1-1:
Screening Procedural Outline (AI468048)
Procedure
Screening Visit
(42-day screening period)
Notes
CD4+ and CD8+ T-cell count
X
HBV Surface Antigen
X
HCV Serology
X
Urine toxicology (drugs of abuse)
X
Could aid in the selection of appropriate study candidates.
Pharmacodiagnostic (PDx) samplea
X
Plasma collection to be banked for potential future use in development of 
novel predictive assay(s)
Resistance Testing
(HIV-1 Drug Resistance)
PhenoSense GT Plus Integrase
X
Complete set of test results may take up to 4 weeks.
PhenoSense Gag
X
Next Generation Seq. - Qs Gag
X
Exploratory Resistance
(HIV-1 Drug Resistance)
X
Molecular analysis at BMS WFD Discovery of baseline resistant samples 
and baseline sensitive controls in cases of subsequent on-treatment 
virologic failure
a By definition, a pharmacodiagnostic sample (PDx) is a pre-treatment test to determine whether or not a patient is likely to respond to a drug (ie, a predictive 
test). Based on the results of clinical studies with BMS-955176, BMS may have to develop a PDx assay. Thus, PDx samples obtained at Screening in this 
study would be used for that sole purpose.
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Eligibility Assessments
Inclusion/Exclusion Criteria
X
Non-Laboratory Safety Assessments
Full Physical Examination
WK 12, 24, 48, 96/ET
See Section 5.3.1 for requirements
Targeted Physical Examination
X
WK 4, 8, 16, 32, 40, 60, 72, 84
See Section 5.3.1 for requirements
Vital Signs & Physical 
Measurements
X
X
See Section 5.3.1 for requirements
Adherence Assessments
X
X
Including review of Dosing Diaries
Pre-treatment Events
X
See Table 5.1-1
Adverse Events Assessments
X
X
X
Serious and Non-serious AEs
Concomitant Medications
X
X
X
See Section 5.3.3
ECG
X
WK 4, 12, 24, 48, 96/ET
See Section 5.3.4 for requirements
Pregnancy Test
X
X
X
For females under age 55, an FSH 
level must be on record to confirm 
she is not a WOCBP if pregnancy 
testing is not being performed.
If positive urine, request serum 
hCG quant. on lab requisition.
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Provide WOCBP with Home 
Pregnancy test kit(s) to be used 
during the in-clinic visit interval
WK 16, 24, 32, 40,
48, 60, 72, 84
Provide One Kit at Weeks 16 - 40
Provide Two Kits at Weeks 48 - 84
WOCBP subjects perform test Q4 
weeks at home and report results to 
site.
Laboratory Assessments for Safety and Efficacy and Other Endpoints
Fasting Chemistry
X
X
Fasting overnight
Fasting Lipid Panel
X
WK 4, 12, 24, 48, 96/ET
Fasting overnight
Hematology
X
X
Urinalysis
X
X
Fractional Excretion of Phosphorous 
(FePO4)
(Urine creatinine and phosphorus, 
Serum creatinine and phosphorus)
X
WK 48 and 96/ET
Plasma HIV-1 RNA
X
X
X
If collecting an HIV-1 RNA at an 
UNSCHEDULED visit, also collect 
samples for Resistance and 
Exploratory Resistance Testing
CD4 and CD8 T-cell counts
X
X
HBV Surface Antigen
WK 48 and 96/ET
HCV Serology
WK 48 and 96/ET
Positive HCV Ab will reflex to 
HCV RNA
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Resistance Testing
(HIV-1 Drug Resistance)
PhenoSense GT Plus Integrase
X
X
Samples stored and tested if needed
(ie, analyses of subjects if deemed 
clinically relevant)
See Section 5.4.2.2
PhenoSense Gag
X
X
Next Generation Seq. - Qs Gag
X
X
Exploratory Resistance
(HIV-1 Drug Resistance)
X
X
Samples stored and tested
retrospectively if needed (ie,
exploratory analyses for subjects if 
deemed clinically relevant)
Intensive PK sample collection
X
Use of PK Tools for data collection 
recommended.
See Section 5.5.1 for requirements
Sparse PK sample collection
WK 4, 8, 12, 16, 24
See Section 5.5.2 for requirements
Bone Biomarkers
(P1NP and CTX)
X
WK 12 and 24/ET
Serum collection
Renal Biomarkers
(2-microglobulin and creatinine)
X
WK 48 and 96/ET
Urine collection
Backup Serum and Plasma Sample
X
X
Samples stored and tested if needed
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Outcomes Measures
EQ-5D-3L Form
X
WK 12, 24, 32, 40, 48,
60, 72, 84, 96
Health Outcomes Questionnaire
FAHI Form
X
WK 12, 24, 32, 40, 48,
60, 72, 84, 96
Functional Assessment of HIV 
Infection
Clinical Drug Supply
Call IVRS to Randomize
X
Dispense Study Drug
X
X
There is no dispensation at Week 96 
or ET.
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value). The Screening Period for this study is 42 days.
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultations 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant (eg, a previously failed inclusion criterion).
Rescreening is different than Retesting. Rescreening is the process of Re-enrollment and requires 
that all procedures be repeated in an entirely new screening period. Rescreening will also be 
allowed. If it is clinically reasonable, and upon Investigator assessment (and in consultation with 
the BMS Medical Monitor, if necessary), a subject may be rescreened multiple times during the 
entire course of the enrollment period. Therefore, subjects may be Rescreened, if, in the opinion 
of the Investigator, a current clinical outlook of the subjects seems favorable for study inclusion 
(and if the patient never received study medication in this trial).
The assigned patient identifier (PID) for the subject must be Screen Failed in the IVRS. A new 
call must be made to the IVRS for the assignment of a new PID for the subject, and all Screening 
parameters must be done again in reference to the new PID (See Section 3.3.1, Inclusion 
Criteria 2f). Subject must also be re-consented with the new PID.
5.2
Study Materials
The sponsor will provide each investigative site with the following:

BMS-955176 Investigator Brochure (IB) and any relevant safety addenda or updates

Protocol and any Amendments to the Protocol

Instructions for completing electronic Case Report Forms (eCRFs)

Laboratory Manual from the central laboratory

ECG Machines and manual

IVRS Worksheets to complete when calling the IVRS center to enroll, randomize, and 
discontinue subjects

Patient-reported Outcomes Questionnaires: EQ-5D-3L Health Outcome Questionnaire, FAHI 
(Functional Assessment of HIV Infection)

PK Tools/Job Aids that may be used for detailed instruction about the PK visits, and as a 
comprehensive source for documents of date/times of dosing and blood sampling

Dosing Diaries

Completion by subjects is required
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
Should include daily dose of study medications administered by subject, modified or 
missed

Site staff should review the diaries with the subject at each visit, and, in combination with 
detailed questioning, should be able to provide comprehensive information in the case 
report form, noting discrepancies in the subject’s file. Dosing Diaries should be 
maintained in the subject’s study file.
5.3
Safety Assessments
The investigative team should follow the protocol-specified scheduled of safety-related 
measurements. Only data for the procedures and assessments specified should be submitted to 
BMS on the case report form. Additional procedures and assessments may be performed as part 
of standard of care, however, data for these assessments should remain in the subject’s medical 
record and should not be submitted to BMS, unless specifically requested (ie, as part of an SAE).
5.3.1
Vital Signs and Physical Examinations
The schedule of vital signs, physical examinations, and targeted physical examinations is 
provided in Section 5.1 (Flow Chart/Time and Events Schedule). Vital signs include heart rate, 
blood pressure, respiration rate, and temperature and should be measured after the subject has 
been sitting/resting for at least 5 minutes. Physical measurements include height and weight. 
Targeted physical examinations will include examination of the heart, lungs, skin, abdomen, any 
symptomatic organ system, and general appearance.
5.3.2
Adverse Events
Subjects will be closely monitored throughout the study for any new or ongoing HIV-related 
diagnoses (Appendix 2) and/or adverse events. CDC Class C events that occur from the 
Screening Visit through Day 1 (prior to dosing), will be recorded as Pre-treatment Events. All 
events that occur after dosing on Day 1 will be recorded on the appropriate Adverse Event eCRF. 
Additional information on Adverse Events is provided in Section 6.
5.3.3
Concomitant Medication Assessment
All medications taken from the Screening Visit throughout the duration of the study will be 
reported. In addition, any prior therapy with antiretroviral drugs will be reported
(See Appendix 1 for Prohibited and Precautionary Therapies).
5.3.4
Electrocardiograms
The schedule of electrocardiograms (ECGs) is provided in Section 5.1 (Flow Chart/Time and 
Events Schedule). ECG machines will be provided by a central vendor who will also perform the
read/interpretation of the output.
5.4
Efficacy Assessments
5.4.1
Primary Efficacy Assessment
The primary assessment for efficacy is HIV-1 RNA through Week 24.
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5.4.1.1
Guidelines for Confirmatory Testing of Plasma HIV-1 RNA and 
Resistance testing
A confirmatory HIV-1 RNA viral load should be obtained when:

HIV-1 RNA 40 c/mL if prior suppression 40 c/mL, or

> 1 log10 c/mL increase in HIV-1 RNA at anytime above nadir level where nadir is 
40 c/mL
All efforts should be made to collect this sample within 2-4 weeks from the collection of the 
original sample.
When collecting a blood sample for HIV-1 RNA testing at an Unscheduled visit, samples should 
also be collected for the sets of Resistance and Exploratory Resistance Tests, so that the samples
are available should resistance testing be required or deemed necessary based on the result of the 
HIV-1 RNA test.
Table 5.4.1.1-1:
Management of Detectable HIV-1 RNA, based on Confirmed 
(2-4 weeks from original sample) or Consecutive HIV-1 RNA 
Resulta
Day 1 through Week 24
40 - 399 c/mL
Reinforce Adherence
400 c/mL
Consider the need for resistance testing, in consultation with BMS Medical Monitor.
Consider possible discontinuation of subject, in consultation with BMS Medical Monitor, 
and/or reinforce adherence.
After Week 24 through Week 48
40 - 399 c/mL
Reinforce Adherence
400 - 999 c/mL
Resistance testing will be performed.
If resistance has developed, subject must be discontinued.
If resistance has not developed, consider possible discontinuation of subject, in consultation 
with BMS Medical Monitor, and/or reinforce adherence.
1000 c/mL
Resistance testing will be performed.
Regardless of result of resistance tests, subject must be discontinued (see Section 3.5).
After Week 48
< 200 c/mL
Reinforce Adherence
200 c/mL
Subject must be discontinued (see Section 3.5). 
If 400 c/mL, consider the need for resistance testing, in consultation with BMS Medical 
Monitor.
a When discontinuation is required or otherwise warranted and resistance results are needed, subject may continue 
on study medication/on study until resistance testing results are available.
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5.4.1.2
Protocol Defined Virologic Failure
Protocol Defined Virologic Failure (PDVF) is defined by a subject meeting one of the following 
three criteria:
1) Confirmed > 1 log10 c/mL increase in HIV-1 RNA at anytime above nadir level where nadir 
is 40 c/mL
2) Confirmed HIV-1 RNA 400 c/mL after Week 24
3) Failure to suppress last HIV-1 RNA to < 400 c/mL within Week 24, 48, or 96 week snapshot 
window
In addition to the clinical management outlined in section 5.4.1.1, samples meeting criteria for 
PDVF will also be sent for resistance and exploratory resistance testing.
5.4.2
Secondary Efficacy Assessments
5.4.2.1
CD4+ and CD8+ T-Cells
CD4+ and CD8+ T-cells counts and percentages will be assessed using flow cytometry. The 
schedule of assessments is provided in Section 5.1 (Flow Chart/Time and Events Schedule). 
Procedures for samples collection and processing are provided in the central clinical laboratory 
manual.
5.4.2.2
Drug Resistance Testing
Plasma samples for viral drug resistance testing will be collected at Screening for all subjects and 
the HIV-1 drug resistance genotype will be analyzed to rule out resistance to any component of 
the study regimen or specific resistance mutations as outlined in Section 3.3.2, Exclusionary 
Criteria. At subsequent visits, samples for emergent drug resistance testing (both genotypic and 
phenotypic) will be collected and stored to be as outlined in Section 5.4.1.
5.5
Pharmacokinetic Assessments
It is extremely important to record the exact dose and time of the dose(s) taken the day prior to 
the visit/collection, and the exact date and time of the sample collection, even if drawn slightly 
off-schedule.
5.5.1
Intensive Pharmacokinetic Assessment
A subset of subjects (about 12 subjects per treatment group) will participate in an optional 
Intensive PK assessment at Week 2 (window Day 12-16).
Intensive PK samples collected in this study will provide for the assessment of BMS-955176, 
ATV, RTV, and DTG to support the secondary and exploratory objectives (to characterize the 
PK of BMS-955176, DTG, and ATV (with or without RTV) when given in combination, and to 
compare steady-state exposures of DTG when co-administered with BMS-955176 and 
ATV/RTV to DTG when co-administered with TDF and ATV/RTV).
Intensive PK sampling begins with a morning pre-dose (0 hour) sampling, ie, prior to the 
administration of the morning doses of the study drugs on the day of the visit. The sampling 
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should also begin 24 hours after the morning doses of the study drugs that were taken the day 
prior to the visit.
The subsequent 11 time points include samplings through Hour 12, with the last sample collected 
at Hour 24. The subject will either stay overnight or will return to the clinic so that the final 
sample can be collected at Hour 24.
It is critical to capture the exact date and time of each PK sample collection, even if drawn 
slightly off-schedule. There is no specified collection window end for which any one time point 
should be abandoned as the schedule progresses. If a sample collection time point is missed/late 
and the next collection time point has not yet been reached, collect the missed time point, and 
record the exact time of that collection, then get back on track for the next time point/on-time 
collection.
Table 5.5.1-1 lists the sampling schedule to be followed for the assessment of intensive 
pharmacokinetics. Further details of PK blood collection and sample processing will be provided 
in the central clinical laboratory manual.
Table 5.5.1-1:
AI468048 Intensive Pharmacokinetic Sampling Schedule at Week 2
Time 
(Event)
Time 
(Relative to Dosing)
Hour: Min
PK
Blood Sample
Study Week 2
(window Day 12-16)
0 (morning pre-dose)
00:00
X
1 Hr
01:00
X
2 Hr
02:00
X
2.5 Hr
02:30
X
3 Hr
03:00
X
4 Hr
04:00
X
4.5 Hr
04:30
X
5 Hr
05:00
X
6 Hr
06:00
X
8 Hr
08:00
X
12 Hr
12:00
X
24 hr (morning pre-dose)
24:00
X
5.5.2
Sparse Pharmacokinetic Assessments
All subjects will provide Sparse PK samples (as part of the regular blood collection) for the 
assessment of BMS-955176, ATV, RTV and DTG at visit Weeks 4- 24.
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Of the five visits (Week 4 - 24), it is requested that the following guidelines are followed:

At any one visit Week 4 through Week 24, the Sparse PK sample must be collected 
approximately 24 hours (between 20 and 28 hours) after the dose that was taken the morning 
before and before the morning dose is taken on the day of the visit

At the remaining four visits Week 4 through Week 24, the blood collections may be done 
without any specific consideration to timing of previous dose administration (taken either the 
day before the visit or on the day of the visit), though it is critical that the date and time of the 
most previous dose of study drug is recorded in the eCRF so that the exact interval between 
dose and blood sampling can be calculated for accurate PK analysis
PK Samples need to be tested on an ongoing basis prior to the Week 24 database lock and 
analysis.
5.6
Biomarker Assessments
In this study, BMS is confirming the safety of BMS-955176 demonstrated in the Phase 2a study 
to date. The proposed sample population of treatment-experienced adults in Arms 3, 4, and 5, 
will provide a representation of the potential benefits of BMS-955176 on nucleoside and RTV 
based toxicities of interest (ie, renal toxicity, bone mineral density, and dyslipidemia): Arms 3 
and 4 relative to Arms 1, 2, and 5.
Specifically, to evaluate for renal toxicity we will evaluate clinically relevant parameters and 
biomarkers for glomerular and tubular toxicity, which may include but are not limited to: 
fractional excretion of phosphorous and urinary β2-microglobulin/creatinine, in all available 
subjects. To evaluate for bone-related toxicity, clinically relevant bone biomarkers for both 
formation and resorption will be evaluated in all available subjects. These may include but are 
not limited to: N-terminal Propeptide of Type 1 procollagen (P1NP) and Cross-linked 
C-telopeptide of Type 1 collagen (CTX). The bone and renal biomarkers will be collected and 
measured at time points specified in Table 5.1-2 Additionally, back-up plasma and serum 
samples (at Baseline, Week 24, and Week 48) will be obtained for potential future evaluation of 
the safety of BMS-955176.
Samples will be collected at the screening visit for HIV-1 Gag sequencing, phenotypic 
susceptibility (PhenoSense Gag) and potential pharmacodiagnostic analysis as specified in Table 
5.1-1. These samples may be analyzed, if deemed clinically relevant, as a predictive marker of 
clinical response.
Any remaining blood and urine specimens that are available after completion of the designated 
analyses may be used in the future for identification of potentially predictive or 
pharmacodynamic markers of study drug activity or to enhance the understanding around disease 
biology, except where prohibited by local laws or regulations.
5.7
Outcomes Research Assessments
Increases in CD4 counts and avoidance of opportunistic infections and other AIDS-defining 
illnesses have been shown in many studies to improve health related quality of life (HRQoL). To 
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help assess whether use of BMS-955176 will result in a better quality of life outcome, both a 
disease specific quality of life assessment and a generic quality of life assessment will be 
administered. Disease specific instruments are more sensitive to disease specific changes in 
quality of life and are more likely to show improvement with new interventions. The generic 
instruments are needed because Health Technology Authorities often require use of these 
instruments for cost-effectiveness modeling.
The Functional Assessment of HIV (FAHI) is the disease specific instrument that will be used. 
The FAHI evaluates physical well-being, functional and global well-being, emotional 
well-being/living with HIV, social well-being and cognitive functioning. It yields a total score 
and individual subscale scores.
The EQ-5D-3L is the generic instrument that will be used. The EQ-5D-3L includes two parts: the 
EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L 
descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some 
problems, extreme problems. The EQ VAS records the respondents’ self-rated health on a 
100 point, vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable health 
state’ and ‘Worst imaginable health state.’
5.8
Other Assessments 
We will obtain back-up plasma and serum samples for current/future evaluation of the efficacy, 
safety and tolerability of BMS-955176. 
Should any new safety signal develop during the course of the ongoing analysis of the Phase 2a 
trial, appropriate measures for evaluation and management will be incorporated into the design 
of the Phase 2b trial via a protocol amendment.
5.9
Results of Central Assessments
The following describes the centrally assessed parameters and the timing with which they will be 
shared with investigators, if pertinent. Some parameters are relevant to ongoing subject 
management during the study and will be provided to the site for such purpose, while others are 
not relevant to subject management during the study and results may only be shared in a 
summarized way at the end of the study.

Samples sent to the central lab vendors for safety and efficacy assessments and that are tested 
real time will be provided to the sites as soon as results are available

The results of the read of each ECG will be sent to the site by the central ECG vendor as 
soon as results are available

Samples collected on-treatment for resistance testing will be tested if deemed clinically 
relevant (eg, if the development of resistance is suspected). If tested, results will be reported 
to the site

Other samples (including but not limited to biomarker assessments, exploratory resistance, 
pharmacodiagnostics) may not be tested immediately, and may only be tested if deemed 
clinically relevant. Results may be suppressed from laboratory reports and may not be 
provided to the sites
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
Individual PK results will not be reported to the site; the overall PK assessments will be 
included in the CSR

Individual assessments of the Outcomes research will not be reported to the site; the overall 
Outcomes assessments will be included in the CSR
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs).
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above).
Examples of such events include, but are not limited to, intensive treatment in an emergency 
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room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization). Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must
be handled as
SAEs. 
(See Section 6.1.1 for reporting pregnancies).
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies:

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason)

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing.
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
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SAEs, whether related or not related to study drug, and pregnancies, must be reported to BMS 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on 
a Pregnancy Surveillance Form (electronic or paper forms). The preferred method for SAE data 
reporting collection is through the eCRF. The paper SAE/pregnancy surveillance forms are only 
intended as a back-up option when the eCRF system is not functioning. In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
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
Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours and in accordance with SAE reporting procedures 
described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important.
All occurrences of overdose must be reported as an SAE (see Section 6.1.1 for reporting details).
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6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury in HIV-1 mono-infected subjects is defined as:
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic
6.7
Other Safety Considerations
Any 
significant 
worsening
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
6.7.1
Toxicity Management
6.7.1.1
Management of Elevations in Liver Transaminases
The following Table 6.7.1.1-1 summarizes the management of elevations in liver transaminases:
Table 6.7.1.1-1:
Management of Elevations in Liver Transaminases Grade Level of 
AST or ALT Recommendationsa
Grade
Recommendation
Grade1
None
Grade 2
none
Grade 3
Confirm elevation, evaluate for potential causes (including but not limited to alcohol or other 
substance abuse, concomitant medications, reactivation of existing or de novo infection with 
hepatitis viruses) consult with BMS Medical Monitor or designate as soon as possible.
Grade 4
Interrupt all study medications, evaluate for potential causes (including but not limited to alcohol 
or other substance abuse, concomitant medications, reactivation of existing or de novo infection 
with hepatitis viruses), monitor values frequently and consult with BMS Medical Monitor or 
designate as soon as possible. If Grade 4 is deemed related to study medication the subject must 
be discontinued from the study. Otherwise, if reinstitution of study therapy is considered, please
obtain approval from the BMS Medical Monitor or designate.
a If persisting (> Grade 1/2), evaluate for alternative etiologies, including alcohol use and viral hepatitis
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6.7.1.2
Management of Renal Toxicity
Serum phosphate levels and creatinine clearance (CrCl; CCL: as calculated by the Cockcroft 
Gault Equation [see Appendix 4] or eGFR) should be monitored and managed as described in the 
Viread local package insert/label.29 Dose interval adjustments of TDF (Viread) are permitted, as 
described in Section 4.5.2.
6.7.1.3
Management of Hyperbilirubinemia
Most patients taking ATV experience asymptomatic elevations in indirect (unconjugated) 
bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). Hepatic transaminase 
elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. Dose 
modification of ATV is not permitted. Subjects who experience unacceptable jaundice/scleral 
icterus should be discussed with the BMS Medical Monitor or designate to determine if subjects 
are to be discontinued from study. The investigator must contact the BMS Medical Monitor or 
designate prior to discontinuing any subject due to hyperbilirubinemia.
6.7.1.4
Gastrointestinal Toxicity Evaluation and Management Plan
Pre-clinical toxicology studies in rats and dogs (see Section 1.4.1.2) have suggested a potential 
for GI related toxicity with BMS-955176. This section provides general guidance to the 
Investigator on the evaluation and management of primarily upper gastrointestinal symptoms. 
The Investigator may contact the Medical Monitor to discuss evaluation and management 
(including interruption of ARVs or discontinuation of a subject) of any GI symptoms throughout 
the trial.
Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the foundation of proper 
evaluation and management. The following are potential manifestations of some GI 
clinical syndromes that may occur (possibly in combination) during the clinical 
trial. 
Nausea and Vomiting
The investigator should attempt to identify the etiology of these symptoms (and whether 
it is intraperitoneal, extraperitoneal, medication related, infection related, or due to a 
metabolic disorder).36 Medications can cause nausea and vomiting acutely. 
Dyspepsia
The Investigator should identify the presence of red flags (odynophagia, unexplained 
weight loss, recurrent vomiting, GI bleeding, jaundice, palpable mass or adenopathy, or 
family history of GI malignancy). Symptoms of dyspepsia could include early satiety, 
bloating, or belching. Additionally, atypical symptoms of dyspepsia could include: 
pharyngitis, asthma, bronchitis, hoarseness, chest pain, or abdominal pain. 
Ulcerative Disease
Symptoms suggestive of ulceration often are intermittent over a period of weeks to 
months and may be relieved by eating or antacid use;37 penetrating ulcers become more 
acute with localized pain and may not improve with food.38 The development of 
perforation may be indicated by severe diffuse abdominal pain. 
Other Clinical 
Syndromes
Additional diagnostic criteria for other GI disorders potentially encountered in the 
clinical trial are available elsewhere.39
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Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the foundation of proper 
evaluation and management. The following are potential manifestations of some GI 
clinical syndromes that may occur (possibly in combination) during the clinical 
trial. 
PHYSICAL 
EXAMINATION
Physical examination should complement elements obtained from the history37
Acutely, the investigator may assess for signs of intravascular volume depletion 
(eg, orthostasis) and/or aspiration of vomitus as appropriate. Abdominal 
tenderness and guarding may indicate inflammation. The presence of fecal blood 
can indicate mucosal damage (eg, from an ulcer). Complete evaluation of dyspepsia 
should include an oral examination (poor dentition or pharyngeal erythema) and 
lungs for wheezing. 
DIAGNOSTIC 
EVALUATION 
AND 
MANAGEMENT
A major goal in the diagnostic evaluation of a subject with upper GI symptoms is 
to quickly arrive at a final diagnosis without exposing the subject to unnecessary 
(invasive) testing; Investigators should exercise good clinical judgment38 in this 
regard. A major goal of therapy is directed at correcting the underlying 
identifiable medical or surgical abnormalities. Consultation (eg, gastroenterologist) 
is recommended as clinically indicated.
Grade 1 symptoms
Subjects may be treated symptomatically. If subjects develop dyspepsia alone, generally 
only limited and direct diagnostic testing should be performed.37 If the subject has 
dyspepsia they should limit alcohol, caffeine, chocolate, tobacco, other contributing 
concomitant medications (eg, NSAIDs) and eating directly before bedtime. A variety of 
OTC medications are available to address constipation and diarrhea as indicated. Please 
refer to Appendix 1 for Prohibited and Precautionary Therapies.
Grade 2 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

Serum chemistries and assessment of hemoglobin if not recently performed. 

Testing for Helicobacter pylori

Serologies (eg, celiac disease) 

PCR for viruses (eg, CMV)

Iron panel or Vitamin B12 level
For subjects who develop dyspepsia or are infected with H. pylori the use of H2 
antagonists, PPIs, Sucralfate, and antacids are prohibited (see Appendix 1 Prohibited 
Medications). If such therapy is required, discontinuation from the trial is necessary. 
The use of antiemetic’s (eg, Prochlorperazine) can be utilized as indicated. Management 
should be targeted at addressing the underlying pathology.
Grade 3 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

The testing outlined above in Grade 2

A fasting serum gastrin level can be obtained in cases of known ulcers refractory to 
therapy, a family history of the disease, or when surgery is required; of note, H. 
pylori can increase gastrin levels.38

A barium swallow to detect ulcers 

CT to identify gastrointestinal inflammation and a penetrating or perforated ulcer. 
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Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the foundation of proper 
evaluation and management. The following are potential manifestations of some GI 
clinical syndromes that may occur (possibly in combination) during the clinical 
trial. 

Upper endoscopy with biopsy as indicated in order to evaluate dyspepsia further 
(eg, mucosal injury, new onset unexplained dyspepsia in subjects > 55 y/o, or the 
presence of red flags).
Management should be targeted at addressing the underlying pathology.
Grade 4 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

The testing outlined above in Grade 2 and Grade 3

An acute abdominal series

If a perforated ulcer is clinically suspected, surgical consultation may be necessary
Initial management can include correction of hemodynamic and electrolyte 
abnormalities as clinically indicated. After stabilization, management should be targeted 
at addressing the underlying pathology.
a For Grade 2-4 symptoms if any ARV is thought to have a direct causal relationship to the patient’s 
gastrointestinal symptoms, the Investigator should consider discontinuing the subject from the study and 
performing an evaluation/management plan incorporating elements above. The Investigator can consider 
interruption of the potential offending ARV(s) but must balance this with the increased probability of 
development of viral resistance/lack of efficacy. As stated above, prior to discontinuing the subject from the 
study, attempts should be made to discuss with the BMS Medical Monitor unless the safety of the subject is 
acutely at risk.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This is an estimation study, without statistical testing, and hence there are no power 
considerations.
It is expected that response rate for the primary endpoint for all five arms will be somewhere 
around 80%. With this response rate, and 40 subjects per arm, an exact 95% confidence interval 
would run from roughly 64% to 91%.
8.2
Populations for Analyses
The following definitions are used in this document:

Enrolled subjects: Subject who signed an informed consent form and were assigned a 
Patient Identification number (PID);
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
Randomized subjects: Enrolled subjects who received a treatment assignment from the 
IVRS;

Treated subjects: Randomized subjects who received at least 1 dose of BMS-955176 or 
TDF. (Also referred to as the mITT analysis set)
8.3
Endpoints
8.3.1
Primary Endpoint(s)Stage 1 and Stage 2
The primary endpoint for Stage 1 and Stage 2 is the proportion of subjects with plasma HIV-1 
RNA < 40 c/mL at Week 24. This will be assessed with the FDA snapshot algorithm. This uses 
the last on-treatment plasma HIV-1 RNA measurement, within an FDA-specified visit window, 
to determine response. 
8.3.2
Secondary Endpoint(s)

The antiviral efficacy will be determined by the proportion of subjects with plasma HIV-1 
RNA < 40 c/mL at Weeks 48 and 96 using the FDA snapshot algorithm

The antiviral efficacy will also be assessed by the proportion of subjects with plasma HIV-1 
RNA < 200 c/mL at Weeks 24, 48 and 96 using the FDA snapshot algorithm approach with 
positive response defined as HIV-1 RNA < 200 c/mL

The emergence of HIV drug resistance among samples sent for drug resistance testing will be 
assessed using the most recent version of the IAS-USA list of HIV-1 drug resistance 
mutations

Changes from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the 
percentage of CD4+ T-cells will be assessed using on-treatment laboratory results, and 
pre-specified visit windows

The frequency of SAEs and AEs leading to discontinuation (DC) will be tabulated directly 
from the case report forms (CRFs). The summary will count the number of subjects that have 
at least one event

The occurrence of new AIDS defining events (CDC Class C events) will be tabulated from 
the CRFs. The summary will count the number of subjects that have at least one event

The steady-state plasma PK of BMS-955176 will be assessed using the intensive PK data, 
collected at Week 2 from a subset of subjects
8.4
Analyses
In general, categorical variables are tabulated with counts and percents. Continuous variables are 
summarized with univariate statistics (eg, mean, median, standard error).
Longitudinal analyses use pre-defined visit week windows. Unless otherwise specified, windows 
around planned measurement times are constructed based on the midpoint between planned 
study visits (ie, half the duration of time between study visits), and data are summarized at each 
scheduled visit. 
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For the calculation of descriptive statistics of observed data, subjects must have a baseline 
measurement to be evaluable for longitudinal tabulations of parameter values and changes from 
baseline. 
Tabulations of the following endpoints present the number of unique subjects with an event: 
protocol deviations; interruptions of study therapy; non-study medications; adverse events; and 
laboratory abnormalities. Thus, multiple occurrences of the same event are counted only once 
per subject.
8.4.1
Demographics and Baseline Characteristics
The following demographic and baseline characteristics will be summarized by treatment arm
and overall using the treated subjects:

Demographics: age, race, ethnicity, gender, geographic region;

Disease characteristics at baseline: plasma HIV-1 RNA level, CD4+ T-cell counts and 
percentages, CD8+ T-cell counts, HIV-1 subtype;

Laboratory tests at baseline;

Pre-treatment CDC Class C AIDS events;

Prior medications
8.4.2
Efficacy Analyses
The efficacy analyses will be based on the treated subjects.
8.4.2.1
Primary Efficacy Analyses
The primary efficacy endpoint is the proportion of subjects with plasma HIV-1 RNA < 40 c/mL 
at the Week 24 snapshot within each stage. This endpoint is assessed with the FDA snapshot 
algorithm. The primary analysis will be based on a modified ITT (mITT) approach. A sensitivity 
analysis will be conducted using an observed values approach. The two approaches will be 
implemented as follows:

Modified ITT: The numerator will be based on subjects with plasma HIV-1 RNA < 40 c/mL 
at Week 24. The denominator will be based on all treated subjects

Observed values: Similar to the mITT approach, the numerator will be based on subjects with 
plasma HIV-1 RNA < 40 c/mL at Week 24. However, the denominator will be based on the 
treated subjects with plasma HIV-1 RNA at Week 24
Response rates will be tabulated by treatment arm (within the stage) with exact binomial 95% 
confidence intervals.
Subgroup summaries will be provided to examine the impact of baseline viral load and HIV-1 
Clade (Clade AE versus Other) for both the mITT and the observed values approach. Other 
subgroup summaries may be provided to examine the impact of other important covariates such 
as CD4+ count, sex, geographic region, etc
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8.4.2.2
Secondary Efficacy Analyses
The following secondary endpoints will be summarized by treatment arm:

Proportion of subjects with HIV-1 RNA < 40 c/mL at Week 48 and Week 96 using mITT 
and observed values

Proportion of subjects with HIV-1 RNA < 200 c/mL at Week 24, 48 and 96 using mITT and 
observed values

Change from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the 
percentage of CD4+ T-cells over time

Newly emergent genotypic substitutions (using all on-treatment isolates) will be tabulated by 
treatment arm

The newly emergent phenotypic resistance profile (using all on-treatment isolates) will be 
tabulated by treatment arm
8.4.3
Safety Analyses
The investigators will determine the intensity of adverse events (AEs) and the relationship of 
AEs to study therapy. The investigators’ terms will be coded and grouped by system organ class 
using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) in 
production at BMS. AEs will be presented by system organ class and preferred term. 
Presentations will include both non-serious and serious adverse events, unless specified 
otherwise. If a subject had an adverse event with different intensities over time, then only the 
greatest intensity will be reported.
Deaths will be listed for enrolled subjects without regard to onset.
In analyses of fasting lipids over time, values will be excluded after the start of serum lipid 
reducing agents.
The frequency of the following safety events will be summarized by treatment arm for treated 
subjects:

SAEs

AEs leading to discontinuation of study therapy

AEs by intensity

CDC Class C AIDS events

Laboratory abnormalities by toxicity grade
8.4.4
Pharmacokinetic Analyses
The following PK parameters will be summarized by treatment arm:

Cmax: maximum observed plasma concentration

Tmax: time of maximum observed plasma concentration
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
Ctau: observed plasma concentration at the end of a dosing interval (eg, concentration at 
24 hours)

C0: observed pre-dose plasma concentration

AUC(TAU) : area under the concentration-time curve in one dosing interval
8.4.4.1
Sparse Pharmacokinetic Analyses
Sparse pharmacokinetic data will be used in population PK, PK/PD and, as available, PK/VK 
analyses.
8.4.4.2
PK/PD and PK/VK Analyses
PK data obtained from this study will be pooled with data from other studies to perform an 
integrated population PK analysis, exposure-response analyses for selected safety and efficacy 
endpoints, and, as available, viral kinetic modeling of BMS-955176 in combination with other 
ARVs to support the on-going development of BMS-955176. These analyses will facilitate 
optimal dose selection for future Phase 3 studies. 
The population PK, exposure-response, and, as available, viral kinetic analyses, will be reported 
separately.
8.4.5
Biomarker Analyses
Details about the biomarker analyses will be provided in the Statistical Analysis Plan (SAP).
8.4.6
Outcomes Research Analyses
Details about the outcomes research analyses will be provided in the SAP.
8.4.7
Other Analyses (including Virologic Futility)
An analysis of virologic futility will be performed at Week 24 when the last randomized subject 
in Stage 1 completes their Week 24 visit. This analysis will be conducted to evaluate whether the 
BMS-955176 arm shows significantly worse antiviral efficacy (HIV-1 RNA < 40 c/mL using the 
FDA snapshot algorithm) than the TDF-containing arm. The comparison of Arms 1 (containing 
BMS-955176) to Arm 2 (containing TDF) will be made with one-sided, Fisher’s exact tests, 
conducted at the 0.01 probability level.
An analysis of virologic futility will be performed at Week 24 when the last randomized subject 
in Stage 2 completes their Week 24 visit. This analysis will be conducted to evaluate whether a 
BMS-955176 arm shows significantly worse antiviral efficacy (HIV-1 RNA < 40 c/mL using the 
FDA snapshot algorithm) than the TDF-containing arm. The comparison of Arms 3-4
(containing BMS-955176) to Arm 5 (containing TDF) will be made with one-sided, Fisher’s 
exact tests, conducted at the 0.01 probability level.
8.5
Interim Analyses
There are two interim analyses scheduled before the start of Stage 2.
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The first interim analysis will be conducted after approximately 50% of the randomized subjects
have completed 24 weeks of therapy in Stage 1. This analysis will use the BMS equivalent of 
SDTM (Study Data Tabulation Model) data (“level 1” data) to facilitate the development of 
models for: population pharmacokinetics; exposure-response relationships; and, as available,
viral kinetics.
A second interim analysis will be conducted after the last subject has completed 24 weeks of 
therapy in Stage 1. This will be an analysis of the available efficacy, safety, resistance and 
pharmacokinetic data.
The schedule for additional analyses will depend upon the decision to initiate the Stage 2, as well 
as the recruiting time frame of Arms 1 & 2 relative to the time frame for Arms 3, 4, and 5. If 
Stage 2 is initiated, and recruiting follows projected timelines, then it is anticipated that analyses 
will be conducted when:

The last subject in Arms 3, 4, and 5 completes the Week 24 visit

The last subject in Arms 1 and 2 completes the Week 96 visit

The last subject in Arms 3, 4, and 5 completes the Week 96 visit
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
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currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the 
source documents:
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS.
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
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9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include the investigational product 
and the non-investigational product(s). Records or logs must comply with applicable regulations 
and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted)

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
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9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
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The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete Abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Female subjects must continue 
to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to 
forego complete abstinence.
If two forms of contraception is required, Complete abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as complete 
avoidance of heterosexual intercourse is an acceptable form of 
contraception for all study drugs. This also means that abstinence is the 
preferred and usual lifestyle of the patient. This does not mean periodic 
abstinence (eg, calendar, ovulation, symptothermal, profession of 
abstinence for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of contraception. Subjects 
who choose complete abstinence are not required to use a second method 
of contraception, but female subjects must continue to have pregnancy 
tests. Acceptable alternate methods of highly effective contraception must 
be discussed in the event that the subject chooses to forego complete 
abstinence
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11
LIST OF ABBREVIATIONS
Term
Definition
3TC
Lamivudine
AE
adverse event
AI
accumulation index
AIDS
Acquired Immunodeficiency Syndrome
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after the 
first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ARV
antiretroviral
AST
aspartate aminotransferase
ATV
atazanavir
ATV/r
atazanavir boosted with ritonavir
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of 
the last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
BID, bid
bis in die, twice daily
BCRP
Breast cancer reactive protein
BDC
Bile duct-cannulated
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BVM
bevirimat
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Term
Definition
c
copies
c/mL
copies per milliliter
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
CA
capsid
cART
Combination antiretroviral therapy
Cavg
average concentration
Cexpected-tau
expected concentration in a dosing interval
CD
Cluster designation (CD4; CD8)
CDC
Centers for Disease Control
CFC
corrected fold change
CFR
Code of Federal Regulations 
CI
confidence interval
CrCl
creatinine clearance
CLR
renal clearance
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CMV
cytomegalovirus
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Css,avg
average steady-state plasma concentration
CSR
Clinical study report
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
Trough observed plasma concentration
CT
Computed tomography
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Term
Definition
CTA
clinical trial agreement
CTX
Cross-linked C-telopeptide of Type 1 collagen
CYP
cytochrome p-450
D/C
discontinue
DDI
drug-drug interaction
DHHS
Department of Health and Human Services
dL
deciliter
DTG
dolutegravir
EC
Ethics committee
EC
effective concentration
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EFV
efavirenz
eg
exempli gratia (for example)
E-R
exposure-response
ESR
Expedited Safety Report
ET
Early termination or End of Treatment
EU
European Union
FAHI
Functional Assessment of HIV Infection
FDA
Food and Drug Administration
FDC
Fixed dose combination
FSH
follicle stimulating hormone
FTC
emtricitabine
g
gram
GFR
glomerular filtration rate
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
GSH
glutathione
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Term
Definition
h; hr
hour
HAART
Highly active antiretroviral therapy
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
hepatitis C virus
HCO3-
bicarbonate
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
HS
Human serum
HuSA
Human serum albumin
IAS
International AIDS Society
IB
Investigator brochure
IC
Inhibitory concentration
ICD
International Classification of Diseases
ICF
informed consent form
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
INI
Integrase inhibitor
IP
investigational product
IRB
Institutional Review Board
IU
International Unit
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
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Term
Definition
GALT
Gut associated lymphoid tissue
GI
gastrointestinal
kg
kilogram
L
liter
MAD
multiple ascending dose
MC
micronized crystalline
mg
milligram
MI
Maturation inhibitor
MIC
minimum inhibitory concentration
min
minute
mITT
Modified Intent to Treat
mL
milliliter
mmHg
millimeters of mercury
msec
millisecond
MOA
mechanism of action
g
microgram
M
micromolar
N
number of subjects or observations
N/A
not applicable
ng
nanogram
nM
nanomolar
NIMP
non-investigational medicinal products 
NNRTI
Non- nucleoside reverse transcriptase inhibitor
NOAEL
No observed adverse effect level
NOEL
No observed effect level
NRTI
nucleoside reverse transcriptase inhibitor
NSAID
nonsteroidal anti-inflammatory drug
pDILI
potential drug induced liver injury
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
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Term
Definition
PD
pharmacodynamics
PI
protease inhibitor
PDVF
Protocol-defined virologic criteria
PK
pharmacokinetics
PPI
proton pump inhibitor
PR
atrial depolarization to ventricular depolarization
PT
prothrombin time
PTT
partial thromboplastin time
QC
quality control
QD, qd
quaque die, once daily
QRS
interval representing the time for ventricular depolarization
QT
Duration of ventricular electrical activity
QTcF
QT corrected for heart rate using Frederica’s formula
RAL
raltegravir
RBC
red blood cell
RNA
ribonucleic acid
RTV
ritonavir
SAD
single ascending dose
SDD
spray-dried dispersion
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDTM
Study Data Tabulation Model
SOP
Standard Operating Procedures
SP1
spacer peptide 1
Subj
subject
STR
single tablet regimen
t
temperature
T
time
TDF
tenofovir
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Term
Definition
TDF/FTC
Truvada (TDF 300 mg + FTC 200 mg)
TAO
Trial Access Online, the BMS implementation of an EDC capability
TAM
Thymidine analogue mutation
T-HALF
Half life
T-HALFeff_AUC
Effective elimination half life that explains the degree of AUC 
accumulation observed
Tmax, TMAX
time of maximum observed concentration
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UGT
UDP-glucuronosyltransferase
ULN
upper limit of normal
US
United States
VF
virologic failure
VK
Viral kinetics
VLP
Virus-like particles
WBC
white blood cell
WFD
Wallingford, Connecticut, USA
WHO
World Health Organization
Wk or WK
week
WOCBP
women of childbearing potential
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12
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European AIDS Clinical Society. European Guidelines for treatment of HIV-infected adults 
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Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
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United States Department of Health and Human Services, Food and Drug Administration, 
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Gupta S.K., Lombaard J., Echevarria J., et. al. HIV NRTI BMS-986001 in Antiretroviral-
Naive Subjects: Week 24/49 Analyses. ICAAC 2014 Oral Abstract: H-642
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Study AI468001 Randomized, Double-Blinded, Placebo-Controlled, Single and Multiple 
Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
BMS-955176 in Healthy Subjects. Document Control No. 930071044
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Study AI468002 Randomized, Placebo-Controlled, Multiple-Dose Study to Evaluate the 
Pharmacodynamics, Safety and Pharmacokinetics of BMS-955176 (Double-Blinded) and 
BMS-955176 with Atazanavir +/- Ritonavir (Open-Labelled) in HIV-1 Infected Subjects. 
Draft Document Control No. 930087017
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Min 
S., 
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Walmsley SL., Antela A., Clumeck N., et. al. Dolutegravir plus abacavir-lamivudine for the 
treatment of HIV-1 infection. NEJM 2013 369(19):1807-18.
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Raffi F., Jaeger H., Quiros-Roland E., et. al. Once-daily dolutegravir versus twice-daily 
raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week 
results from a randomised, double-blind, non-inferiority trial. Lancet ID. 2013 13(11): 
927-35.
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Cahn P., Pozniak AL., Mingrone H,. et. al. Dolutegravir versus raltegravir in antiretroviral-
experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, 
double-blind, non-inferiority SAILING study. Lancet 2013 382(9893):700-8.
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Stellbrink HJ., Reynes J., Lazzarin A., Dolutegravir in antiretroviral-naive adults with 
HIV-1: 96-week results from a randomized dose-ranging study. AIDS 2013 27(11):1771-8.
13
Eron JJ., Clotet B., Durant J., Safety and efficacy of dolutegravir in treatment-experienced 
subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING 
Study. JID 2013 207(5): 740-748.
14
Sanne I, Piliero P, Squires K, Thiry A, Schnittman S. Results of a phase 2 clinical trial at 48 
weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at 
three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. 
J Acquir Immune Defic Syndr. Jan 1 2003;32(1):18-29.
15
Bertz RJ, Persson A, Chung E, et al. Pharmacokinetics and pharmacodynamics of atazanavir-
containing antiretroviral regimens, with or without ritonavir, in patients who are 
HIV-positive and treatment-naive. Pharmacotherapy. Mar 2013;33(3):284-294.
16
Molto J, Santos JR, Valle M, et al. Monitoring atazanavir concentrations with boosted or 
unboosted regimens in HIV-infected patients in routine clinical practice. Ther Drug Monit. 
Oct 2007;29(5):648-651.
17
Goutelle S, Baudry T, Gagnieu MC, et al. Pharmacokinetic-pharmacodynamic modeling of 
unboosted Atazanavir in a cohort of stable HIV-infected patients. Antimicrob Agents 
Chemother. Jan 2013;57(1):517-523.
18
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. 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed Nov 
30, 2013.
19
Malan DR, Krantz E, David N, Wirtz V, Hammond J, McGrath D. Efficacy and safety of 
atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy 
regimens in antiretroviral-naive patients. J Acquir Immune Defic Syndr. Feb 1 
2008;47(2):161-167.
20
Landman R, Diallo MB, Gueye NF, et al. Efficacy and safety of unboosted atazanavir in 
combination with lamivudine and didanosine in naive HIV type 1 patients in Senegal. AIDS 
Res Hum Retroviruses. May 2010;26(5):519-525.
21
Gianotti N, Seminari E, Guffanti M, et al. Evaluation of atazanavir Ctrough, atazanavir 
genotypic inhibitory quotient, and baseline HIV genotype as predictors of a 24-week 
virological response in highly drug-experienced, HIV-infected patients treated with 
unboosted atazanavir. New Microbiol. Apr 2005;28(2):119-125.
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22
Giuntini R, Martinelli C, Ricci E, et al. Efficacy and safety of boosted and unboosted 
atazanavir-containing antiretroviral regimens in real life: results from a multicentre cohort 
study. HIV Med. Jan 2010;11(1):40-45.
23
Two Drug Combination Studies with BMS-955176 and HIV Antiviral Agents. Version 1.0. 
June 2013. DCN 930071469
24
Song I., Borland J., Chen S. Effect of atazanavir and atazanavir/ritonavir on the 
pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572. Br. J. 
Pharm. 2011 72(1):103-108
25 BMS-955176 Investigator Brochure, Version 2.0, July 2013 DCN 930056146
26 BMS-955176 Investigator Brochure, Version 3.0, April 17, 2014 DCN 930056146
27 Partial response to FDA “May Proceed” Letter dated 27 Sep 2013 for IND 118,936. Bristol-
Myers Squibb Company; Jan 2014. Document Control No. 930076507 2.0. Insert this 
additional reference: “Evaluation of cross-resistance of HIV-1 Maturation Inhibitor 
BMS-955176 toward HIV-1 protease inhibitor resistant viruses. Bristol-Myers Squibb 
Company; 30-Sept-2014. Document Control No. 930083565.”
28 Evaluation of Cross Resistance of HIV-1 Maturation Inhibitor BMS-955176 Toward HIV-1 
Protease Inhibitor Resistant Viruses. Document Control No. 930083565
29 Gilead 
Sciences. 
Prescribing 
Information 
for 
TDF. 
Available 
at: 
http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/viread/viread_pi.pdf.
Accessed Dec 31, 2014
30
ViiV 
Healthcare. 
Prescribing 
Information 
for 
DTG. 
Available 
at: 
https://www.viivhealthcare.com/media/58599/us_tivicay.pdf. Accessed Dec 31, 2014.
31 BMS. 
Prescribing 
Information 
for 
ATV. 
Available 
at: 
http://packageinserts.bms.com/pi/pi_reyataz.pdf. Accessed Dec 31, 2014
32 AbbVie. 
Prescribing 
Information 
for 
RTV. 
Available 
at: 
http://www.rxabbvie.com/pdf/norvirtab_pi.pdf. Accessed Dec 31, 2014
33 Evaluation of Cross-Resistance of HIV-1 Maturation Inhibitor BMS-955176 Toward HIV-1 
Protease Inhibitor Resistant Viruses. DCN 930083565
34
Kestelman P. et. al., Efficacy of the Simultaneous Use of Condoms and Spermicides Family 
Planning Perspectives.Vol 23 (5); October 1991.
35
Gabbay MB, Thomas J, Gibbs A, Hold P. A Randomized Crossover Trial of The Impact of 
Additional Spermicide on Condom Failure Rates. Sex Transm Dis 2008; 35: 862-8.
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36
Hasler WL Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrisons 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill
37
Hasler WL and Owyang C Approach to the Patient with Gastrointestinal Disease. Chapter 
290. Harrisons Principles of Internal Medicine 18th edition. 2012. McGraw Hill
38
Soll AH and Graham DY. Peptic Ulcer Disease. Chapter 40. Textbook of Gastroenterology. 
5th edition. 2009. Blackwell Publishing
39
Rome Foundation. Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders. 
Available: http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed 
Dec 22 2014
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APPENDIX 1
LISTINGS OF PROHIBITED AND PRECAUTIONARY
THERAPIES
General Notes: 

Guidelines for the use of drugs with established or other potentially significant drug 
interactions listed in the Package Inserts of the marketed ARV agents used by subjects 
participating in this study (Reyataz, Norvir, Viread, Tivicay) should be followed. 

Medications listed in the Package Inserts as contra-indicated with the other marketed ARV 
agents used by subjects participating in this study are not permitted. 

Any immunizations deemed appropriate by the subject’s physician are permitted provided 
that the immunization is given > 4 weeks from any HIV-1 RNA measurement.

A subject may not be co-enrolled in a concomitant trial unless it is approved by the Medical 
Monitor prior to randomization.
Prohibited Therapies
Drugs that should not be administered throughout the duration of the study:
Anticonvulsants: Carbamazepine, 
Phenobarbital, Phenytoin
Use with ATV may result in decreased ATV concentrations. Use 
of Carbamazepine may result in decreased DTG concentrations.
Oral Antifungals: Itraconazole, 
Posaconazole, and Voriconazole
Use with ATV can result in increased ATV concentrations
Antimycobacterials: Rifampin, 
Rifapentine, Rifabutin
These antimycobacterials decrease ATV plasma concentrations
and may decrease BMS-955176 plasma concentrations.
St. John’s wort
Use with ATV or DTG may result in loss of antiviral therapeutic 
effect
GI motility agent: Cisapride
Potential for serious and/or life threatening reactions such as 
cardiac arrhythmias
Pimozide
Potential for serious and/or life threatening reactions such as 
cardiac arrhythmias
Zetia (ezetimibe)
Ezetimibe is a substrate of OATP1B1 (of which BMS-955176 is 
an inhibitor in vitro).
Dofetilide
Use with DTG may result in the potential for increased Dofetilide 
plasma concentrations and the risk for serious and/or life 
threatening events
Alfuzosin
ATV increases Alfuzosin concentrations which can result in 
hypotension
Benzodiazepines: Triazolam and 
Midazolam
ATV can increase the concentration of these Benzodiazepines 
with the potential to increase sedation or respiratory depression
Ergot derivatives: 
Dihydroergotamine, ergotamine, 
ergonovine, methylergonovine
ATV can increase potential for ergot toxicity (e.g. peripheral 
vasospasm)
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HMG-CoA Reductase Inhibitors: 
Lovastatin, Simvastatin, 
Atorvastatin, Pitavastatin, 
Rosuvastatin, Pravastatin
Use with ATV may result in increased levels of HMG-CoA 
Reductase Inhibitors and potential for serious reactions such as 
myopathy
Antacids, H2 receptor angatonists, 
Proton Pump Inhibitors, Sucralfate
Use with ATV may result in decreased plasma concentrations of 
ATV. Use of Antacids containing Aluminium, Magnesium, or 
Calcium may result in decreased levels of DTG.
Macrolides: Clarithromycin
Use with ATV may result in increased Clarithromycin levels and 
QTc prolongation
Buprenorphine
Use with ATV may increase levels of Buprenorphine
Quetiapine
Use with ATV may increase levels of Quetiapine
Salmeterol
Use with ATV may result in increased levels of Salmeterol
Avanafil
Use with ATV may result in increased Avanafil levels
All drugs with antiretroviral 
activity other than those 
considered study therapy
Any drugs with antiretroviral activity not considered study 
therapy may interfere with the assessments of the study.
Precautionary Therapies
Drugs that should be administered with caution during the study:
Hormonal Contraceptives
Hormonal Contraceptives cannot be relied upon as a highly 
effective method of contraception. 
See Protocol Section 3.3.1, for more information on Highly 
Effective Methods of Contraception.
Antidepressants: Trazodone, 
Tricyclic Antidepressants (TCA)
Use with ATV/r may result in increased plasma concentrations of 
trazodone and TCA
Antimalarials: 
Atovaquone/Proguanil, Mefloquine
Use with ATV/r may result in decreased Atovaquone/Proguanil 
levels. The effect of Mefloquine on ATV/r is unknown.
Benzodiazepines: Alprazolam and 
Diazepam
ATV can increase the concentration of these Benzodiazepines 
Calcium Channel Blockers
Use with ATV may result in increased concentrations of CCB’s. 
Non-topical Corticosteroids: 
Budesonide, Fluticasone, 
Prednisone, Methylprednisolone, 
Prednisolone, Triamcinolone
Use with ATV/r may result in increased levels of glucocorticoids 
and adrenal insufficiency
Dexamethasone
Use with ATV may result in reduced levels of ATV.
Colchicine
Use with ATV may result in increased Colchicine levels
Metformin
Use with DTG may result in increased levels of metformin. 
A cation-containing (e.g. 
Magnesium) laxative
If used with DTG the laxative should be taken 2 hours before or 
6 hours after taking concomitant laxatives.
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APPENDIX 2
AIDS-DEFINING DIAGNOSES
I.
PARASITIC INFECTIONS
Pneumocystis carinii (PC)
1011
PC pneumonia histologically proven.
1012
PC pneumonia, clinical diagnosis by the following specifications and confirmed HIV 
infection:
A history of dyspnea on exertion or non-productive cough of recent onset (within the past 
3 months).
AND
Chest X-ray evidence of diffuse bilateral interstitial or gallium scan evidence of diffuse 
bilateral pulmonary disease;
AND
Arterial blood gas analysis showing an arterial pO2 of < 70 mmHg or a low respiratory 
diffusing capacity (< 80% of predicted values) or an increase in the alveolar-arterial 
oxygen tension gradient;
AND
Successful response to appropriate therapy and no evidence of pneumonias of other 
etiologies.
1013
Pneumocystis carinii, histologically proven, at a site other than lungs.
Toxoplasmosis (in patients > 1 month old)
1021
Toxoplasmosis, clinical diagnosis (of brain only) by the following specifications and 
confirmed HIV infection:
Recent onset of a neurologic disease consistent with toxoplasmosis;
AND
Brain imaging evidence of a mass lesion (on computed tomography, nuclear magnetic 
resonance of radiography enhanced by injection of contrast medium);
AND
Serum antibody to toxoplasmosis and successful response to therapy for toxoplasmosis.
1022
Toxoplasmosis, of brain or internal organs other than liver, spleen or lymph nodes. 
Proven by microscopy.
Isosporiasis
1031
Isosporiasis causing chronic diarrhea of > 1 month. Proven by microscopy.
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Cryptosporidiosis
1041
Cryptosporidiosis causing chronic diarrhea of > 1 month. Proven by microscopy.
II.
FUNGAL INFECTIONS
Candidiasis
2011
Candidiasis, Esophageal, definitive diagnosis by the following specifications:
Gross inspection by endoscopy or autopsy or by microscopy (histology or cytology) on a 
specimen obtained directly from the tissues affected (including scrapings from the 
mucosal surface), not from a culture.
2012
Candidiasis, Esophageal, presumptive diagnosis by the following specifications and 
confirmed HIV infection:
Recent onset of retrosternal pain on swallowing:
AND
Oral candidiasis diagnosed by the gross appearance of white patches or plaques on an 
erythematous base OR by the microscopic appearance of fungal mycelial filaments in an 
uncultured specimen scraped from the oral mucosa;
AND
Response to appropriate therapy.
2013
Candidiasis, Bronchial/Pulmonary, definitive diagnosis by the following specifications; 
Gross inspection by endoscopy or autopsy or by microscopy (histology or cytology) on a 
specimen obtained directly from the tissues affected (including scrapings from the 
mucosal surface), not from a culture.
Cryptococcosis
2022
Cryptococcosis, Extra-pulmonary, proven by microscopy (histology or cytology), culture 
or detection of antigen in a specimen obtained directly from the tissues affected or a fluid 
from those tissues.
Histoplasmosis
2031
Histoplasmosis, Disseminated (at a site other than or in addition to lungs or cervical or 
hilar lymph nodes), proven by microscopy (histology or cytology), culture or detection of 
antigen in a specimen obtained directly from the tissues affected or a fluid from those 
tissues.
Coccidioidomycosis
2041
Coccidioidoidomycosis, Disseminated (at a site other than or in addition to lungs or 
cervical or hilar lymph nodes), proven by microscopy (histology or cytology), culture or 
detection of antigen in a specimen obtained directly from the tissues affected or a fluid 
from those tissues.
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2042
Coccidioidomycosis, clear reactivation of prior infection, proven by microscopy 
(histology or cytology), culture or detection of antigen in a specimen obtained directly 
from the tissues affected or a fluid from those tissues.
III.
BACTERIAL INFECTIONS
Mycobacterium
3001
Mycobacterium (unidentified species). Presumptive diagnosis, by the following 
specifications and confirmed HIV infection.
Acid fast bacilli (AFB) positive stain of specimen obtained from endoscopic biopsy or 
from a normal sterile site other than lungs, skin or cervical or hilar lymph nodes. Species 
NOT identified by culture.
Mycobacterium tuberculosis
3011
Mycobacterium tuberculosis, Pulmonary, definitive diagnosis proven by culture, without 
evidence of upper respiratory infection symptoms of Mycobacterium tuberculosis that 
could account for the positive culture.
3012
Mycobacterium tuberculosis, definitive diagnosis proven by culture, of at least one extra 
pulmonary site regardless of concurrent pulmonary involvement.
3013
Mycobacterium tuberculosis, Disseminated, definitive diagnosis proven by culture.
Mycobacterium avium intracellulare
3022
MAI in Blood, proven by culture.
3023
MAI Colitis, proven by histology and culture. (This does not include MAI of the stool 
alone).
3024
MAI, Disseminated, at a site other than or in addition to lungs or cervical or hilar lymph 
nodes, proven by culture.
Mycobacterium Kansasii, Mycobacterium Scrofulaceum and Other Atypical 
Mycobacterium
3032
M. Kansasii, in Blood, proven by culture.
3033
M. Kansasii Colitis, proven by histology and culture. (NOT including positive M. 
Kansasii of stool alone).
3034
M. Kansasii, Disseminated, at a site other than or in addition to lungs, or cervical or hilar 
lymph nodes, proven by culture.
3035
M. Scrofulaceum or other Atypical Mycobacterium, proven by culture.
Salmonella
3041
Salmonella, recurrent Bacteremia (non-typhoid), proven by culture.
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IV.
VIRAL INFECTIONS
Cytomegalovirus
4011
CMV, Pneumonitis, pathologically or histologically confirmed. Serum antibody titer and 
culture alone is not sufficient for the diagnosis.
4012
CMV, Esophagitis, as diagnosed by histology, pathology or culture of an esophageal 
lesion. Serum antibody titer and culture of other than esophageal tissue is not sufficient 
for the diagnosis.
4013
CMV, Retinitis as evidenced by a characteristic appearance on serial ophthalmoscopic 
examinations (eg, discrete patches of retinal whitening with distinct borders, spreading in 
a centrifugal manner, following blood vessels, progressing over several months, 
frequently associated with retinal vasculitis, hemorrhage, and necrosis). Resolution of 
active disease leaves retinal scarring and atrophy with retinal pigment epithelial mottling.
4014
CMV, Colitis, as diagnosed by histology, pathology or culture of a colonic lesion. Serum 
antibody titer and culture of other than colonic tissue is not sufficient for the diagnosis.
4015
CMV, Encephalitis, as diagnosed by histology, pathology or culture of brain tissue or 
CSF. Serum antibody titer and culture of other than brain tissue or CSF is not sufficient 
for the diagnosis.
Herpes Simplex (in patients > 1 month old).
4021
HSV, Disseminated (but not encephalitis alone), proven by microscopy (histology or 
cytology), culture or detection of antigen in a specimen obtained directly from affected 
tissues.
4022
HSV, Esophagitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for the diagnosis.
4023
HSV, Bronchitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for the diagnosis.
4024
HSV, Pneumonitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for diagnosis.
4025
HSV, GI, other than mouth, throat, or peri-rectal, as diagnosed by microscopy (histology 
or cytology), culture or detection of antigen in a biopsy specimen obtained directly from 
affected tissue. Serological measurement and culture from other than the affected tissue is 
not sufficient for diagnosis.
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4026
HSV, Mucocutaneous, ulcers persisting for 1 month despite appropriate therapy, as 
diagnosed by microscopy (histology or cytology), culture or detection of antigen in a 
biopsy specimen obtained directly from affected tissue. Serological measurement and 
culture from other than the affected tissue is not sufficient for the diagnosis.
Progressive Multifocal Leukoencephalopathy
4041
Progressive Multifocal Leukoencephalopathy, proven by microscopy.
VI.
NEOPLASTIC DISEASES
Kaposi’s Sarcoma
6011
Kaposi’s sarcoma, Mucocutaneous, proven by microscopy.
6012
Kaposi’s sarcoma. Mucocutaneous, presumptive diagnosis with characteristic gross 
appearance and confirmed HIV infection.
6013
Kaposi’s sarcoma, Visceral.
6014
Kaposi’s sarcoma, other than above.
Lymphoma of the Brain
6021
Primary Lymphoma of the brain at any age, proven by microscopy.
Non-Hodgkins Lymphoma
6031
Small Non-cleaved lymphoma (either Burkitt or non-Burkitt type).
6032
Immunoblastic sarcoma, equivalent to any of the following, although not necessarily all 
in combination: Immunoblastic lymphoma, large-cell lymphoma, diffuse histocytic 
lymphoma.
Cervical Carcinoma
6041
Histologically proven invasive carcinoma of the cervix.
VII.
OTHER CONDITIONS
HIV Dementia/Motor Defects
7011
HIV Dementia, clinical findings of disabling cognitive and/or motor dysfunction 
interfering with occupation or activities of daily living progressing over weeks to months, 
in the absence of a concurrent illness or condition other than HIV infection that could 
explain the findings. Method to rule out such concurrent illnesses and conditions must 
include cerebrospinal fluid examination and either brain imaging (computed tomography 
or magnetic resonance) or autopsy.
Slim Disease or HIV Wasting Syndrome
7021
HIV Wasting Syndrome, findings of profound involuntary weight loss > 10% of baseline 
body weight plus either chronic diarrhea (at least two loose stools per day for 30 days) 
or chronic weakness and documented fever (for 30 days, intermittent to constant) in the 
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absence of a concurrent illness or condition other than HIV infection that could explain 
the findings (eg, cancer, tuberculosis, cryptosporidiosis, or other specific enteritis).
7061
Recurrent pneumonia, acute onset within 12 months of most recent episode.
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APPENDIX 3
DAIDS TOXICITY GRADES
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APPENDIX 4
COCKCROFT-GAULT EQUATION TO CALCULATE SERUM 
CREATINE CLEARANCE
Online calculator:
http://nephron.com/cgi-bin/CGSI.cgi
Manual calculation:
Male:
Estimated Creatinine Clearance =
(140-age in years) x Body Weight (kg)
72 x Serum Creatinine (mg/dL)
Female:
Estimated Creatinine Clearance =
(140-age in years) x Body Weight (kg) x 0.85
72 x Serum Creatinine (mg/dL)
1 pound = 0.4536 kilograms
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Page:
1
Protocol Number:
AI468048
IND Number:
118,936
Ex-US
Non-IND
EUDRACT Number
N/A
Date:
28-Jan-2015
Revised Date:
03-Jun-2015
CLINICAL PROTOCOL AI468048
A Phase 2b Randomized, Active-Controlled, Staged, Open-Label Trial to Investigate Safety and 
Efficacy of BMS-955176 in Combination with Dolutegravir and Atazanavir (with or without 
Ritonavir) in Treatment-Experienced HIV-1 Infected Adults
Revised Protocol Number: 02
Incorporates Amendment(s): 05
Study Director/Central Medical Monitor
 DO, MPH
5 Research Parkway
Office 201D
Wallingford, CT  06492 USA
Telephone (office): 
Fax: 
24-hr Emergency Telephone Number
USA:
International: 
Bristol-Myers Squibb Research and Development
Virology Clinical Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
5 Research Parkway
Wallingford, CT 06492
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
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2
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 02
03-Jun-2015
Incorporates Amendment 05
Amendment 05
03-Jun-2015
To mitigate the risk of randomizing subjects infected with HIV-1 with an 
unknown efficacy profile, exclusion criteria have been modified to now 
exclude subjects with Clade AE as well as those subjects who have failed a 
previous boosted PI- or Integrase strand transfer inhibitor (INSTI)-
containing regimen for which resistance analyses were not conducted at the 
time of failure. 
To remove “male condoms with spermicide” as a highly effective method 
of contraception (moved to the list of less effective methods) and require 
the use of a highly effective method of contraception as specified in the 
Clinical 
Trials 
Facilitation 
Group 
Recommendations 
Related 
to 
Contraception and Pregnancy Testing in Clinical Trials.  Most 
contraception methods were more clearly defined, including the removal of 
any text relative to hormonal methods used by female study subjects who 
are WOCBP, since they can’t be counted among the methods used at all.
Pregnancy was added as a reason to be discontinued from the study, and the 
practice of Rescreening was more clearly defined, an administrative change 
was made to clearly indicate that AIDS History will be taken at Screening,
In addition, at Week 24, a Time to Loss of Virologic Response analysis will 
be conducted as a sensitivity analysis that compliments the snapshot 
analysis, and a definition of virologic rebound was added.
A table of the laboratory assessments in detail was added as an appendix, 
and the appendix of the DAIDS Toxicity Table (updated 2009) was 
removed to include a link to the more current 2014 version of the table. In 
addition, and a table of laboratory assessment was added as a new appendix
Other changes, more administrative in nature, have been included.
Revised 
Protocol 01
19-Mar-2015
Incorporates Amendment 04
Amendment 04
19-Mar-2015
Incorporated information that more clarify the Week 24 data (consisting of 
efficacy, safety, and pharmacokinetic data) to be used to confirm the doses 
for Stage 2 and to trigger the start of Stage 2 of the study relative to other 
analyses conducted under the protocol for other purposes.
Removed the requirement that all Sparse PK samples need to be collected 
as pre-AM dose samplings.  Only one visit Weeks 4- 24 (as opposed to all 
visits Weeks 4 - 24) needs to be performed in the morning and to have the 
blood collected as a pre-AM dose sampling; (includes the deletion of 
Table 5.5.2-1).
Administrative changes.
Original 
Protocol
28-Jan-2015
Not applicable
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SYNOPSIS
Clinical Protocol AI468048
Protocol Title: A Phase 2b Randomized, Active-Controlled, Staged, Open-label Trial to Investigate Safety and 
Efficacy of BMS-955176 in Combination with Dolutegravir and Atazanavir (with or without Ritonavir) in 
Treatment-Experienced HIV-1 Infected Adults
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Subjects in each arm and per stage will begin QD dosing (in the morning, with a meal) with 
BMS-955176 in combination with atazanavir (ATV) [with or without ritonavir (RTV)] and dolutegravir (DTG), or 
tenofovir (TDF) in combination with atazanavir boosted with ritonavir (ATV/r) and DTG, for a duration of 
96 weeks.
Stage 1:

Arm 1: BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, OR

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Study Phase: 2b
Research Hypothesis: This Phase 2b study will evaluate whether the combination of BMS-955176 with ATV (with 
or without RTV) and DTG is efficacious, safe, and well-tolerated in HIV-1 infected treatment-experienced adults.
Objectives:
Primary Objective Stage 1

To assess the antiviral efficacy of BMS-955176 120 mg and a TDF 300 mg-containing arm, each when given in 
combination with ATV/r 300/100 and DTG 50 mg by determining the proportion of treatment-experienced 
subjects with plasma HIV-1 RNA < 40 c/mL at Week 24 in Stage 1.
Primary Objective Stage 2

To assess the antiviral efficacy of two doses (120 and 180 mg) of BMS-955176, each when given in 
combination with unboosted ATV 400 mg and DTG 50 mg, and to assess the antiviral efficacy of TDF 300 mg 
when given in combination with and ATV/r 300/100 mg and DTG 50 mg by determining the proportion of 
treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at Week 24 in Stage 2. 
Secondary Objectives

To assess the antiviral efficacy of BMS-955176 Arms, and TDF-containing regimens (TDF + ATV/r + DTG), 
by determining the proportion of treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at 
Weeks 48 and 96

To assess the antiviral efficacy of BMS-955176 Arms, and TDF-containing regimens, by determining the 
proportion of treatment-experienced subjects with plasma HIV-1 RNA < 200 c/mL at Weeks 24, 48, 96
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
To assess the emergence of HIV drug resistance in samples selected for drug resistance testing (according to 
criteria outlined in Protocol Section 5.4.1)

To assess efficacy of BMS-955176 Arms, and TDF-containing regimens, by using the mean changes from 
baseline in log10 HIV-1 RNA, CD4+ T-cell counts, and percentage of CD4+ T-cells

To assess the safety and tolerability of BMS-955176 in treatment-experienced subjects by measuring frequency 
of SAEs and AEs leading to discontinuation

To assess disease progression as measured by the occurrence of new AIDS defining events 
(CDC Class C events)

To characterize the pharmacokinetics of BMS-955176 when co-administered with ATV (with or without 
ritonavir) and DTG in treatment-experienced HIV-1 infected subjects
Study Design: This is a randomized, active-controlled, staged, open-label clinical trial. Approximately 
200 treatment-experienced subjects total will be randomized into the study. In Stage 1, approximately 80 subjects 
will be randomized 1:1 (approximately 40 per arm) to either of the treatment arms containing BMS-955176 or TDF 
in combination with boosted atazanavir (ATV/r) and DTG. In Stage 2, approximately 120 subjects will be 
randomized 1:1:1 (approximately 40 per arm) to either of the two BMS-955176 treatment arms containing 
unboosted ATV and DTG, or to the TDF-containing Arm containing ATV/r and DTG.
Stage 1:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, OR

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
A Continuation Dose of BMS-955176 will be selected based on Week 24 data from Stage 1 and from study 
AI468038 (BMS-955176 in ARV treatment-naive HIV-1 infected subjects) with which subjects in Stage 1, Arm 1 
may transition to for the remainder of the study. The transition may occur on or after Week 48.
The data from the Week 24 analysis for AI468038 and Stage 1, including safety, efficacy and pharmacokinetics, will 
be examined to trigger the start of Stage 2 (utilizing unboosted ATV in the experimental arms) and confirm the two 
doses of BMS-955176 (in the experimental arms) for study in Stage 2.
After the Stage 2 Week 24 endpoint, a Continuation Dose of BMS-955176 will be selected based on data from 
Stages 1 and 2, and study AI468-038 with which subjects in Stage 2, Arms 3 and 4 will transition to for the 
remainder of the study. The switch in Stage 2 may occur sooner, between Week 24 and Week 48, or it may be after 
Week 48.
The assigned backbone for each arm, ATV and DTG, or ATV/r and DTG, will remain unaltered throughout the 
study.
All subjects in both stages are expected to receive study treatment for 96 weeks.
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Arm 2
TDF
300 mg QD
+ ATV/r + DTG
Day 1
Begin dosing
Arm 3
BMS-955176 
120 mg QD
+ ATV + DTG
1 Virologic Futility will be evaluated at Week 24 
(see Section 8.4.7).  
Results of Week 24 Stage 1 AI468-048 & AI468-038 
Confirm the Start of Stage 2   
Arm 4
BMS-955176 
180 mg QD
+ ATV + DTG
40
40
Week 2
Week 24
Week 24 Analysis1
Intensive PK subset
4 Based on totality of data from both studies the 
Continuation Dose for Arms 3 & 4 may be 
identified.  
Number
Randomized
STAGE 2
Week 96
Week 96 Analysis/End of Study
Week 48
Week 48 Analysis
The Switch to the Continuation Dose4,3     
is expected to occur on or after Week 48, 
but could occur sooner.
Arm 1
BMS-955176 
120 mg QD
+ ATV/r + DTG
Week 2
Number
Randomized
Week 24
Week 24 Analysis1
Day 1
Begin dosing
Intensive PK subset
40
40
Week 48
Week 96
Week 48 Analysis
Week 96 Analysis/End of Study
The Switch to             
the Continuation Dose2,3
may occur on or after 
Week 48 
STAGE 1
BMS-955176
Continuation Dose QD 
+ ATV/r + DTG
Arm 5
TDF
300 mg QD
+ ATV/r + DTG
40
3 The actual switch of subjects of BMS-955176 
subjects to that Continuation Dose may occur when 
all of the subjects have reached at least Week 48 
(though it could occur sooner in Stage 2).
BMS-955176
Continuation Dose QD
+ ATV + DTG
2 Based on Week 24 data from Arms 1 & 2 and 
from AI468-038, the Continuation Dose for 
Arm 1 may be identified.  
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Study Population:
Key Inclusion Criteria:

Men and non-pregnant women, at least 18 years of age (or minimum age as determined by local regulatory or as 
legal requirements dictate)

Antiretroviral treatment-experienced, defined as having documented evidence of having failed 1 or 2 regimens 
that include 2 or 3 classes of ARV (with or without documented resistance)

Confirmed Plasma HIV-1 RNA 400 copies/mL

CD4+ T-cell count > 50 cells/mm3

Screening genotype/phenotype indicating susceptibility to study drugs (unboosted ATV, FC < 2.2; DTG; TDF)
Key Exclusion Criteria:

Antiretroviral treatment-experienced adults who have failed > 2 ARV regimens

Antiretroviral treatment-experienced adults infected with Clade AE

Subjects who have failed a previous boosted PI- or Integrase strand transfer inhibitor (INSTI)-containing 
regimen for which resistance analyses were not conducted at the time of failure

Resistance or partial resistance to any study drug

Three or more of the following PI mutations, historical or documented: M36I/V, M46I/L/T, G48M/V, 
I54V/L/T/M/A, G73S/A/C/T, V82A/F/T/S/I, or L90M

Any major ATV mutations, historical or documented: I50L, I84V/A, N88D/S

Any major TDF mutation, historical or documented: K65R or T69ins

Three or more of the following non-accessory thymidine analogue mutations (TAMs): M41L, D67N, K70R, 
L210W, T215Y/F, K219Q/E

Any major mutations for raltegravir (RAL), elvitegravir (or clinically suspected INI resistance), historical or 
documented: T66IAK, E92Q, S147G, N155H, Q148H/K/R, Y143C/H/R, E157Q

Chronic HBV/HCV (Positive blood screen for HBsAg; Positive blood screen for HCV Ab and HCV RNA)

ALT or AST > 3 × ULN

Alkaline Phosphatase > 5 × ULN

Bilirubin 1.5 × ULN

History of decompensated cirrhosis or active decompensated cirrhosis

Hemoglobin < 8.0 g/dL

Platelets < 50,000 cells/mm3
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for AI468048
Medication 
Potency 
IMP/Non-IMP 
BMS-955176 
60 mg or 120 mga
IMP
Tenofovir (TDF)
300 mg
Non-IMP
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Study Drug for AI468048
Medication 
Potency 
IMP/Non-IMP 
Atazanavir (ATV)
200 mg and 300 mg
IMP
Ritonavir (RTV)
100 mg
Non-IMP
Dolutegravir (DTG)
50 mg
IMP and Non-IMP, based on 
country approval status
a The 180 mg dose of BMS-955176 will be constructed with BMS-955176 60 mg + BMS-955176 120 mg
Study Assessments: Efficacy assessments will include plasma HIV-1 RNA measurements. Safety Assessments will 
include blood chemistry and hematology, ECGs, Physical Exams and Vital Signs, and assessment of non-serious 
AEs, SAEs and AEs leading to discontinuation.
Statistical Considerations:
Sample Size:
This is an estimation study, without statistical testing, and hence there are no power considerations.
It is expected that response rate for the primary endpoint for all five arms will be somewhere around 80%. With this 
response rate, and 40 subjects per arm, an exact 95% confidence interval would run from roughly 64% to 91%.
Endpoints:
Primary Endpoint(s) for Stage 1 and Stage 2
The primary endpoint for Stage 1 and Stage 2 is the proportion of subjects with plasma HIV-1 RNA < 40 c/mL at 
Week 24. This will be assessed with the FDA snapshot algorithm. This uses the last on-treatment plasma HIV-1 
RNA measurement, within an FDA-specified visit window, to determine response
Secondary Endpoint(s)

The antiviral efficacy will be determined by the proportion of subjects with plasma HIV-1 RNA < 40 c/mL at 
Weeks 48 and 96 using the FDA snapshot algorithm

The antiviral efficacy will also be assessed by the proportion of subjects with plasma HIV-1 RNA < 200 c/mL 
at Weeks 24, 48 and 96 using the FDA snapshot algorithm approach with positive response defined as HIV-1 
RNA < 200 c/mL

The emergence of HIV drug resistance among samples sent for drug resistance testing will be assessed using the 
most recent version of the IAS-USA list of HIV-1 drug resistance mutations

Changes from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the percentage of 
CD4+ T-cells will be assessed using on-treatment laboratory results, and pre-specified visit windows

The frequency of SAEs and AEs leading to discontinuation (DC) will be tabulated directly from the case report 
forms (CRFs). The summary will count the number of subjects that have at least one event.

The occurrence of new AIDS defining events (CDC Class C events) will be tabulated from the CRFs. The 
summary will count the number of subjects that have at least one event.

The steady-state plasma PK of BMS-955176 will be assessed using the intensive PK data, collected at Week 2 
from a subset of subjects.
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Analyses:
There are two interim analyses scheduled before the start of Stage 2.
The first interim analysis will be conducted after approximately 50% of the randomized subjects have completed 
24 weeks of therapy in Stage 1. This analysis will use the BMS equivalent of SDTM (Study Data Tabulation Model) 
data (“level 1” data) to facilitate the development of models for: population pharmacokinetics; exposure-response 
relationships; and, as available, viral kinetics.
A second interim analysis will be conducted after the last subject has completed 24 weeks of therapy in Stage 1. 
This will be an analysis of the available efficacy, safety, resistance and pharmacokinetic data.
The schedule for additional analyses will depend upon the decision to initiate the Stage 2, as well as the recruiting 
time frame of Arms 1 & 2 relative to the time frame for Arms 3, 4, and 5. If Stage 2 is initiated, and recruiting 
follows projected timelines, then it is anticipated that analyses will be conducted when:

The last subject in Arms 3, 4 and 5 completes the Week 24 visit

At Week 24, a Time to Loss of Virologic Response (TLOVR) analysis will be conducted as a sensitivity 
analysis that compliments the snapshot analysis

The last subject in Arms 1 and 2 completes the Week 96 visit

The last subject in Arms 3, 4 and 5 completes the Week 96 visit
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale to support study design ............................................................ 
1.1.2 Rationale to support the dose selection ................................................... 
1.1.3 Rationale to support drug combinations.................................................. 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
1.4.1 Background Information BMS-955176 .................................................... 
1.4.1.1 Mechanism of Action....................................................................... 
1.4.1.2 Nonclinical studies .......................................................................... 
1.4.1.3 Clinical studies................................................................................ 
1.4.2 Background Information on TDF ............................................................ 
1.4.3 Background Information on DTG ............................................................ 
1.4.4 Background Information on ATV ............................................................. 
1.4.5 Background Information on RTV ............................................................. 
1.4.6 Drug-Drug Interactions ........................................................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Screening.................................................................................................. 
3.1.2 Day 1/Baseline Visit ................................................................................. 
3.1.2.1 Day 1/Baseline Visit for Arms 1 and 2 - Stage 1 ............................ 
3.1.2.2 Day 1/Baseline Visit for Arms 3, 4 and 5 - Stage 2 ........................ 
3.1.3 Week 2 Intensive PK Visit ........................................................................ 
3.1.4 Visits Week 4 - 96 ..................................................................................... 
3.1.5 Selection of the Continuation Dose of BMS-955176 ............................... 
3.1.5.1 Selection of the Continuation Dose, and the Switch for Stage 1 .... 
3.1.5.2 Selection of the Continuation Dose, and the Switch for Stage 2 .... 
3.1.6 End of the study ........................................................................................ 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
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3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Instructions for Dose Administration ...................................................... 
4.5.1.1 General Instructions ....................................................................... 
4.5.1.2 Specific Dosing Instructions for Initial Treatment Arm Assignment
...............................................................................................................
4.5.2 Dose Modifications .................................................................................. 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Vital Signs and Physical Examinations ................................................... 
5.3.2 Adverse Events ......................................................................................... 
5.3.3 Concomitant Medication Assessment ...................................................... 
5.3.4 Electrocardiograms ................................................................................. 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.1.1 Guidelines for Confirmatory Testing of Plasma HIV-1 RNA and 
Resistance testing .................................................................................. 
5.4.1.2 Protocol Defined Virologic Failure ................................................ 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.4.2.1 CD4+ and CD8+ T-Cells ............................................................... 
5.4.2.2 Drug Resistance Testing ................................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Intensive Pharmacokinetic Assessment .................................................... 
5.5.2 Sparse Pharmacokinetic Assessments ...................................................... 
5.6 Biomarker Assessments .................................................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
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5.8 Other Assessments ............................................................................................ 
5.9 Results of Central Assessments ........................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
6.7.1 Toxicity Management ............................................................................... 
6.7.1.1 Management of Elevations in Liver Transaminases ....................... 
6.7.1.2 Management of Renal Toxicity ....................................................... 
6.7.1.3 Management of Hyperbilirubinemia ............................................... 
6.7.1.4 Gastrointestinal Toxicity Evaluation and Management Plan ......... 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s)Stage 1 and Stage 2 ................................................. 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Efficacy Analyses .............................................................. 
8.4.2.2 Secondary Efficacy Analyses .......................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.4.1 Sparse Pharmacokinetic Analyses .................................................. 
8.4.4.2 PK/PD and PK/VK Analyses .......................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses (including Virologic Futility) ......................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
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9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 LISTINGS OF PROHIBITED AND PRECAUTIONARY 
THERAPIES ........................................................................................................... 
APPENDIX 2 AIDS-DEFINING DIAGNOSES.......................................................... 
APPENDIX 3 DAIDS TOXICITY GRADES .............................................................. 
APPENDIX 4 COCKCROFT-GAULT EQUATION TO CALCULATE SERUM 
CREATINE CLEARANCE .................................................................................... 
APPENDIX 5 LABORATORY ASSESSMENTS ....................................................... 
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1
INTRODUCTION AND STUDY RATIONALE
1.1
Study Rationale
Despite advances in prevention and care, HIV/AIDS remains a significant epidemic in both the 
US and worldwide. AIDS remains the 6th leading cause of death, internationally. Globally, 
approximately 35 million people were living with HIV infection in 2013.1 A number of these 
patients include those who are treatment-experienced. Note: the use of the term 
“treatment-experienced” herein refers to subjects who have failed at least one or two 
antiretroviral (ARV) regimens and who may be harboring drug resistant virus (current or 
archived) to at least one drug class.
In contrast to current HIV treatment guidelines for treatment-naïve patients, the recommended 
composition of combination
antiretroviral therapy (cART) is far less uniform for 
treatment-experienced subjects.2,3 The level of detail in the DHHS and EACS guidelines leads to 
a lack of uniformity in treatment for patients in later lines of therapy. Moreover, drug related 
toxicities (both short and longer term) in treatment-experienced subjects necessitate vigilance 
and continued monitoring. Thus, there is a need for new and efficacious agents with novel 
mechanisms of action (MOA) and favorable safety/tolerability profiles. Given the aging HIV-1 
infected population and overall fewer number of ARV options for treatment-experienced 
patients, there is a need for a more simplified regimen that may have a better long-term safety 
profile such as that of a nucleoside- and booster-sparing cART regimen. As discussed below, this 
study 
evaluates 
the 
merits 
of 
a 
nucleoside-sparing 
cART 
regimen 
and 
a 
nucleoside/booster-sparing cART regimen in Stage 1 and 2, respectively.
Given the aforementioned challenges with existing treatment in ARV treatment-experienced 
adults, the two primary objectives of this two stage, Phase 2b study are to: 1) To study the 
efficacy of one dose (120 mg) of BMS-955176 (a novel HIV-1 maturation inhibitor) when given 
in combination with atazanavir boosted with ritonavir (ATV/r) 300/100 mg and dolutegravir 
(DTG) 50 mg in Stage 1, and 2) to study the efficacy of two doses (120 and 180 mg) of 
BMS-955176 when given in combination with unboosted ATV 400 mg and dolutegravir (DTG) 
50 mg in Stage 2.
Ultimately this Phase 2b clinical trial will provide supportive data in the context of a therapeutic 
dose of BMS-955176 and the clinical safety/efficacy/resistance of the proposed component(s) of 
a single tablet regimen (STR, that is also a nucleoside/ritonavir sparing ARV strategy) for 
Phase 3 trial development in HIV-1 infected treatment-experienced subjects. Specifically, two 
arms in Stage 2 will contain the individual ARV components of a potential STR: BMS-955176, 
ATV, and DTG.
1.1.1
Rationale to support study design
This Phase 2b open-label clinical trial design is in general agreement with published Food and 
Drug 
Administration 
(FDA)
guidance.4
Initially,
in 
Stage 
1, 
approximately 
80 treatment-experienced HIV-1 infected subjects will be randomized 1:1 (approximately 40 per 
treatment group) to one experimental arm (Arm 1) and a TDF-containing arm (Arm 2). Stage 1
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(see Figure 3.1.6-1) will study the efficacy of one dose (120 mg) of BMS-955176 when given in 
combination with ATV/r (300/100 mg) and DTG (50 mg). At the Week 24 primary endpoint of 
Stage 1, Bristol-Myers Squibb (BMS) will conduct an analysis of efficacy, safety, and 
pharmacokinetics. Combined with the Week 24 primary endpoint of AI468038 (see below), this 
analysis will be used to 1) select a continuation dose for BMS-955176 in Arm 1 of study 
AI468048, 2) trigger the start of Stage 2 (utilizing unboosted ATV in the experimental arms) of 
study in AI468048, and 3) confirm the two doses of BMS-955176 (in the experimental arms) for 
study in Stage 2 of study AI468048 (see below for further details).
AI468038 is a concurrent Phase 2b study in HIV-1 infected treatment naive adults; the primary 
objective is to evaluate three doses of BMS-955176 (60, 120, and 180 mg) and EFV when given 
in combination with TDF/FTC by determining the proportion of subjects with HIV-1 RNA < 40 
c/mL at Week 24.
To mitigate the clinical concerns of a potential subtherapeutic regimen and the subsequent 
development of virologic failure/resistance, the clinical trial design will contain a second stage. 
Specifically in Stage 2, approximately 120 additional treatment-experienced HIV-1 infected 
subjects will begin randomization 1:1:1 (approximately 40 per treatment group) to Arms 3, 4,
and 5 based upon the results of two concurrent analyses:

Results of the Week 24 analysis in Stage 1, including an analysis for virologic futility (see 
Section 8.4.7)

Results of the Week 24 analysis in AI468038 (treatment-naïve HIV-1 infected adults)
Thus, Stage 2 (Arms 3, 4, and 5) will not enroll if the likelihood of a subtherapeutic regimen 
(in Arms 3 and 4) is high based upon the results of the Week 24 analyses from either AI468038 
or Stage 1 of AI468048. Note, subjects in Arm 5 (Stage 2) will receive the same ARV regimen 
as subjects in Arm 2 (Stage 1); Arm 5 in Stage 2 exists to maintain similar baseline demographic 
and clinical characteristics among subjects who are randomized to the three Arms in Stage 2. 
This staged design allows Stage 2 (Arms 3, 4, and 5) to begin recruitment in a clinically 
de-risked fashion and accomplish this study’s Stage 2 primary study objective: to study the 
efficacy of two doses (120 mg and 180 mg) of BMS-955176 when given in combination with 
unboosted ATV 400 mg and DTG 50 mg. Ultimately, the totality of data from the Week 24 
primary endpoint of Stage 2 (Arms 3, 4, and 5), Stage 1 (Arms 1 and 2), and all arms in the 
AI468038 study will be used to select a continuation dose for BMS-955176 in Arms 3 and 4 of 
study AI468048. Across all five arms of this study, subjects will receive treatment with three 
fully-active ARVs (see Section 1.1.3, Rationale to support any drug combinations). Ultimately, 
subjects in experimental Arms 1, 3, and 4 will be given a continuation dose of BMS-955176 
which has acceptable efficacy, safety, and tolerability (see Figure 3.1.6-1) for subsequent 
development in HIV-1 treatment-experienced adults. 
Since the Phase 2a study AI468002 did not include any subjects infected with HIV-1 clade AE
(see Section 1.4.1.3), this multinational Phase 2b trial will not include Clade AE subjects. The 
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study duration is expected to be 96 weeks in length to assess durability of response and longer 
term safety and tolerability.
1.1.2
Rationale to support the dose selection
Phase 1 and Phase 2a clinical trials (AI4680015 and AI4680026) investigating BMS-955176 
utilized a spray-dried dispersion (SDD) suspension. However, this Phase 2b study will utilize a 
micronized crystalline (MC) tablet.
In the concomitant dose-finding Phase 2b study in HIV-1 infected treatment naive adults for 
BMS-955176 (AI468038), doses of BMS-955176 of 60 mg, 120 mg, and 180 mg MC tablet are 
proposed for assessment. These doses are based upon modeling and simulation and formulation 
considerations. A population pharmacokinetic model was developed using single dose 
(10 mg - 120 mg SDD) and multiple dose (10 mg to 80 mg SDD) data in healthy subjects 
(AI468001) as well as multiple dose data in HIV-1 clade B-infected subjects (5 mg to 120 mg
SDD for 10 days, AI468002). An exposure-response analysis was conducted using data from 
Part A of the Phase 2a clinical trial where HIV-1 clade B infected subjects received 
BMS-955176 monotherapy (Dose range: 5 - 120 mg) for 10 days. The exposure-response 
relationship was assessed via an Emax model using observed BMS-955176 steady state Cmin. The 
primary endpoint was predicted maximum viral load decline from baseline.
Steady state BMS-955176 Cmin values in HIV-infected subjects administered MC tablet with 
food were projected according to the following data and assumptions:

Exposures in HIV-infected subjects are 35% less than normal healthy volunteers based on 
observations from AI468001 and AI468002 study

Single dose data projected to multiple dose using accumulation index from AI468001 study

BMS-955176 exposures from the MC tablet formulation with food were projected based on 
studies AI468001 and AI468034. The impact of food on the 60 mg MC tablet dose was 
assumed to be that observed for the 40 mg MC suspension formulation in AI468001. 
Exposures to BMS-955176 120 mg MC tablet with food were determined from observed data 
in Study AI468034, where BMS-955176 C24 increased approximately 70% when 120 mg 
MC tablet was given with a high fat meal, relative to fasted conditions. Finally, exposures to 
BMS-955176 180 mg MC tablet with food were assumed to be 1.5-times that of 120 mg MC 
tablet with food
Figure 1.1.2-1 depicts the simulated maximum viral load decline in HIV-infected subjects 
administered BMS-955176 MC tablet under fed conditions.
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Figure 1.1.2-1:
Simulated Maximum Viral Load Decline from Baseline Under Fed 
Conditions1
1 Solid lines are 10th and 90th percentiles and the median of simulated data, shaded area is the 90% confidence 
interval of simulated data, vertical solid lines are the 25th to 75th percentile of the simulated steady state 
BMS-955176 Cmin for the 60 mg MC tablet dose, vertical dotted lines are the 25th to 75th percentile of the 
simulated steady state BMS-955176 Cmin for the 120 mg MC tablet dose, and vertical dashed and dotted lines 
are the 25th to 75th percentile of the simulated steady state BMS-955176 Cmin for the 180 mg MC tablet dose.
While baseline EC90 was not a covariate included in the model due to the lack of significance; 
this covariate, among others, was considered marginally significant and it is possible this 
covariate will become important with additional data.
Although data from AI468002 Part C (in HIV-1 clade C infected subjects) were not included in 
the exposure-response assessment described above, BMS-955176 doses 40 mg SDD once daily 
demonstrated median maximal reductions in HIV-1 RNA > 1 log10 in both clade B and clade C 
HIV-1-infected subjects (see Section 1.4.1.3); thus, doses of BMS-955176 60 mg, 120 mg, and 
180 mg are expected to yield a similar response in HIV-1 infected subjects of either clade.
Because the lowest dose assessed in AI468038 (BMS-955176 60 mg) has the potential for a 
suboptimal antiviral response and possible development of resistance, BMS-955176 120 mg in 
combination with ATV/r and DTG will be assessed in Stage 1 of this study. Based on previous 
data that demonstrated exposures to BMS-955176 increase approximately 50% when given in 
combination with RTV, exposures to BMS-955176 120 mg given in combination with ATV/r are 
expected to result in exposures similar to BMS-955176 180 mg given without RTV. Finally, 
BMS-955176 180 mg will not be used in Stage 1 because exposures (when administered with 
RTV) are expected to exceed those previously studied in clinical trials.
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Table 1.1.2-1 depicts the projected exposure multiples of BMS-955176 60 mg, 120 mg, and 
180 mg MC tablet with food at the NOAEL for pre-clinical findings of interest.
Table 1.1.2-1:
Exposure Multiples of BMS-955176 at NOAELa
Species/ Study 
NOAEL
Multiples
Dose 
(mg/kg/d)
Exposure
PK 
Parameter
60 mg
120 mg
180 mg
Rat/6-month (stomach 
histologic changes) 
No NOAEL
AUC
---
---
---
Dog/9-month (stomach 
histologic changes) 
1
AUC:
64.9 gh/mL
AUC 
3
2
1
Dog/1-month (heart rate)
20
Cmax:
17.8 g/mL 
Cmax
19
10
5
Dog/ Cardiovascular 
telemetry (heart rate) 
2
Cp:
1.93 g/mL 
Cmax
2
1
0.5
Mouse/EFD 
45
AUC:
197 gh/mL 
AUC
10
6
3
a Exposure multiple = animal value ÷ human value. Projected human Cmax values are 0.94, 1.79, and 3.61 g/mL 
and steady state AUC values are 19.3, 35.8, and 69.2 g•h/mL at 60, 120, and 180 mg in HIV-1 subjects 
receiving BMS-955176 MC tablets with high fat meal, respectively. High fat meal provides the highest exposure 
relative to other meal types or fasted state.
With regard to heart rate and the NOAEL of 1.93 g/mL observed in the cardiovascular 
telemetry study in dogs (N=2), it is noted that the projected exposure multiple is 1 at a dose of 
120 mg MC tablet in HIV-infected subjects. However, to date, there have been no clinically 
meaningful changes in heart rate observed in subjects treated with BMS-955176 up to 28 days
(in Part B of the Phase 2a study). With regard to stomach histologic changes, no NOAEL could 
be established based on the 6-month rat study and the projected exposure multiples from the 
9-month dog study are relatively low (eg, 2-fold at the 120 mg MC tablet dose). Despite these 
preclinical findings, a dose of BMS-955176 120mg MC tablet will provide exposures in this 
study which are expected to be generally safe and well tolerated based on existing clinical data 
(see Section 1.4.1).
Data from Study AI468034 demonstrated that BMS-955176 120 mg MC tablet AUC increased 
53% when given with a high fat meal, relative to fasted conditions. Furthermore, preliminary 
data from Study AI468049 demonstrated that a light meal, a standard meal, and a high fat meal 
increased BMS-955176 180 mg MC tablet AUC 1.8-, 2.1-, and 2.5-fold, respectively, relative to 
fasted conditions. Taken together, these data suggest that exposures to BMS-955176 MC tablet 
at doses up to 180 mg increase in a linear fashion when given with food and that similar 
exposures are observed regardless of meal type.
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In total, BMS-955176 120 mg is expected to be safe, well-tolerated, and efficacious in Stage 1 
and will inform the selection of a Stage 1 continuation dose and aspects of Stage 2 (as described 
in detail within Section 1.1.1).
The doses of BMS-955176 in Stage 2 will be confirmed based upon the Week 24 analyses
(efficacy, safety, and pharmacokinetics) of both Stage 1 and Study AI468038. As described in 
this protocol, the doses in Stage 2 are proposed to be BMS-955176 120 mg and 180 mg in Arms 
3 and 4, respectively.
1.1.3
Rationale to support drug combinations
This study co-administers BMS-955176, with unboosted ATV 400 mg QD or ATV/r 300/100 mg
QD, and DTG 50 mg. The drug combinations within this clinical trial design will provide 
supportive data in the context of a therapeutic dose of BMS-955176 and the clinical 
safety/efficacy/resistance of the proposed components (Stage 2, Arms 3 and 4) of a single tablet 
regimen (STR) for Phase 3 trial development. Ultimately, BMS will seek approval of 
BMS-955176 for use in treatment-experienced HIV-1 infected adults (including either a STR; 
FDC; and/or monoentity). 
The rationale for using a backbone of ATV and DTG in this treatment-experienced patient 
population is based upon established safety, efficacy, and tolerability of the individual 
components. DTG alone provides a 2.46 log10 c/mL reduction in HIV-1 RNA when administered 
as monotherapy for 10 days.7 Furthermore, DTG has been recently approved and is generally 
safe.8,9,10,11,12 Lastly, ATV/r is often used in treatment-experienced adults’ second-line therapies 
or beyond (for example, in individuals who may have failed an non-nucleoside reverse 
transcriptase inhibitor (NNRTI) and/or integrase inhibitor (INI) based regimen).2,4
This Phase 2b design allows treatment-experienced adults in the experimental arms to be 
exposed to three fully active ARVs (from three classes). Subjects will benefit from each ARV 
(except RTV) independently providing a > 1 log10
c/mL decrease in HIV-1 RNA
(see Section 1.4.1.3 for details on Phase 2a results [AI468002]). BMS expects the combination of 
two agents (unboosted ATV and DTG) with one investigational agent (BMS-955176) to provide 
a generally improved safety/tolerability profile relative to the respective arm containing ATV/r 
(Arms 3 and 4 relative to Arm 1, respectively) or TDF (Arms 3 and 4 relative to Arm 5, 
respectively).
There is a potential risk of a subtherapeutic regimen to treatment-experienced subjects enrolled 
in Arms 3 and 4 since unboosted ATV is only approved for use in treatment-naïve HIV infected 
adults (within the US) and the therapeutic dose of BMS-955176 has not been established.
Unboosted ATV (400 mg) in treatment-naïve adults results in a 1.41 log10 c/mL reduction in 
HIV-1 RNA after two weeks of monotherapy.13 Despite the monotherapy based reduction in 
HIV-1 RNA, pharmacokinetic data of unboosted ATV in prospective clinical trials,14
cross-sectional,15 and retrospective analyses16 generally supports the finding of DHHS defined 
subtherapeutic ATV levels (< 150 ng/mL) in patients.17
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In a randomized, open-label clinical trial, ATV/r has demonstrated non-inferiority to unboosted 
ATV (TLVOR: 75% vs 70% VR-OC: 87% vs 76%, respectively), similar declines in HIV-1 
RNA (approx -3.1 log10 c/mL), and increase in CD4 cell counts within treatment-naïve adults. 
However, the unboosted ATV arm had an increased number of subjects with emerging ATV and 
lamivudine (3TC) resistance. In particular, the difference in nucleoside/nucleotide reverse 
transcriptase inhibitor (NRTI) resistance was markedly greater in the unboosted ATV compared 
to RTV boosted ATV arm.18 Of note, in this clinical trial (AI468048) NRTIs are not used in the 
experimental Arms 1, 3, and 4. Similar single arm, prospective studies have replicated the viral 
efficacy and immunologic response using unboosted ATV in treatment-naïve HIV infected 
adults.19
Insights from limited data regarding the use of unboosted ATV in treatment-experienced adults 
have demonstrated a viral decay ranging from -1.4 to -2.7 log10 c/mL over 24 weeks of therapy 
in combination with NRTIs (such as TDF, 3TC, and didanosine).20 Also, observational data 
(mean: 24 months of follow-up) has shown similar percentages of subjects with their last HIV 
RNA being undetectable (80% vs 83%) after receiving unboosted and RTV boosted ATV, 
respectively.21
Taking the key findings from studies of ATV in both treatment-naïve and treatment-experienced 
HIV infected adults, Arms 3 and 4 containing unboosted ATV may have the potential for 
increased resistance (relative to Arm 1 containing RTV boosted ATV) and the development of 
virologic failure. However, several other factors must be taken into consideration. First, these 
Arms will use three potent (> 1 log10
c/mL) ARVs in combination. Moreover, 
treatment-experienced subjects who have failed one or two prior regimens are likely to be either 
naïve to ATV treatment (prior NNRTI- and/or INI-class failure) or will need to be fully 
susceptible to approved ARVs (including unboosted ATV, see Section 3.3.2). Second, both the 
combination of ATV and DTG with BMS-955176 independently have demonstrated additivity to 
synergy in-vitro22 (see Section 1.4.1.3 for clinical data on the combination of ATV and 
BMS-955176). Third, unboosted ATV increases the geometric mean ratio of Ctrough for DTG by 
a factor of 2.8.23 Fourth, in normal healthy volunteers, multiple dose administration of 
BMS-955176 40 mg (SDD suspension formulation) with ATV 400 mg for 14 days resulted in an 
approximate 25% increase in the AUC(TAU) of BMS-955176 administration alone24 and 
preliminary PK data from the Phase 2a (AI468002) demonstrated that BMS-955176 AUC(TAU) 
increased approximately 37% and 52% when ATV was combined with BMS-955176 40 and 
80 mg (SDD suspension formulation), respectively, relative to administration of BMS-955176 
alone. It is clinically unclear whether higher exposures of DTG and BMS-955176 would lead to 
a decreased incidence of unboosted ATV resistance in the context of Arms 3 and 4 
(BMS-955176 120 and 180 mg + ATV + DTG). Combined with these factors, BMS proposes to 
mitigate the potential risk of increased resistance by 1) studying two doses of BMS-955176 
(120 and 180 mg) in combination with unboosted ATV and DTG, and 2) using a two stage 
clinical trial design with Stage 2 (Arms 3, 4, and 5) enrolling after the Week 24 analysis
(efficacy, safety, and pharmacokinetics) of Stage 1 (Arms 1 and 2) and AI468038 are completed, 
and 3) only enrolling subjects who are susceptible to study medication (including unboosted 
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ATV), (see Section 1.1.1, Rationale to support study design). This risk mitigation is employed to 
decrease the probability of exposure to a subtherapeutic regimen and increase the probability of 
establishing clinical efficacy (number of responders at the Week 24) in treatment-experienced 
HIV-1 infected adults.
BMS expects BMS-955176 120 and 180 mg given with unboosted atazanavir to be generally 
safe and well-tolerated. Subjects in Arms 3 and 4 treated with unboosted ATV would potentially 
benefit from a more favorable lipid profile, fewer gastrointestinal (GI) side effects, and 
decreased indirect hyperbilirubinemia. In total, the potential clinical risks for subjects 
randomized to Arms 3 and 4 in Stage 2 do not outweigh the potential benefits of a Nucleoside-
and Booster-sparing cART regimen that may offer both efficacy and long-term safety (including 
but not limited to improved bone mineral density, improved renal function, and improved lipid 
profile). Please see Section 1.5 for further details on the overall risk/benefit assessment.
1.2
Research Hypothesis 
This Phase 2b study will evaluate whether the combination of BMS-955176 with ATV (with or 
without RTV)
and DTG
is efficacious, safe, and well-tolerated
in HIV-1 infected 
treatment-experienced adults.
1.3
Objectives(s)
1.3.1
Primary Objective
Primary Objective Stage 1

To assess the antiviral efficacy of BMS-955176 120 mg, and a TDF 300 mg-containing arm,
each when given in combination with ATV/r 300/100 mg and DTG 50 mg by determining 
the proportion of treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at 
Week 24 in Stage 1.
Primary Objective Stage 2

To assess the antiviral efficacy of two doses (120 and 180 mg) of BMS-955176, each when 
given in combination with unboosted ATV 400 mg and DTG 50 mg, and to assess the 
antiviral efficacy of TDF 300 mg when given in combination with ATV/r 300/100 mg and 
DTG 50 mg by determining the proportion of treatment-experienced subjects with plasma 
HIV-1 RNA < 40 c/mL at Week 24 in Stage 2. 
1.3.2
Secondary Objectives

To assess the antiviral efficacy of BMS-955176 arms, and TDF-containing regimens (TDF + 
ATV/r + DTG), by determining the proportion of treatment-experienced subjects with plasma 
HIV-1 RNA < 40 c/mL at Weeks 48 and 96

To assess the antiviral efficacy of BMS-955176 arms, and TDF-containing regimens, by 
determining the proportion of treatment-experienced subjects with plasma HIV-1 RNA 
< 200 c/mL at Weeks 24, 48, 96
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
To assess the emergence of HIV drug resistance in samples selected for drug resistance 
testing (according to criteria outlined in Sections 5.4.1.1 and 5.4.1.2)

To assess efficacy of BMS-955176 arms, and TDF-containing regimens, by using the mean 
changes from baseline in log10 HIV-1 RNA, CD4+ T-cell counts, and percentage of CD4+ 
T-cells

To assess the safety and tolerability of BMS-955176 in treatment-experienced subjects by 
measuring frequency of SAEs and AEs leading to discontinuation

To assess disease progression as measured by the occurrence of new AIDS defining events 
(CDC Class C events)

To characterize the pharmacokinetics of BMS-955176 when co-administered with ATV 
(with or without ritonavir) and DTG in treatment-experienced HIV-1 infected subjects
1.3.3
Exploratory Objectives

To determine the effect of BMS-955176 arms, and TDF-containing regimens, on renal 
clinical parameters and biomarkers through Weeks 48 and 96

To determine the effect of BMS-955176 arms, and TDF-containing regimens, on bone 
biomarkers through Weeks 12 and 24

To assess the impact of baseline (pre-therapy) Gag polymorphisms on the efficacy of 
BMS-955176 by determining the proportion of treatment-experienced subjects with plasma 
HIV-1 RNA < 40 c/mL, HIV-1 RNA < 200 c/mL, and the changes from baseline in log10
HIV-1 RNA at Weeks 24, 48 and 96, by baseline polymorphisms

To characterize the steady-state plasma PK of DTG when co-administered with BMS-955176 
and ATV (with or without RTV) in treatment-experienced subjects. The effect of 
BMS-955176 on DTG PK in the presence of ATV (without RTV) may be assessed relative to 
historical data

To compare steady-state exposures of DTG when co-administered with BMS-955176 and 
ATV/RTV to DTG when co-administered with TDF and ATV/RTV

To characterize the PK of ATV when co-administered with DTG and BMS-955176, with or 
without RTV

To explore PK/PD and PK/viral kinetic (VK) relationships between BMS-955176, ATV, 
and/or DTG exposure and both efficacy and safety endpoints

To assess the impact of the study therapies on health-related quality of life measures
1.4
Product Development Background
1.4.1
Background Information BMS-955176
1.4.1.1
Mechanism of Action
BMS-955176 is an HIV-1 maturation inhibitor (MI), a novel class of anti-HIV-1 drugs that 
prevents the maturation of HIV-1 virions by binding near a key structural element within the Gag 
polyprotein that is required for virion maturation and assembly. Maturation inhibitors block the 
last protease cleavage event between Gag protein segments designated as capsid (CA) protein 
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p24 (p24) and spacer peptide 1 (SP1), resulting in the release of immature noninfectious virus 
particles. BMS-955176 has excellent potency and broad spectrum activity, and mechanism of 
action studies indicate that BMS-955176 is a true MI, with a mechanism of action distinct from 
current antiretroviral agents.25 Development of BMS-955176 could potentially lead to novel 
HIV-1 treatment regimens in treatment-experienced HIV-1 patients.
1.4.1.2
Nonclinical studies
Nonclinical Pharmacology and Microbiology
BMS-955176 specifically inhibits HIV-1 protease cleavage at the CA(p24)/SP1 junction within 
the Gag protein in both HIV-1-infected cells and purified HIV-1 Gag virus-like particles (VLPs). 
Radiolabeled BMS-955176 specifically binds to purified HIV-1 Gag VLPs, and its binding is 
dose-dependently inhibited by related MIs and is reversible. BMS-955176 does not directly 
inhibit HIV-1 protease nor bind to a small HIV-1 protease peptide substrate. These results 
indicate that BMS-955176 inhibits late in the HIV-1 life cycle by specific binding to immature 
capsid structures at or near the CA(p24)/SP1 junction, thereby inhibiting cleavage at that 
particular site. In cell culture, the range of values for the concentration producing 50% effect 
(EC50) of BMS-955176 against 7 common laboratory strains of HIV-1 was 1.6 to 10.5 nM 
(mean = 6.0 3.5 nM). Using a reverse transcriptase readout, a phenotyping analysis of 
93 subtype B viruses whose genotypes are representative of 96% of the diversity (found in the 
Los Alamos National Laboratory [LANL] database) in Gag sequences indicates that the mean 
EC50 of this cohort was 2.7 1.9 nM, with a median value of 2.2 nM and a range between 0.6 to 
12 nM. A similar analysis of 23 isolates of subtype C viruses found a mean EC50 of 
6.1 3.1 nM, a median value of 5.6 nM, and a range from 2.5 to 16 nM. When evaluated against 
clinical isolates in peripheral blood mononuclear cells (PBMCs), BMS-955176 exhibited a mean 
EC50 of 24 24 nM against a cohort (N = 22) of subtype B viruses. Activity was also observed 
against viruses from subtypes A, C, D, F, and G, with average EC50 values for 96% of tested 
isolates (N = 41) between 5.9 and 87 nM. Clinical isolates from the CRF01_AE subtype were 
approximately 2- to 3-fold less susceptible to BMS-955176 (average EC50 77 nM, N = 7) 
viruses. BMS-955176 was active against 1 of 3 human immunodeficiency virus type-2 (HIV-2)
isolates (EC50 = 15 nM). BMS-955176 retains complete activity against reverse transcriptase 
(RT), protease, and integrase inhibitor-resistant viruses, with EC50 values similar to wild-type 
(wt) viruses, while the potency of currently approved nucleotide/nucleoside reverse transcriptase 
inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors 
(PIs), and integrase inhibitors (INIs) was undiminished when tested against viruses with reduced 
susceptibility to BMS-955176. BMS-955176 maintained activity against a panel of PI-resistant 
isolates from PI-treated subjects harboring a variety of major and minor PI-resistance
determinants in both protease and Gag.26,27 Protein binding to 100% human serum (HS) was 
86%, and in the presence of 40% HS supplemented with additional human serum albumin 
(HuSA) to match physiologic concentrations, BMS-955176 exhibited an approximately 4-fold 
reduction of antiviral activity. Selection for resistance to BMS-955176 in cell culture identified
changes that map to amino acids adjacent to the CA(p24)/SP1 cleavage site. These include an 
amino acid substitution of A364V or a combination of V362I with secondary changes (V370A, 
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A374P or I376V). In vitro, virus with the A364V change exhibited a drastic loss of susceptibility 
to BMS-955176 (>100-fold), while the V362I plus secondary change-containing viruses were 
generally less sensitive to BMS-955176 (median EC50 25 nM, range 7.1 to 167 nM). In 2-drug 
combination studies with representative drugs from NRTI, NNRTI, PI, and INI classes, all 
combinations produced additive to synergistic effects, suggesting that BMS-955176 should be 
amenable for use in combination with any of these agents.
Bevirimat (BVM), a first-generation MI, demonstrated proof of concept and dose-dependent 
anti-HIV-1 potency in both Phase 1 and Phase 2 clinical studies. Patients infected with HIV-1 
sensitive to BVM demonstrated an approximate 1.2 log10 decline in HIV-1 RNA. However, 
approximately 50% of patients harboring naturally occurring polymorphisms located close to the 
CA(p24)/SP1 cleavage site showed a significantly reduced response to BVM treatment. In 
addition, BVM exhibited a large reduction in antiretroviral activity in the presence of human 
serum. BMS-955176 was developed to address the key flaws of BVM by providing improved 
coverage of BVM-resistant polymorphic variants and improved potency in serum. BMS-955176 
has been shown to be active against viruses with resistance from all marketed ARVs, and to 
possess a low serum effect. Development of BMS-955176 could potentially lead to novel HIV-1 
treatment regimens in treatment-experienced HIV-1 patients.
Nonclinical Pharmacokinetics
The absolute oral bioavailability of BMS-955176 was low (3.89% to 26.8%) in all preclinical 
species (mice, rats, dogs, and monkeys). In the dog, though there was a positive food effect and 
no pH dependent absorption, upon repeat dosing a less than dose-proportional increase in 
exposure was observed. BMS-955176 distributed preferentially into the duodenum, liver, and 
lymph nodes with little penetration into the brain. Protein binding was 86.1% in human serum 
and 78% to 94% in animal sera
In human in vitro systems, the metabolism of BMS-955176 was primarily mediated via 
cytochrome P450 (CYP)3A4. In vivo in rats, dogs, and monkeys, BMS-955176 was the 
predominant drug-related component in plasma following a single oral dose of BMS-955176. 
BMS-955176 was eliminated principally via metabolism followed by excretion in bile with little 
renal excretion. 
In vitro, BMS-955176 was an inhibitor of CYP2C8 (concentration at which 50% inhibition 
observed [IC50] = 28.5 M), CYP3A4 (IC50 = 32 M), and uridine diphosphate 
glucuronosyltransferase (UGT)1A1 (IC50 = 20 M) enzymes. No P-gp inhibition or 
time-dependent inhibition of CYPs was observed. BMS-955176 was not an inducer of CYP1A2, 
CYP2B6, or CYP3A4. The steady state Cmax of BMS-955176 180 mg tablet in HIV-infected 
patients with food is projected to be approximately 5.2 M. Thus, the potential exists for 
BMS-955176 to inhibit CYP2C8, CYP3A4, and/or UGT1A1 in vivo and increase exposures to 
co-administered drugs that are metabolized by these enzymes. Furthermore the potential exists 
for drug-drug interactions (DDI) if BMS-955176 is co-administered either with an inhibitor or 
inducer of CYP3A4 or P-gp.
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BMS-955176 was a substrate of mouse P-glycoprotein (P-gp) based on higher bioavailability in 
P-gp knock-out mice when BMS-955176 was co-administered with elacridar, a potent inhibitor 
of P-gp and breast cancer resistance protein (BCRP). BMS-955176 could not be reliably assessed 
as a substrate for human P-gp due to nonspecific binding and low solubility. In vitro, 
BMS-955176 inhibited organic anion transporting polypeptide (OATP)1B1 and OATP1B3 
(IC50 5.3 and 4 M, respectively), but was not an inhibitor of P gp, sodium taurocholate 
cotransporting polypeptide (NTCP), organic anion transporter (OAT)1, OAT3, multiple 
drug-resistance protein (MRP)2, and bile salt export pump (BSEP). These findings suggest a 
potential for DDI between BMS-955176 (as the perpetrator) and substrates of OATP1B1 and 
OATP1B3, but not with those of P-gp, NTCP, OAT1, OAT3, MRP2, and BSEP. Furthermore, 
the potential exists for drug-drug interactions (DDI) if BMS-955176 is co-administered either 
with an inhibitor or inducer of CYP3A4 or P-gp. Preliminary data indicate that BMS-955176 
does not inhibit OCT2, a transporter that is inhibited by dolutegravir (DTG), a drug with which 
BMS-955176 is planned to be co-administered.
Nonclinical Toxicology
The toxicity profile of BMS-955176 was evaluated in single- and repeat-dose toxicity, 
genotoxicity, phototoxicity, safety pharmacology, sensitization, reproductive toxicity and 
embryo-fetal development studies. The scope of the toxicologic evaluation for BMS-955176
supports its proposed clinical use for HIV-1 infection. Unless otherwise mentioned, all animal 
studies were dosed by the oral route with an aqueous methylcellulose suspension of a 
BMS-955176 spray-dried dispersion (SDD). 
BMS-955176 was not phototoxic, mutagenic, or clastogenic in vitro and was not genotoxic in a 
rat micronucleus assay at 300 mg/kg/day (AUC 279 g·h/mL). BMS-955176 was not a skin 
sensitizer in the local lymph node assay in the mouse. BMS-955176 had a low potential (IC50 or 
EC50 > 5 M [> 3.45 µg/mL]) for in vitro off-target interactions on a broad range of enzymes, 
transporters, and receptors, including cardiac ion channels. 
In safety pharmacology evaluations in rats, there were no respiratory findings and no direct 
central nervous system (CNS) findings. Decreases in motor activity, arousal, and rearing were 
considered secondary to general toxicity (ie, body weight decreases).
Cardiovascular safety pharmacology evaluations were conducted in rabbits, rats, and dogs. In the 
definitive oral single-dose cardiovascular safety study in conscious telemeterized dogs, blood 
pressure and electrocardiogram were was unaffected at 20 mg/kg; however, increases in heart 
rate (mean 33% to 57% of pretest vehicle) were observed at 8 and 20 mg/kg. The increase in 
heart rate at these doses was primarily due to increases in 2 dogs at each dose that had higher 
plasma concentrations (12.83 g/mL) relative to the dogs without effects on heart rate 
(6.81 g/mL). The no-observed-effect level (NOEL) for cardiovascular effects in dogs was 
2 mg/kg (plasma concentration of 1.93 µg/mL). Importantly, there was no change in heart rate at 
20 mg/kg/day at higher plasma concentrations (Cmax 17.8 µg/mL) in the 1-month study in 
dogs (below). 
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Taken together, BMS-955176 has low potential for respiratory, CNS, and cardiovascular effects 
and no cardiovascular effects have been observed in humans to date.
Two-week, 1-month, and 6-month studies were conducted in rats. As the 2-week study was of 
limited scope, only the 1-month and 6-month studies are presented in this summary. 
BMS-955176 was administered for 1 month at doses of 30, 100, or 300 mg/kg/day. While there 
was no mortality at 100 mg/kg/day, the high dose of 300 mg/kg/day was associated with 
pronounced signs of clinical toxicity and early euthanasia of all the rats at that dose level on 
Days 8 to 9. The dose of 30 mg/kg/day was tolerated. The intermediate dose of 100 mg/kg/day 
(AUC 357 g·h/mL) resulted in dose-limiting toxicity including persistent reduction in food 
consumption and body weights. A number of minor hematology (including red cell parameter 
changes with no consistent effect on the erythron) and serum chemistry changes (including 
increased alkaline phosphatase and alanine aminotransferase) without correlating histologic liver 
findings) occurred at 30 and 100 mg/kg/day; these changes were considered not adverse due to 
small magnitude, occurrence only in 1 sex, and lack of microscopic correlates, and most were 
secondary to decreases in food consumption and body weight. Dose-related gastrointestinal 
toxicity was primarily characterized by morphologic changes in the stomach at 100 mg/kg/day 
and the stomach and small and large intestines at 300 mg/kg/day. At the end of the 2-week 
postdose recovery period, there was complete recovery of all BMS-955176-related findings at 
30 mg/kg/day. At 100 mg/kg/day, all findings recovered with the exception of increased red cell 
distribution width in females, minimally higher (1.94×) ALT activity in 1 male without any 
histologic correlates, and decreased mean prostate gland (with seminal vesicles) weights. The 
low dose of 30 mg/kg/day (AUC 113.5 g·h/mL) was considered the no-observed-adverse-effect 
level (NOAEL) because the body weight and food consumption changes were minimal and 
transient and there were no BMS-955176-related morphologic changes.
In a 6-month oral toxicity study in rats with 1-month recovery period, BMS-955176 was 
administered at doses of 10, 25, or 50 mg/kg/day. BMS-955176-related effects were similar to 
those observed in the 1-month rat study and occurred at all doses (10 mg/kg/day; 
AUC 71 gh/mL). Findings included decreased body weight, food consumption, and in the 
stomach, minimal to marked atrophy involving both parietal and chief cells, minimal to mild 
single-cell necrosis and minimal regeneration in the glandular mucosa, which were partially 
reversible at the end of the 1-month recovery period. A NOAEL was not established in this 
study.
Five-day, 1-month, and 9-month repeat-dose studies were conducted in dogs. As the 5-day 
toxicokinetics and tolerability studies were of limited scope, only the 1-month and 9-month
studies are presented here. In the 1-month study, BMS-955176 was administered at doses of 2, 8, 
or 20 mg/kg/day. Increased incidences of sporadic vomiting and liquid, yellow, and/or mucoid 
feces occurred at all doses, but had no apparent effect on the overall health of these animals. 
At 20 mg/kg/day, additional findings included occasional decreases in food consumption in a 
few animals, loss of body weight (up to 8%) in 2 females, a minimal increase in serum ALT 
activity (2.10× pretest) in 1 female with no microscopic correlates, and minimal single-cell 
necrosis of stomach glandular epithelium. All BMS-955176-related changes were fully 
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reversible by the end of the 2-week recovery period. The dose of 8 mg/kg/day was considered a 
NOAEL (AUC 219.5 g·h/mL) since the sporadic clinical observations had no adverse effects 
on the general health of the animals and there were no BMS-955176-related morphologic 
changes. 
In a 9-month oral toxicity study in dogs with 1-month recovery period, BMS-955176 was 
administered at 0 (vehicle), 1, 3, or 10 mg/kg/day. BMS-955176-related effects were similar to 
those observed in the 1-month dog
study
and
occurred at doses 3 mg/kg/day 
(AUC 135 gh/mL). Findings included salivation (only males at 10 mg/kg/day), fur thinness 
(males), thin appearance, and abnormal feces (yellow, liquid, pale and/or mucoid) that occurred 
sporadically throughout the study; increases in mean food consumption; minimal to marked chief 
cell depletion in the glandular stomach. Additional findings at 10 mg/kg/day included thin 
appearance that correlated with decreases in body weight in food consumption; occasional 
vomitus in males; in the stomach, minimal to moderate mucous cell hyperplasia (often associated 
with glandular dilatation) correlating with increased thickness macroscopically (males only) and 
minimal to marked parietal cell depletion and single-cell necrosis of glandular epithelial cells; 
and increases in serum gastrin values (1.31 to 4.56× highest control value) for several dogs that
may have reflected the reductions in gastric parietal cells. The NOAEL was 1 mg/kg/day 
(AUC 64.9 gh/mL).
The embryo-fetal development (EFD) studies were conducted in 3 species (rabbits, rats, and 
mice) instead of the standard 2 species due to poor maternal tolerability and inability to achieve 
adequate systemic exposures in rabbits.
In a definitive EFD study in pregnant mice, BMS-955176 was administered at doses of 15, 45, or 
150 mg/kg/day from gestation day (GD) 6 through 15. BMS-955176 was a selective 
developmental toxicant in mice. Dose of 100 mg/kg/day was associated with an increase in 
embryo-fetal lethality (cumulative postimplantation losses of 11.5%, relative to 3.9% in control 
litters, attributed to increased incidences of dead fetuses, early resorptions and late resorptions). 
Cleft palate and exencephaly were observed in a few fetuses; additionally, marginal reductions in 
fetal body weight (5% relative to control values) were observed. There was no maternal toxicity 
at any dose tested. The developmental NOAEL was 45 mg/kg/day (AUC 213 g·h/mL).
In a definitive EFD study in pregnant rats, BMS-955176 was administered at doses of 10, 30, or 
100 mg/kg/day from GD 6 through 15. BMS-955176 was not a selective developmental toxicant. 
Developmental toxicity (reduced fetal body weights, increases in fetal alterations, and reduced 
fetal ossification) occurred only at 100 mg/kg/day; whereas, maternal toxicity (clinical 
observations, reduced body weights, and reduced food consumption) was observed at 
30 mg/kg/day. The developmental NOAEL was 30 mg/kg/day (AUC 114 gh/mL). 
In an EFD study in pregnant rabbits, BMS-955176 was administered at a dose of 80 mg/kg/day 
from GD 7 through 19. BMS-955176 was not a developmental toxicant in rabbits at 
80 mg/kg/day (AUC 3.26 gh/mL), at which reductions in maternal food consumption and 
weight gain were observed.
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In the fertility and early embryonic development study in rats, BMS-955176 was evaluated at 
doses of 10, 30, or 100/60 mg/kg/day in males and females. BMS-955176 did not affect 
reproduction or early embryonic development at doses 100 mg/kg/day that produced overt 
toxicity. The reproductive NOAEL was 100/60 mg/kg/day (AUC 210 g•h/mL) in male rats and
100 mg/kg/day (AUC 458 g•h/mL) in female rats.
Overall, results from the nonclinical toxicology studies demonstrate that BMS-955176 has a low 
potential for cardiovascular effects, is toxic to the gastrointestinal tract, and is a selective 
developmental toxicant. Clinical monitoring of vital signs (heart rate, systolic and diastolic blood 
pressure) and for gastrointestinal adverse events (AEs) (eg, nausea, vomiting, diarrhea, or fecal 
changes), along with screening for potential renal tubular injury, have not indicated any potential 
for these AEs in Phase 1 or proof of concept (POC) studies in humans. Clinical protocols will 
ensure that appropriate contraceptive measures will be followed to minimize the risk of 
pregnancy while enrolling women of child-bearing potential (WOCBP) males subjects who are 
sexually active with (see Section 3.3.1 Inclusion Criteria).
1.4.1.3
Clinical studies
Phase 1
The safety, tolerability, and PK of BMS-955176 were evaluated in a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD, 10-120 mg) and multiple ascending 
dose (MAD, 10-80 mg QD for 14-28 days) study in healthy subjects (AI468001). No SAEs, 
deaths, or discontinuations related to study drug occurred. No clinically meaningful trends were 
observed in vital signs, physical exam findings, laboratory values, or ECGs. Following 
single-dose and multiple-dose administration of BMS-955176, a slightly less than 
dose-proportional increase in Cmax and AUC(INF) was observed over the dose ranges studied. 
Steady state was reached in approximately 7 days following multiple-dose once daily 
administration of BMS-955176. The half life (T-HALF) of BMS-955176 is approximately 
35 hours. 
Study AI468034 assessed the relative bioavailability and dose proportionality of BMS-955176 
MC tablet - the formulation that will be used in the current study. Relative to 80 mg SDD 
suspension, the bioavailability of BMS-955176 120 mg MC tablet was approximately 23% 
lower. Furthermore, consistent with the low solubility of BMS-955176, considerable overlap in 
exposures was observed between 60 mg, 120 mg and 180 mg MC tablet, when given under 
fasted conditions. The impact of food on exposures to BMS-955176 120 mg MC tablet was 
assessed in Study AI468034 as well; a high fat meal increased BMS-955176 AUC approximately 
50% with negligible impact on BMS-955176 Cmax.
Study AI468049 assessed the impact of a light meal, a standard meal, and a high fat meal on the 
PK of BMS-955176 180 mg MC tablet. Preliminary results demonstrate that, relative to fasted 
conditions, BMS-955176 Cmax is increased approximately 2-fold with all three meal types, while 
BMS-955176 AUC increased approximately 1.8-, 2.1-, and 2.5-fold with a light meal, a standard 
meal, and a high fat meal, respectively. These results, taken together with those from AI468034 
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described above, demonstrate that the impact of food on exposures to BMS-955176 is 
dose-dependent with the degree of impact increasing with increasing dose. Preliminary safety 
results from AI468049 indicate that GI adverse events (eg, nausea, vomiting, loose stools) only 
occurred in the fed arms (where the BMS-955176 exposures were higher) relative to the fasted 
arms.
Study AI468049 assessed the impact of a light meal, a standard meal, and a high fat meal on the 
PK of BMS-955176 180 mg MC tablet. Preliminary results demonstrate that, relative to fasted 
conditions, BMS-955176 Cmax is increased approximately 2-fold with all three meal types, while 
BMS-955176 AUC increased approximately 1.8-, 2.1-, and 2.5-fold with a light meal, a standard 
meal, and a high fat meal, respectively. These results, taken together with those from AI468034 
described above, demonstrate that the impact of food on exposures to BMS-955176 is 
dose-dependent with the degree of impact increasing with increasing dose.
Phase 2a
A randomized, double-blind, placebo-controlled proof of concept study in HIV subjects has 
completed enrollment and is undergoing analysis (AI468002). The three parts of this study were: 
1) Part A evaluated doses of 5, 10, 20, 40, 80, and 120 mg of BMS-955176 (SDD suspension) 
given for 10 days in HIV-1 clade B infected subjects, 2) Part B compared the antiviral activity of 
BMS-955176 (SDD suspension) administered with ATV (with or without RTV) against standard 
of care (TDF + FTC + ATV/r) for 28 days in HIV-1 clade B infected subjects, and 3) Part C 
evaluated BMS-955176 40 and 120 mg (SDD suspension) given for 10 days in HIV-1 clade C 
infected subjects. See Table 1.4.1.3-1 for baseline demographics. 
Preliminary results from the Phase 2a study (AI468002) in HIV-1 (clade B and C only) infected 
adults showed that at effective doses, a maximum median reduction in HIV-1 RNA ranging from 
1.3 to 1.7 log10 was observed. In the Phase 2b study BMS-955176 doses estimated to provide 
similar exposure to effective doses in the Phase 2a study will be used. Moreover, when 
BMS-955176 was combined with ATV RTV, these combinations resulted in maximum median 
declines in HIV-1 RNA ranging from 1.9 to 2.2 log10 (see Table 1.4.1.3-2). These results are 
generally similar to the antiviral effect demonstrated by other classes of ARVs in short-term
monotherapy trials, and thus BMS-955176 should contribute substantially with other ARVs to 
form an effective cART regimen. Lastly, preliminary safety data show acceptable safety and 
tolerability across all Phase 2a arms. Most AEs were Grade 1-2 and were most frequently due to 
an indirect hyperbilirubinemia; the levels seen with BMS-955176 and ATV/r were similar to 
those seen with ATV/r combined with TDF/FTC. The arms containing BMS-955176 and 
unboosted ATV had bilirubin levels that were approximately half of those observed in the arms
containing ATV/r. Last, arms containing BMS-955176 alone did not show elevated bilirubin
levels. Many of these events occurred in subjects who were randomized to an arm containing 
BMS-955176 and ATV. Of the Grade 2-4 related AEs, many were due to headache and an 
increase in hyperbilirubinemia. Many of the AEs of hyperbilirubinemia occurred in subjects also 
receiving ATV.
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Table 1.4.1.3-1:
Phase 2a Baseline Demographics and Characteristics of Subjects 
(Preliminary Results)
Treatment Arm
Subjects
(n)
Median 
age
Male
White
Median 
HIV 
RNA 
(log10
c/ml)
Median 
CD4 
(cells/mm3)
Part A (Clade B, 10 days 
monotherapy)
BMS-955176 5 mg
8
43.5
8 (100)
6 (75.0)
4.09
437
BMS-955176 10 mg
8
39
7 (87.5)
7 (87.5)
4.02
539
BMS-955176 20 mg
8
33
8 (100)
8 (100)
3.59
512
BMS-955176 40 mg
8
38
8 (100)
8 (100)
4.03
536
BMS-955176 80 mg
8
31.5
8 (100)
8 (100)
3.82
504
BMS-955176 120 mg
8
37.5
8 (100)
8 (100)
3.84
498
Placebo
12
36
12 
(100)
12 
(100)
3.98
458
Part B (Clade B, 28 days therapy)
BMS-955176 40 mg + ATV 400 mg
8
32.5
8 (100)
6 (75)
4.04
581
BMS-955176 40 mg + ATV 300 mg + 
RTV 100 mg
8
34
8 (100)
8 (100)
4.45
480
BMS-955176 80 mg + ATV 400 mg
8
31.5
8 (100)
7 (87.5)
4.15
549
Truvada® + ATV 300 mg + RTV 
100 mg
4
32.5
4 (100)
4 (100)
4.12
427.5
Part C (Clade C, 10 days 
monotherapy)
BMS-955176 40 mg
7
35
4 (57.1)
2 (28.6)
4.53
554
Placebo
2
38.5
2 (100)
0 (0)
3.78
304
Table 1.4.1.3-2:
Maximum Decline Log10 HIV-1 RNA (Preliminary Results)
Treatment 
Mean 
S.D. 
Median 
Max
Min
Part A (Clade B, 10 days monotherapy)
BMS-955176 5 mg
-0.49
0.217
-0.498
-0.78
-0.22
BMS-955176 10 mg
-1.05
0.351
-0.976
-1.76
-0.64
BMS-955176 20 mg
-1.17
0.645
-1.115
-2.12
-0.13
BMS-955176 40 mg
-1.55
0.352
-1.701
-1.88
-0.93
BMS-955176 80 mg
-1.52
0.257
-1.555
-1.82
-1.04
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Table 1.4.1.3-2:
Maximum Decline Log10 HIV-1 RNA (Preliminary Results)
Treatment 
Mean 
S.D. 
Median 
Max
Min
BMS-955176 120 mg
-1.53
0.478
-1.654
-2.07
-0.83
Placebo
-0.48
0.581
-0.381
-1.46
0.56
Part B (Clade B, 28 days therapy)
BMS-955176 40 mg + ATV 400 mg
-1.89
0.273
-1.858
-2.37
-1.49
BMS-955176 40 mg + ATV 300 mg + RTV 100 
mg
-2.22
0.676
-2.202
-3.52
-1.24
BMS-955176 80 mg + ATV 400 mg
-2.3
0.307
-2.228
-2.68
-1.87
Truvada® + ATV 300 mg + RTV 100 mg
-2.41
0.495
-2.39
-3.04
-1.83
Part C (Clade C, 10 days monotherapy)
BMS-955176 40 mg
-1.5
0.439
-1.285
-2.03
-1.04
Placebo
0.12
0.141
0.12
0.02
0.22
The pharmacokinetics of BMS-955176 were assessed in HIV-1 infected subjects in AI468002. 
Overall, exposures to BMS-955176 are approximately 30% to 35% lower in HIV-1-infected 
subjects compared to healthy subjects administered the same doses and formulation of 
BMS-955176. Furthermore, exposures to BMS-955176 increased in a generally linear fashion up 
to 40 mg, with a less than dose proportional increase in exposures between 40 mg and 80 mg, 
and considerable overlap in exposures between 80 mg and 120 mg.
1.4.2
Background Information on TDF
Tenofovir disoproxil fumarate (TDF) is an analog of the nucleotide adenosine 
5’-monophosphate. TDF inhibits HIV-1 reverse transcriptase and is indicated in combination 
with other ARVs for the treatment of HIV-1 infection. The most common adverse reactions 
include rash, diarrhea, headache, pain, depression, asthenia, and nausea. Clinicians are warned 
about new onset or worsening renal impairment, decreases in bone density, and immune 
reconstitution syndrome. For more information concerning TDF, please refer to the 
TDF/Viread® SmPC or TDF/Viread® USPI.28
1.4.3
Background Information on DTG
Dolutegravir (DTG) is a HIV-1 integrase strand transfer inhibitor indicated in combination with 
other ARVs for the treatment of HIV-1 infection. The most common adverse reactions of 
moderate to severe intensity include insomnia, fatigue, and headache. Clinicians are warned 
about immune reconstitution syndrome. For more information concerning DTG, please refer to 
the DTG/Tivicay SmPC or the DTG/Tivicay USPI.29
1.4.4
Background Information on ATV 
Atazanavir is a protease inhibitor indicated for use in combination with other ARVs for the 
treatment of HIV-1 infection. The most common adverse reactions include nausea, 
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jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral 
neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. Clinicians are warned 
about hyperbilirubinemia, nephrolithiasis, and cholelithiasis. For more information concerning 
ATV please refer to the ATV/Reyataz® SmPC or ATV/Reyataz® USPI.30
1.4.5
Background Information on RTV
Ritonavir is a protease inhibitor indicated in combination with other ARVs for the treatment of 
HIV-1 infection. The most frequently reported adverse drug reactions with RTV alone or in 
combination with other ARVs include diarrhea, nausea, vomiting, abdominal pain, paresthesia, 
rash, and fatigue/asthenia. Clinicians are warned about total cholesterol and triglyceride 
elevations. For more information concerning RTV please refer to the RTV/Norvir® SmPC or 
RTV/Norvir® USPI.31
1.4.6
Drug-Drug Interactions
In AI468001, coadministration of BMS-955176 as a single dose following two doses of 100 mg 
RTV resulted in an approximate 48% increase in BMS-955176 AUC(INF), consistent with
inhibition of CYP3A4 and/or P-gp. Multiple-dose administration of BMS-955176 with daily 
400 mg ATV and a standard meal for 14 days resulted in a modest (~25%) increase in the 
BMS-955176 AUC(TAU).
Study AI468005 assessed the two-way interaction between BMS-955176 40 mg (administered as 
an SDD suspension) and TDF at steady state in healthy subjects. Relative to administration of 
each drug alone, neither BMS-955176 nor TDF exposures were meaningfully impacted upon 
coadministration.
Study AI468041 assessed the impact of BMS-955176 80 mg (administered as an SDD 
suspension) on the pharmacokinetics of the components of a combined oral contraceptive 
containing ethinyl estradiol (EE) and norgestimate (NGM). Exposures to both EE and 
norelgestromin (NGMN), the active metabolite of NGM were reduced in the presence of 
BMS-955176. Furthermore, one subject had a serum progesterone level > 300 ng/dL while 
BMS-955176 and the oral contraceptive were concomitantly administered, indicative of 
ovulation and contraceptive failure.
Finally, in vitro data suggest that BMS-955176 may inhibit OATP1B1 and OATP1B3 and 
exposures to substrates of these transporters, such as HMG-CoA reductase inhibitors, may 
increase when co-administered with BMS-955176.
1.5
Overall Risk/Benefit Assessment
The preclinical and clinical safety data demonstrate that BMS-955176 administered at doses in 
this Phase 2b study (120, and 180 mg) should be well tolerated without a major clinically 
relevant impact on safety. Moreover, there have been no identified safety risks from 
completed/ongoing clinical studies to date.
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The preclinical toxicology studies demonstrate two potential risks to subjects:
First, BMS-955176 is a selective developmental toxicant. Developmental toxicity (skeletal 
alterations in rats; cleft palate and reduced fetal body weights in mice) were observed in 
embryofetal development studies. In order to address this concern, subjects will be required to 
use two methods of contraception (as described in Section 3.3.1 Inclusion Criteria) and undergo 
routine urine pregnancy testing (as described in the T&E Tables in Section 5.1). Furthermore, 
due to results from Study AI468041 that demonstrates reduced exposures to the components of a 
combination oral hormonal contraceptive containing ethinyl estradiol and norgestimate when 
given concomitantly with BMS-955176, oral hormonal contraceptives cannot be used as a 
method of contraception by WOCBP in this study.
Second, single or repeat oral doses of BMS-955176 were associated with sporadic vomiting in 
dogs and unformed and/or liquid feces in rats and dogs. In rats at 10 mg/kg/day there were 
decreases in body weight and food consumption; in the stomach there was atrophy involving 
both parietal and chief cells, single-cell necrosis and regeneration in the glandular mucosa, and 
modest increases in serum gastrin values. At higher doses (100 mg/kg/day) in rats there were 
additional findings in the intestines (distended jejunum, ileum, and cecum; hyperplasia of the 
crypt epithelium in the jejunum; ulcers and erosions in the cecum; and decreased mucosal cell 
extrusion and increased mucus in the colon). 
Similar gastric changes were seen in dogs. At 20 mg/kg/day there was single-cell necrosis of the 
stomach glandular epithelium. At 3 mg/kg/day gastric changes showed chief cell depletion. 
At 10 mg/kg/day changes in the stomach included: mucous cell hyperplasia correlating with 
increased thickness macroscopically, parietal cell depletion, single-cell necrosis of glandular 
epithelial cells, and modest increases in serum gastrin values. Unlike the rats, no changes were 
observed elsewhere in the alimentary canal including the gastroesophageal junction and the 
duodenum. There was no evidence of macrocytosis. Measurement of Total Protein and Albumin 
revealed no clinically relevant changes. The stomach histologic findings were BMS-955176 
dose- and duration dependent. In the 1-month studies, vomiting and fecal changes stopped soon 
after dosing cessation, and microscopic lesions in the stomach and/or intestines reversed 
completely within a 2-week treatment-free period. In the 6 month study in rats and the 9-month 
study in dogs, microscopic lesions in the stomach partially recovered after a 1 month treatment 
free period. The NOAEL was 1 mg/kg/day (AUC 64.9 mg•h/mL) in the 9-month study in dogs, 
and was not established in the 6-month study in rats. Investigative studies for gastric toxicity in 
rats and dogs indicated similar findings with both SDD and MC forms, and with no clear 
evidence that the gastric toxicity is a direct local effect of BMS-955176. The mechanism and 
clinical relevance of these gastrointestinal findings is unknown at present (see below).
A Phase 1 study (AI468001) in healthy volunteers evaluated single and multiple doses of 
BMS-955176 for 14-28 days both alone and in certain arms, in combination with ATV or RTV. 
Overall the safety data demonstrated that BMS-955176 was generally safe and well tolerated. 
A Phase 2a (AI468002) study in HIV-1 infected adults evaluated several doses of BMS-955176 
given alone or in combination with ATV RTV for 10-28 days. The preliminary results show 
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acceptable safety and tolerability across all arms. There were no deaths, SAEs, or AEs leading to 
discontinuation. There were no clinically relevant changes in vital signs, lab parameters, or 
EKGs. Most of the AEs were Grade 1-2 and were most frequently due to hyperbilirubinemia 
(primarily observed in treatment arms with ATV). Of the GI AEs, most were attributable to 
diarrhea or loose/watery stools. Many of these events occurred in subjects who were randomized 
to an arm containing BMS-955176 and ATV. Of the Grade 2-4 related AEs, many were due to 
headache and an increase in hyperbilirubinemia. Many of the AEs of hyperbilirubinemia 
occurred in subjects also receiving ATV; moreover, the three arms with the highest average total 
bilirubin occurred in subjects receiving both BMS-955176 and ATV. Clinical changes/symptoms 
consistent with the GI findings from dogs and rats (described above) were not seen in the 
preliminary data set from short-term therapy with BMS-955176 in HIV-1 infected adults. 
In this treatment-experienced study population, we estimate GI safety multiples of 2× and 1×, 
(based on NOAEL in 9-month dog study), corresponding to projected human exposures at 
BMS-955176 doses of 120 and 180 mg.
While no clinically relevant GI safety signals have been observed in AI468001 or AI468002, in 
this clinical trial, subjects will undergo routine targeted and complete history/physical exams in 
addition to regular laboratory measurements (including CBC and chemistries). This will initially 
occur more frequently than in standard clinical practice and allow for increased vigilance for any 
potential GI toxicity. Guidance on the evaluation and management of potential GI toxicity is 
outlined in Section 6.7.1.4.
Subjects in this clinical study will benefit from receiving cART potentially containing 
BMS-955176. Preliminary data from the Phase 2a (Part A, B and C) study show a maximum 
median reduction in HIV-1 RNA (clades B and C) ranging from 1.3 to 1.7 log10 in the dose arms 
estimated to provide similar exposure to those in this current study. When BMS-955716 was 
combined with ATV RTV (Part B) this resulted in maximum median declines in HIV-1 RNA 
ranging from 1.9 to 2.2 log10. These results are generally similar to the antiviral effect 
demonstrated by other classes of ARVs. Thus, BMS-955176 should contribute with other ARVs 
substantially to form an effective cART regimen.
As with any antiretroviral study in HIV-1-infected subjects, there is a risk for the development of 
treatment failure and the development of drug resistance associated mutations to BMS-955176 
and/or other antiretrovirals. However, drug resistance to the maturation inhibitor would not be 
anticipated to result in cross-resistance to any other ARV class, including protease inhibitors.32
Ongoing analysis of preliminary data from the Phase 2a study is evaluating both emergent 
genotypic and phenotypic changes after short term monotherapy with BMS-955176. The use of 
three fully susceptible agents as a part of cART is expected to decrease the probability of 
virologic failure and drug resistance. Initially in this clinical trial, measurement of HIV-1 RNA 
will occur more frequently than in standard clinical practice which will allow for increased 
vigilance for the development of lack of efficacy/resistance. Finally, an analysis for virologic 
futility will occur at Week 24 (see Section 8.4.7).
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As described earlier, treatment-experienced adults enrolled in Arms 3-4 may be exposed to a 
subtherapeutic regimen and may be at higher risk for virologic failure and the development of 
resistance. In order to decrease this probability, this clinical trial uses a two-stage design 
whereby enrollment in Arms 3-5 will be dependent upon the results of the Week 24 analyses
(efficacy, safety, and pharmacokinetics) in Stage 1 and Study AI468038. This will minimize the 
risk of virologic failure and resistance to subjects enrolled in Arms 3-4 because clinical data will 
already have been generated using BMS-955176 with ATV/r (Arm 1) in Stage 1.
Of note, the other ARVs used in this clinical trial have a known and acceptable risk benefit ratio 
and are frequently prescribed to HIV-1 infected adults as a part of standard of care.
Taken together, the clinical data to date show that BMS-955176 has potent antiretroviral activity 
and is generally safe and well tolerated in healthy volunteers and HIV-1 infected adults. These 
factors should allow subjects to benefit from achieving viral suppression whilst taking a 
generally safe and well-tolerated new antiretroviral; additionally subjects in Arms 1, 3, and 4 
may benefit from a cART regimen that is nucleoside and nucleoside/booster sparing, 
respectively. Specifically, these subjects may benefit from improved bone mineral density, renal 
function, and lipid profiles. The risks, including teratogenicity, GI toxicity, and drug resistance, 
will be appropriately managed by following guidance in the study protocol.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
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investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion.
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented.
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The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a randomized, active-controlled, staged, open-label clinical trial. Approximately 
200 treatment-experienced HIV-1 subjects will be randomized to one of five treatment arms
(approximately 40 per arm) in a staged fashion.
The data from the Week 24 analysis of Stage 1 and AI468038, including safety, efficacy and 
pharmacokinetics, will be examined to trigger the start of Stage 2 and confirm the two doses of 
BMS-955176 for study in Stage 2.
Stage 1:
In Stage 1, subjects will be randomly assigned 1:1 to one of two treatment arms and on Day 1 
will begin dosing with:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:
In Stage 2, subjects will be randomly assigned 1:1:1 to one of three treatment arms and on Day 1 
will begin dosing with: 

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
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3.1.1
Screening
The screening period begins with the subject’s signature on the informed consent form (ICF).
The subject is then enrolled via the Interactive Voice Response System IVRS (or its web-based 
equivalent) See Section 4.4.
If the subject meets all eligibility criteria, the subject must be randomized within the 42 day 
screening period.
3.1.2
Day 1/Baseline Visit
3.1.2.1
Day 1/Baseline Visit for Arms 1 and 2 - Stage 1
In Stage 1, approximately 80 subjects will be randomized 1:1 (approximately 40 per arm) to 
either of the treatment arms containing boosted atazanavir (ATV/r).
On the Day 1 Visit, subjects in Arms 1 and 2 will begin QD dosing with BMS-955176 or TDF, 
each in combination with ATV/r and DTG (see Section 4.5 for additional details of Selection and 
Timing of Dose).

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
3.1.2.2
Day 1/Baseline Visit for Arms 3, 4 and 5 - Stage 2
In Stage 2, approximately 120 subjects will be randomized 1:1:1 (approximately 40 per arm) to 
either of the two BMS-955176 treatment arms containing ATV, or to the TDF Arm.
On the Day 1 Visit, subjects will begin QD dosing with BMS-955176 in combination with ATV 
and DTG, or TDF in combination with ATV/r and DTG (see Section 4.5 for additional details of 
Selection and Timing of Dose).

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r QD 300/100 mg + DTG 50 mg QD
3.1.3
Week 2 Intensive PK Visit
Subjects with anemia, defined as Hemoglobin < 11.0 g/dL, should be excluded from 
participation in the Week 2 Intensive PK Substudy.
Subjects in all arms will have the opportunity to participate in an elective Intensive PK Substudy 
visit at Week 2 (window for visit: Day 12-16). Approximately 60 subjects, 12 subjects from each 
arm, are expected to participate in the substudy; BMS may allow the substudy to over-enroll in 
an effort to have a sufficient number of complete datasets.
The series of 12 blood draws begins with pre-dose (0-hour) blood samples to be collected
approximately 24 hours (20-28 hrs) after the morning doses of study drugs that were taken on the 
day before. Ten more samplings are drawn through the 12-hr time point, with one final sampling 
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collected at the 24-hr time point, requiring the subject to either remain overnight in the clinic, or 
to return the next morning; the final 24-hr sample will be collected prior to administration of the 
morning doses of study drugs (See Section 5.5.1).
PK Tools/Job Aids will be provided to assist with the proper sequencing of dosing and blood 
sample collections, as well as the collection of required data.
3.1.4
Visits Week 4 - 96
Subjects are expected to be treated for the duration of 96 weeks. In each Stage, after Day 1 and 
the optional Intensive PK visit at Week 2, subjects will be required to attend 12 more in-clinic 
study visits over the 96-week treatment period, as follows:

Visits are conducted every 4 weeks from Week 4 through Week 16

Visits are conducted every 8 weeks from Week 24 through Week 48

Visits are conducted every 12 weeks from Week 60 through Week 96
Visits should be scheduled as an interval from the Day 1/Randomization date, and within a 
window of 5 days earlier or later.
One of the visits Week 4 - 24 should meet the very specific timing requirements as outlined in 
Section 5.5.2 for a pre-AM dose blood collection.
Telephonic visits will be conducted with each subject at visit Weeks 20, 28, 36, 44, 54, 66, 78,
and 90 to conduct an adherence assessment and to continue retention efforts
3.1.5
Selection of the Continuation Dose of BMS-955176
3.1.5.1
Selection of the Continuation Dose, and the Switch for Stage 1
Once all subjects in Stage 1 have reached Week 24*, BMS will conduct an interim analysis of 
efficacy, safety, resistance and pharmacokinetics.
As described in Section 8.4.7, an analysis of Virologic Futility will also occur. If Arm 1 meets 
criteria for Virologic Futility at Week 24, the clinical trial will be terminated.
The Week 24 analysis of Arms 1 and 2, combined with the Week 24 analysis of all Arms in the 
AI468038 study, will be used to select a Continuation Dose of BMS-955176 for Arm 1 in this 
study. Subjects in the BMS-955176 Treatment Arm 1 may subsequently be transitioned to a
selected Continuation Dose.
Subjects in the Arm containing TDF will continue with the TDF treatment regimen.
The assigned backbone will not change.
The Week 24 efficacy, safety, and pharmacokinetic analyses from Stage 1 and study AI468038 
will also trigger the start of Stage 2.
* If the Continuation Dose cannot be clearly identified using the Week 24 data, the study 
will continue in original fashion until an analysis of the Week 48 data can be performed 
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and the Continuation Dose is selected. If a Continuation Dose cannot be selected based 
upon the Week 24 data, this does not preclude the ability to start recruitment of Stage 2.
After the Continuation Dose is selected, and once all of the logistics (eg, distribution of clinical 
drug supplies, activation of the new portion of the IVRS) have been completed globally, the 
transition of the subjects in Arm 1 to the Continuation Dose will occur. It is anticipated that this 
transition will occur on or after all subjects have reached Week 48 (the earliest subjects to begin 
study treatment could be well beyond Week 48 when the switch to the Continuation Dose 
occurs).
3.1.5.2
Selection of the Continuation Dose, and the Switch for Stage 2
Once all subjects in Stage 2 have reached Week 24, BMS will conduct an analysis of efficacy, 
safety, resistance and pharmacokinetics.
As described in Section 8.4.7, an analysis of Virologic Futility will also occur. If a BMS-955176 
dose arm meets criteria for Virologic Futility at Week 24, subjects in said arm will begin dosing 
with the next highest available remaining dose of BMS-955176.
The data from AI468038 and AI468048 (Stages 1 and 2) will be used to select a Continuation 
Dose of BMS-955176 for Arms 3 and 4. Subjects in the BMS-955176 Treatment Arms 3 and 4 
will subsequently be transitioned to a selected Continuation Dose. It is anticipated that this 
transition may occur on or after all subjects have reached Week 48, or it could occur sooner after 
Week 24.
The assigned backbone will not change.
Subjects in the arm containing TDF will continue with this assigned treatment regimen.
3.1.6
End of the study
The end of the study will occur when the last study visit has been completed, defined as the final 
subject completing their final study visit (expected to be a Week 96 or Early Termination visit).
The study design schematic is presented in Figure 3.1.6-1.
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Figure 3.1.6-1:
Study Design Schematic
Arm 2
TDF
300 mg QD
+ ATV/r + DTG
Day 1
Begin dosing
Arm 3
BMS-955176 
120 mg QD
+ ATV + DTG
1 Virologic Futility will be evaluated at Week 24 
(see Section 8.4.7).  
Results of Week 24 Stage 1 AI468-048 & AI468-038 
Confirm the Start of Stage 2   
Arm 4
BMS-955176 
180 mg QD
+ ATV + DTG
40
40
Week 2
Week 24
Week 24 Analysis1
Intensive PK subset
4 Based on totality of data from both studies the 
Continuation Dose for Arms 3 & 4 may be 
identified.  
Number
Randomized
STAGE 2
Week 96
Week 96 Analysis/End of Study
Week 48
Week 48 Analysis
The Switch to the Continuation Dose4,3     
is expected to occur on or after Week 48, 
but could occur sooner.
Arm 1
BMS-955176 
120 mg QD
+ ATV/r + DTG
Week 2
Number
Randomized
Week 24
Week 24 Analysis1
Day 1
Begin dosing
Intensive PK subset
40
40
Week 48
Week 96
Week 48 Analysis
Week 96 Analysis/End of Study
The Switch to             
the Continuation Dose2,3
may occur on or after 
Week 48 
STAGE 1
BMS-955176
Continuation Dose QD 
+ ATV/r + DTG
Arm 5
TDF
300 mg QD
+ ATV/r + DTG
40
3 The actual switch of subjects of BMS-955176 
subjects to that Continuation Dose may occur when 
all of the subjects have reached at least Week 48 
(though it could occur sooner in Stage 2).
BMS-955176
Continuation Dose QD
+ ATV + DTG
2 Based on Week 24 data from Arms 1 & 2 and 
from AI468-038, the Continuation Dose for 
Arm 1 may be identified.  
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3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug. Study drug will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee 
or through another mechanism at the discretion of BMS. BMS reserves the right to terminate 
access to BMS supplied study drug if any of the following occur: a) the marketing application is 
rejected by responsible health authority; b) the study is terminated due to safety concerns; c) the 
subject can obtain medication from a government sponsored or private health program; or 
d) therapeutic alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Ability to understand and sign a written informed consent form
2. Target Population
a) Antiretroviral treatment-experienced, defined as having documented evidence of having
failed, 1 or 2 regimens that include 2 or 3 classes of ARV (with or without documented 
resistance)
b) Confirmed Plasma HIV-1 RNA 400 copies/mL (First value from investigator; second 
value from screening test)
c) CD4+ T-cell count > 50 cells/mm3
d) Screening genotype/phenotype indicating susceptibility to study drugs (unboosted ATV, 
FC < 2.2; DTG; TDF)
e) Estimated Life expectancy 1 year
Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued 
the study as a pre-treatment failure (ie, subject has not been randomized / has not been treated). 
If re-enrolled, the subject must be re-consented and assigned a new PID. (See Section 5.5.1 for 
additional details.)
3. Age and Reproductive Status
a) Males and non-pregnant females
b) At least 18 years of age, (or minimum age as determined by local regulatory or as legal 
requirements dictate)
c) Willingness to use approved highly effective methods of contraception (see below) to 
avoid pregnancy (female subjects who are WOCBP and male subjects who are sexually 
active with WOCBP)
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d) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
e) Women must not be breastfeeding
f)
WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug BMS-955176 plus 12 weeks post-treatment completion.
g) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug BMS-955176
plus 5 half-lives of the study drug BMS-955176 (8 days) plus 90 days (duration of sperm 
turnover) for a total of 98 days post-treatment completion.
h) Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However WOCBP must still undergo 
pregnancy testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. 
All subjects must agree to the use of a highly effective method of contraception as listed below.
In addition male subjects should use condoms during treatment and for 98 days following the last 
treatment when relevant systemic exposure is no longer present.
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to 
use one of the highly effective methods of contraception listed below. 
Study subjects who are WOCBP cannot use hormonal methods of contraception as one of the 
highly effective methods of contraception because there are data to show a lack of effectiveness 
of systemic hormonal contraceptives in women taking BMS-955176. However, WOCBP can 
continue to use hormonal contraceptives, if necessary, in addition to one other non-hormonal 
highly effective methods of contraception.  
Male subjects must inform their female partners who are WOCBP of the contraceptive 
requirements of the protocol and are expected to adhere to using contraception with their partner. 
Relevant exposure of BMS-955176 in female partners of male participants in the study is 
expected to be negligible. Female partners of male subjects participating in the study may use 
hormone based contraceptives as one of the acceptable methods of contraception because 
exposure to the investigational product would be too small to alter exposure of hormonal 
contraceptives.
1.
Nonhormonal IUDs, such as ParaGard
2.
Bilateral tubal occlusion
3.
Vasectomised partner with documented azoospermia 90 days after procedure
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o
Vasectomised partner is a highly effective birth control method provided that partner is 
the sole sexual partner of the WOCBP trial participant and that the vasectomised partner 
has received medical assessment of the surgical success.
4.
Complete abstinence
o
Complete abstinence is defined as the complete avoidance of heterosexual intercourse 
when this is the preferred lifestyle of the patient.
o
Complete abstinence is an acceptable form of contraception for all study drugs and must 
be used throughout the duration of study and for the duration of time as specified above.
o
It is not necessary to use any other method of contraception when complete abstinence is 
elected.
o
Subjects who choose complete abstinence must continue to have pregnancy tests. 
o
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as 
listed below:
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge with spermicide

Male or female condom with or without spermicide 

By male subject’s WOCBP partner only: Progestogen-only oral hormonal contraception, 
where inhibition of ovulation is not the primary mode of action.
* A male and female condom must not be used together
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Antiretroviral treatment-experienced adults who have failed > 2 ARV regimens
b) Resistance or partial resistance to any study drug
c) Three or more of the following PI mutations, historical or documented: M36I/V, 
M46I/L/T, G48M/V, I54V/L/T/M/A, G73S/A/C/T, V82A/F/T/S/I, or L90M
d) Any major ATV mutations, historical or documented: I50L, I84V/A, N88D/S
e) Any major TDF mutation, historical or documented: K65R or T69ins
f)
Three or more of the following non-accessory thymidine analogue mutations (TAMs): 
M41L, D67N, K70R, L210W, T215Y/F, K219Q/E
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g) Any major mutations for raltegravir (RAL), elvitegravir (or clinically suspected INI 
resistance), historical or documented: T66IAK, E92Q, S147G, N155H, Q148H/K/R, 
Y143C/H/R, E157Q
h) Antiretroviral treatment-experienced adults infected with Clade AE
i)
Patients who have failed a previous boosted PI- or Integrase strand transfer inhibitor 
(INSTI)-containing regimen for which resistance analyses were not conducted at the time 
of failure
2. Medical History and Concurrent Diseases
a) A new AIDS defining condition diagnosed within the 30 days prior to screening
(see Appendix 2)
b) Any other clinical condition (including but not limited to active substance use) or prior 
therapy that, in the opinion of the Investigator, would make the subject unsuitable for the 
study; unable to comply with dosing requirements; or unable to comply with study visits; 
or a condition that could affect the absorption, distribution, metabolism or excretion of 
the drug.
3. Physical and Laboratory Test Findings
a) Chronic HBV/HCV (Positive blood screen for HBsAg; Positive blood screen for HCV 
Ab and HCV RNA)
b) ALT or AST > 3 × ULN
c) Alkaline Phosphatase > 5 × ULN
d) Bilirubin ≥ 1.5 × ULN
e) History of decompensated cirrhosis or active decompensated cirrhosis
f)
Hemoglobin < 8.0 g/dL
g) Platelets < 50,000 cells/mm3
h) Estimated eGFR < 60 mL/min (CKD-EPI formula)
i)
Confirmed QT value > 500 msec at Screening or Day 1
j)
Confirmed QTcF value > 470 msec for women and > 450 msec for men at Screening or 
Day 1
k) Confirmed PR Interval > 260 msec (severe first degree AV block) at Screening or Day 1
l)
Confirmed second or third degree heart block at Screening or Day 1
4. Allergies and Adverse Drug Reaction
a) Medications contraindicated for use with investigational/non-investigational study drugs 
(ATV, RTV, DTG, TDF);
or subjects with any known allergies to the 
investigational/non-investigational study drugs (ATV, RTV, DTG, TDF)
b) Current or anticipated treatment with any of the medications listed in Appendix 1, in 
addition to any medications that are contraindicated with ATV, RTV, DTG or TDF
c) Participation in an experimental drug and/or HIV-1 vaccine trial(s) within 30 days prior 
to Screening
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5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A woman of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/mL to confirm menopause.
Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is > 40 mIU/mL at any time 
during the washout period, the woman can be considered postmenopausal:

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
Refer to Appendix 1 which details prohibited and precautionary therapies during the study, 
including specifics about the use of antacids and hormonal methods of contraception.
3.4.2
Other Restrictions and Precautions
None.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment
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
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Pregnancy (subjects should be discontinued in an appropriate manner)

Repeat non-adherence by the subject with the requirements of the protocol or treatment
(as determined by Investigator in consultation with the BMS Medical Monitor)

Evidence of Hepatitis B or C infection

Failure to achieve > 1 log10 c/mL decrease in HIV-1 RNA by Week 8

Confirmed plasma HIV-1 RNA 1000 c/mL after Week 24

Confirmed plasma HIV-1 RNA 200 c/mL after Week 48

Emergence of genotypic and/or phenotypic resistance to any component of the study 
treatment regimen at any time after Screening

Subject requires switching to any other ARV

Development of pDILI (potential drug induced liver injury)

Confirmed QTcB or QTcF value > 500 msec

Confirmed second degree (Type II) or third degree AV block at any time during the study
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. The study drug will be permanently discontinued in an 
appropriate manner.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5 (ie, perform an Early Termination [ET] visit). The only 
exception to this requirement is when a subject withdraws consent for all study procedures 
including post-treatment study follow-up (no such period exists in this study) or loses the ability 
to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
Subjects who discontinue study drug may continue to be followed.
Subject’s contact information will be collected/confirmed throughout the study so that subjects 
who discontinue study drug may continue to be followed for resolution of a pregnancy or SAE.
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3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for AI468048:
Product Description / 
Class and Dosage Form
Potency
IMP/Non-IMP
Blinded or 
Open Label
Packaging/ Appearance
Storage Conditions
(per label)
BMS-955176 
60 mga
IMP
Open Label
Bottle/
A white to off-white, biconvex, 
oval shaped film coated tablet
Store at 2 - 30°C
Protect from light.
Store in a tightly closed container.
BMS-955176
120 mga
IMP 
Open Label
Bottle/
A white to off-white, biconvex, 
capsule shaped film coated tablet
Store at 2 - 30°C
Protect from light.
Store in a tightly closed container.
Tenofovir (TDF)
300 mg
Non-IMP
Open Label
Various packaging configurations
Refer to label on
container or package insert.
Atazanavir (ATV)
200 mg
IMP
Open Label
Bottle/
Blue cap and blue body
printed with white ink
Store at 15 - 30°C
Store in a tightly closed container.
Atazanavir (ATV)
300 mg
IMP
Open Label
Bottle/
Red cap and blue body,
printed with white ink
Store at 15 - 30°C
Store in a tightly closed container.
Ritonavir (RTV)
100 mg
Non-IMP
Open Label
Various packaging configurations
Refer to label on
container or package insert.
Dolutegravir (DTG)
50 mg
Non-IMP or 
IMP,
depending on 
country 
approval status.
Open Label
Various packaging configurations
Refer to label on
container or package insert.
a The 180 mg dose of BMS-955176 will be constructed with BMS-955176 60 mg + BMS-955176 120 mg
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, investigational product(s) is/are: BMS-955176, ATV, and DTG (in countries 
where DTG has not been approved for use). These products will be supplied.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products.
In this protocol, noninvestigational product(s) is/are: TDF, RTV, and DTG (in countries where 
DTG is approved for use). These products will be supplied.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
4.4
Method of Assigning Subject Identification
At the start of the screening period, the investigative staff will call the Assignment Center via an 
Interactive Voice Response System ([IVRS], or its web-based equivalent) designated by the 
sponsor to enroll the subject and to obtain a subject patient identification number (PID).
For subjects who meet the protocol eligibility criteria, the investigative staff will call the IVRS 
and subjects will start treatment.
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Subjects will be randomly assigned in the staged fashion to one of the treatment arms, as
described in Section 3 and as outlined in the AI468048 Study Schematic Figure 3.1.6-1.
Note: All efforts should be made to limit the possibility of randomizing subjects that do not start 
treatment. If a subject is randomized but does not receive study medication, the BMS study team 
must be notified immediately.
4.5
Selection and Timing of Dose for Each Subject
Subjects will be randomized into the treatment arms in a staged fashion described in Section 3.1.
Stage 1:
In Stage 1, subjects will be randomly assigned 1:1 to one of two treatment arms and on Day 1 
will begin dosing with:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:
In Stage 2, subjects will be randomly assigned 1:1:1 to one of three treatment arms and on Day 1 
will begin dosing with:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
4.5.1
Instructions for Dose Administration
4.5.1.1
General Instructions

Subjects should administer doses of each drug from only one bottle at a time, until that bottle 
is empty, before another bottle may be opened. 

Subjects will be required to complete Dosing Diaries so that drug administration can be 
accurately accounted. It is important that sites provide instructions to subjects for completion 
and obtain their acknowledgment that doing so provides critical information for the clinical 
trial.

Dosing times (and study appointment times) must be carefully considered through Week 24 
due to the requirements of the PK collection outlined in Section 5.5.
4.5.1.2
Specific Dosing Instructions for Initial Treatment Arm Assignment
In the morning, with a meal, subjects will take the following:

Arm 1: One pill each from bottles BMS-955176 120 mg, ATV, RTV, and DTG

Arm 2: One pill each from bottles TDF, ATV, RTV and DTG
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
Arm 3: One pill each from bottles BMS-955176 120 mg, DTG, and two pills from bottle
ATV (the unboosted dose of ATV is 400 mg, achieved by 200 mg x 2)

Arm 4: One pill each from bottles BMS-955176 60 mg, BMS-955176 120 mg and DTG, and 
two pills from bottle ATV (the unboosted dose of ATV is 400 mg, achieved by 200 mg x 2)

Arm 5: One pill each from bottles TDF, ATV, RTV and DTG
4.5.2
Dose Modifications
No dose adjustments or changes in intake frequency are allowed for any of the assigned study 
drugs in the protocol, except for the unique case of treatment-limiting renal toxicity which limits 
the use of the TDF. In the event of treatment-limiting renal toxicity, dose interval adjustments for 
TDF are permitted according to the local package insert/label, and only after the completion of 
the Week 2 Intensive PK optional Visit, if the subject is inclined to participate.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment Adherence to the treatment regimen will be critical to the conduct of this study. 
Adherence will be evaluated by the investigative staff at every treatment visit (including 
telephone contact visits) through interviews with the subjects and through examination of 
returned medication. It is expected that site staff attempt to have subjects maintain 90% 
treatment compliance or greater. Subjects should be instructed to bring all unused study 
medication back in the original container to each visit. Site staff are required to review Dosing 
Diaries completed by the subject, and to reinforce their use.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request
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
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (AI468048)
Procedure
Screening Visit
(42-day screening period)
Notes
Eligibility Assessments
Informed Consent
X
Call IVRS to Enroll the subject; PID assigned
X
Inclusion/Exclusion Criteria
X
Medical History
X
AIDS History
X
Non-Laboratory Safety Assessments
Full Physical Examination
X
See Section 5.3.1 for requirements
Vital Signs & Physical Measurements
X
See Section 5.3.1 for requirements
Pre-treatment events
X
Only CDC Class C events with onset during the Screening period
Serious Adverse Events Assessment
X
All SAEs that occur after the ICF has been signed should be reported
ECG
X
See Section 5.3.4 for requirements
Pregnancy Test
X
WOCBP
For females under age 55, an FSH level must be on record to confirm she 
is not a WOCBP if pregnancy testing is not being performed.
If positive urine, request serum hCG quant. on lab requisition.
Laboratory Assessments (See Appendix 5 for full details)
Fasting Chemistry and Lipid Panel
X
Fasting overnight
Hematology
X
Urinalysis
X
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Table 5.1-1:
Screening Procedural Outline (AI468048)
Procedure
Screening Visit
(42-day screening period)
Notes
Plasma HIV-1 RNA
X
This is the confirmatory HIV-1 RNA
(The first value is provided by the PI)
CD4+ and CD8+ T-cell count
X
HBV Surface Antigen
X
HCV Serology
X
Urine toxicology (drugs of abuse)
X
Could aid in the selection of appropriate study candidates.
Pharmacodiagnostic (PDx) samplea
X
Plasma collection to be banked for potential future use in development of 
novel predictive assay(s)
Resistance Testing
(HIV-1 Drug Resistance)
PhenoSense GT Plus Integrase
X
Complete set of test results may take up to 4 weeks.
PhenoSense Gag
X
Next Generation Seq. - Qs Gag
X
Exploratory Resistance
(HIV-1 Drug Resistance)
X
Molecular analysis at BMS WFD Discovery of baseline resistant samples 
and baseline sensitive controls in cases of subsequent on-treatment 
virologic failure
a By definition, a pharmacodiagnostic sample (PDx) is a pre-treatment test to determine whether or not a patient is likely to respond to a drug (ie, a predictive 
test). Based on the results of clinical studies with BMS-955176, BMS may have to develop a PDx assay. Thus, PDx samples obtained at Screening in this 
study would be used for that sole purpose.
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Eligibility Assessments
Inclusion/Exclusion Criteria
X
Non-Laboratory Safety Assessments
Full Physical Examination
WK 12, 24, 48, 96/ET
See Section 5.3.1 for requirements
Targeted Physical Examination
X
WK 4, 8, 16, 32, 40, 60, 72, 84
See Section 5.3.1 for requirements
Vital Signs & Physical 
Measurements
X
X
See Section 5.3.1 for requirements
Adherence Assessments
X
X
Including review of Dosing Diaries
Pre-treatment Events
X
See Table 5.1-1
Adverse Events Assessments
X
X
X
Serious and Non-serious AEs
Concomitant Medications
X
X
X
See Section 5.3.3
ECG
X
WK 4, 12, 24, 48, 96/ET
See Section 5.3.4 for requirements
Pregnancy Test
X
X
X
For females under age 55, an FSH 
level must be on record to confirm 
she is not a WOCBP if pregnancy
testing is not being performed.
If positive urine, request serum 
hCG quant. on lab requisition.
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Provide WOCBP with Home 
Pregnancy test kit(s) to be used 
during the in-clinic visit interval
WK 16, 24, 32, 40,
48, 60, 72, 84
Provide One Kit at Weeks 16 - 40
Provide Two Kits at Weeks 48 - 84
WOCBP subjects perform test Q4 
weeks at home and report results to 
site.
Laboratory Assessments for Safety and Efficacy and Other Endpoints (See Appendix 5 for full details)
Fasting Chemistry
X
X
Fasting overnight
Fasting Lipid Panel
X
WK 4, 12, 24, 48, 96/ET
Fasting overnight
Hematology
X
X
Urinalysis
X
X
Fractional Excretion of Phosphorous 
(FePO4)
(Urine creatinine and phosphorus, 
Serum creatinine and phosphorus)
X
WK 48 and 96/ET
Plasma HIV-1 RNA
X
X
X
If collecting an HIV-1 RNA at an 
UNSCHEDULED visit, also collect 
samples for Resistance and 
Exploratory Resistance Testing
CD4 and CD8 T-cell counts
X
X
HBV Surface Antigen
WK 48 and 96/ET
HCV Serology
WK 48 and 96/ET
Positive HCV Ab will reflex to 
HCV RNA
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Resistance Testing
(HIV-1 Drug Resistance)
PhenoSense GT Plus Integrase
X
X
Samples stored and tested if needed
(ie, analyses of subjects if deemed 
clinically relevant)
See Section 5.4.2.2
PhenoSense Gag
X
X
Next Generation Seq. - Qs Gag
X
X
Exploratory Resistance
(HIV-1 Drug Resistance)
X
X
Samples stored and tested 
retrospectively if needed (ie,
exploratory analyses for subjects if 
deemed clinically relevant)
Intensive PK sample collection
X
Use of PK Tools for data collection 
recommended.
See Section 5.5.1 for requirements
Sparse PK sample collection
WK 4, 8, 12, 16, 24
See Section 5.5.2 for requirements
Bone Biomarkers
(P1NP and CTX)
X
WK 12 and 24/ET
Serum collection
Renal Biomarkers
(2-microglobulin and creatinine)
X
WK 48 and 96/ET
Urine collection
Backup Serum and Plasma Sample
X
X
Samples stored and tested if needed
Outcomes Measures
EQ-5D-3L Form
X
WK 12, 24, 32, 40, 48,
60, 72, 84, 96
Health Outcomes Questionnaire
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Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
FAHI Form
X
WK 12, 24, 32, 40, 48,
60, 72, 84, 96
Functional Assessment of HIV 
Infection
Clinical Drug Supply
Call IVRS to Randomize
X
Dispense Study Drug
X
X
There is no dispensation at Week 96 
or ET.
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value). The Screening Period for this study is 42 days.
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultations 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant (eg, a previously failed inclusion criterion).
Rescreening is different than Retesting. Rescreening is the process of Re-enrollment and requires 
that all procedures be repeated in an entirely new screening period. A one-time Rescreening is 
permitted, if further rescreening is considered for reassessment of enrollment eligibility this 
should be discussed with the Medical Monitor.
The assigned patient identifier (PID) for the subject must be Screen Failed in the IVRS. A new 
call must be made to the IVRS for the assignment of a new PID for the subject, and all Screening 
parameters must be done again in reference to the new PID (See Section 3.3.1, Inclusion 
Criteria 2f). Subject must also be re-consented with the new PID.
5.2
Study Materials
The sponsor will provide each investigative site with the following:

BMS-955176 Investigator Brochure (IB) and any relevant safety addenda or updates

Protocol and any Amendments to the Protocol

Instructions for completing electronic Case Report Forms (eCRFs)

Laboratory Manual from the central laboratory

ECG Machines and manual

IVRS Worksheets to complete when calling the IVRS center to enroll, randomize, and 
discontinue subjects

Patient-reported Outcomes Questionnaires: EQ-5D-3L Health Outcome Questionnaire, FAHI 
(Functional Assessment of HIV Infection)

PK Tools/Job Aids that may be used for detailed instruction about the PK visits, and as a 
comprehensive source for documents of date/times of dosing and blood sampling

Dosing Diaries

Completion by subjects is required

Should include daily dose of study medications administered by subject, modified or 
missed

Site staff should review the diaries with the subject at each visit, and, in combination with 
detailed questioning, should be able to provide comprehensive information in the case 
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report form, noting discrepancies in the subject’s file. Dosing Diaries should be 
maintained in the subject’s study file.
5.3
Safety Assessments
The investigative team should follow the protocol-specified scheduled of safety-related 
measurements. Only data for the procedures and assessments specified should be submitted to 
BMS on the case report form. Additional procedures and assessments may be performed as part 
of standard of care, however, data for these assessments should remain in the subject’s medical 
record and should not be submitted to BMS, unless specifically requested (ie, as part of an SAE).
5.3.1
Vital Signs and Physical Examinations
The schedule of vital signs, physical examinations, and targeted physical examinations is 
provided in Section 5.1 (Flow Chart/Time and Events Schedule). Vital signs include heart rate, 
blood pressure, respiration rate, and temperature and should be measured after the subject has 
been sitting/resting for at least 5 minutes. Physical measurements include height and weight. 
Targeted physical examinations will include examination of the heart, lungs, skin, abdomen, any 
symptomatic organ system, and general appearance.
5.3.2
Adverse Events
Subjects will be closely monitored throughout the study for any new or ongoing HIV-related 
diagnoses (Appendix 2) and/or adverse events. CDC Class C events that occur from the
Screening Visit through Day 1 (prior to dosing), will be recorded as Pre-treatment Events. All 
events that occur after dosing on Day 1 will be recorded on the appropriate Adverse Event eCRF. 
Additional information on Adverse Events is provided in Section 6.
5.3.3
Concomitant Medication Assessment
All medications taken from the Screening Visit throughout the duration of the study will be 
reported. In addition, any prior therapy with antiretroviral drugs will be reported
(See Appendix 1 for Prohibited and Precautionary Therapies).
5.3.4
Electrocardiograms
The schedule of electrocardiograms (ECGs) is provided in Section 5.1 (Flow Chart/Time and 
Events Schedule). ECG machines will be provided by a central vendor who will also perform the
read/interpretation of the output.
5.4
Efficacy Assessments
5.4.1
Primary Efficacy Assessment
The primary assessment for efficacy is HIV-1 RNA at Week 24.
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5.4.1.1
Guidelines for Confirmatory Testing of Plasma HIV-1 RNA and 
Resistance testing
A confirmatory HIV-1 RNA viral load should be obtained when:

HIV-1 RNA 40 c/mL if prior suppression 40 c/mL, or

> 1 log10 c/mL increase in HIV-1 RNA at anytime above nadir level where nadir is 
40 c/mL
All efforts should be made to collect this sample within 2-4 weeks from the collection of the 
original sample.
When collecting a blood sample for HIV-1 RNA testing at an Unscheduled visit, samples should 
also be collected for the sets of Resistance and Exploratory Resistance Tests, so that the samples
are available should resistance testing be required or deemed necessary based on the result of the 
HIV-1 RNA test.  
Table 5.4.1.1-1:
Management of Detectable HIV-1 RNA, based on Confirmed 
(2-4 weeks from original sample) or Consecutive HIV-1 RNA 
Resulta
Day 1 through Week 24
40 - 399 c/mL
Reinforce Adherence
400 c/mL
Consider the need for resistance testing, in consultation with BMS Medical Monitor.
Consider possible discontinuation of subject, in consultation with BMS Medical Monitor, 
and/or reinforce adherence.
After Week 24 through Week 48
40 - 399 c/mL
Reinforce Adherence
400 - 999 c/mL
Resistance testing will be performed.
If resistance has developed, subject must be discontinued.
If resistance has not developed, consider possible discontinuation of subject, in consultation 
with BMS Medical Monitor, and/or reinforce adherence.
1000 c/mL
Resistance testing will be performed.
Regardless of result of resistance tests, subject must be discontinued (see Section 3.5).
After Week 48
40 to < 200 
c/mL
Reinforce Adherence
200 c/mL
Subject must be discontinued (see Section 3.5). 
If 400 c/mL, consider the need for resistance testing, in consultation with BMS Medical 
Monitor.
a When discontinuation is required or otherwise warranted and resistance results are needed, subject may continue 
on study medication/on study until resistance testing results are available.
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5.4.1.2
Protocol Defined Virologic Failure
Protocol Defined Virologic Failure (PDVF) is defined by a subject meeting one of the following 
criteria:
1) Confirmed > 1 log10 c/mL increase in HIV-1 RNA at anytime above nadir level where nadir 
is 40 c/mL
2) Confirmed HIV-1 RNA 400 c/mL after Week 24
3) Confirmed HIV-1 RNA 40 c/mL if prior suppression to < 40 c/mL
4) Failure to have the last on-treatment HIV-1 RNA to < 400 c/mL within Week 24, 48, or 96 
week snapshot window
5) Failure to achieve > 1 log10 c/mL decrease in HIV-1 RNA by Week 8
In addition to the clinical management outlined in section 5.4.1.1, samples meeting criteria for 
PDVF will also be sent for resistance and exploratory resistance testing.
5.4.2
Secondary Efficacy Assessments
5.4.2.1
CD4+ and CD8+ T-Cells
CD4+ and CD8+ T-cells counts and percentages will be assessed using flow cytometry. The 
schedule of assessments is provided in Section 5.1 (Flow Chart/Time and Events Schedule). 
Procedures for samples collection and processing are provided in the central clinical laboratory 
manual.
5.4.2.2
Drug Resistance Testing
Plasma samples for viral drug resistance testing will be collected at Screening for all subjects and 
the HIV-1 drug resistance genotype will be analyzed to rule out resistance to any component of 
the study regimen or specific resistance mutations as outlined in Section 3.3.2, Exclusionary 
Criteria. At subsequent visits, samples for emergent drug resistance testing (both genotypic and 
phenotypic) will be collected and stored to be as outlined in Section 5.4.1.
5.5
Pharmacokinetic Assessments
It is extremely important to record the exact dose and time of the dose(s) taken the day prior to 
the visit/collection, and the exact date and time of the sample collection, even if drawn slightly 
off-schedule.
5.5.1
Intensive Pharmacokinetic Assessment
A subset of subjects (about 12 subjects per treatment group) will participate in an optional 
Intensive PK assessment at Week 2 (window Day 12-16).
Intensive PK samples collected in this study will provide for the assessment of BMS-955176, 
ATV, RTV, and DTG to support the secondary and exploratory objectives (to characterize the 
PK of BMS-955176, DTG, and ATV (with or without RTV) when given in combination, and to 
compare steady-state exposures of DTG when co-administered with BMS-955176 and 
ATV/RTV to DTG when co-administered with TDF and ATV/RTV).
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Intensive PK sampling begins with a morning pre-dose (0 hour) sampling, ie, prior to the 
administration of the morning doses of the study drugs on the day of the visit. The sampling 
should also begin 24 hours (between 20 and 28 hours) after the morning doses of the study drugs 
that were taken the day prior to the visit.
The subsequent 11 time points include samplings through Hour 12, with the last sample collected 
at Hour 24. The subject will either stay overnight or will return to the clinic so that the final 
sample can be collected at Hour 24.
It is critical to capture the exact date and time of each PK sample collection, even if drawn 
slightly off-schedule. There is no specified collection window end for which any one time point 
should be abandoned as the schedule progresses. If a sample collection time point is missed/late 
and the next collection time point has not yet been reached, collect the missed time point, and 
record the exact time of that collection, then get back on track for the next time point/on-time 
collection.
Table 5.5.1-1 lists the sampling schedule to be followed for the assessment of intensive 
pharmacokinetics. Further details of PK blood collection and sample processing will be provided 
in the central clinical laboratory manual.
Table 5.5.1-1:
AI468048 Intensive Pharmacokinetic Sampling Schedule at Week 2
Time 
(Event)
Time 
(Relative to Dosing)
Hour: Min
PK
Blood Sample
Study Week 2
(window Day 12-16)
0 (morning pre-dose)
00:00
X
1 Hr
01:00
X
2 Hr
02:00
X
2.5 Hr
02:30
X
3 Hr
03:00
X
4 Hr
04:00
X
4.5 Hr
04:30
X
5 Hr
05:00
X
6 Hr
06:00
X
8 Hr
08:00
X
12 Hr
12:00
X
24 hr (morning pre-dose)
24:00
X
5.5.2
Sparse Pharmacokinetic Assessments
All subjects will provide Sparse PK samples (as part of the regular blood collection) for the 
assessment of BMS-955176, ATV, RTV and DTG at visit Weeks 4- 24.
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Of the five visits (Week 4 - 24), it is requested that the following guidelines are followed:

At any one visit Week 4 through Week 24, the Sparse PK sample must be collected 
approximately 24 hours (between 20 and 28 hours) after the dose that was taken the morning 
before and before the morning dose is taken on the day of the visit

At the remaining four visits Week 4 through Week 24, the blood collections may be done 
without any specific consideration to timing of previous dose administration (taken either the 
day before the visit or on the day of the visit), though it is critical that the date and time of the 
most previous dose of study drug is recorded in the eCRF so that the exact interval between 
dose and blood sampling can be calculated for accurate PK analysis
PK Samples need to be tested on an ongoing basis prior to the Week 24 database lock and 
analysis.
5.6
Biomarker Assessments
In this study, BMS is confirming the safety of BMS-955176 demonstrated in the Phase 2a study 
to date. The proposed sample population of treatment-experienced adults in Arms 3, 4, and 5, 
will provide a representation of the potential benefits of BMS-955176 on nucleoside and RTV 
based toxicities of interest (ie, renal toxicity, bone mineral density, and dyslipidemia): Arms 3 
and 4 relative to Arms 1, 2, and 5.
Specifically, to evaluate for renal toxicity we will evaluate clinically relevant parameters and 
biomarkers for glomerular and tubular toxicity, which may include but are not limited to: 
fractional excretion of phosphorous and urinary β2-microglobulin/creatinine, in all available 
subjects. To evaluate for bone-related toxicity, clinically relevant bone biomarkers for both 
formation and resorption will be evaluated in all available subjects. These may include but are 
not limited to: N-terminal Propeptide of Type 1 procollagen (P1NP) and Cross-linked 
C-telopeptide of Type 1 collagen (CTX). The bone and renal biomarkers will be collected and 
measured at time points specified in Table 5.1-2 Additionally, back-up plasma and serum 
samples (at Baseline, Week 24, and Week 48) will be obtained for potential future evaluation of 
the safety of BMS-955176.
Samples will be collected at the screening visit for HIV-1 Gag sequencing, phenotypic 
susceptibility (PhenoSense Gag) and potential pharmacodiagnostic analysis as specified in Table 
5.1-1. These samples may be analyzed, if deemed clinically relevant, as a predictive marker of 
clinical response.
Any remaining blood and urine specimens that are available after completion of the designated 
analyses may be used in the future for identification of potentially predictive or 
pharmacodynamic markers of study drug activity or to enhance the understanding around disease 
biology, except where prohibited by local laws or regulations.
5.7
Outcomes Research Assessments
Increases in CD4 counts and avoidance of opportunistic infections and other AIDS-defining 
illnesses have been shown in many studies to improve health related quality of life (HRQoL). To 
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help assess whether use of BMS-955176 will result in a better quality of life outcome, both a 
disease specific quality of life assessment and a generic quality of life assessment will be 
administered. Disease specific instruments are more sensitive to disease specific changes in 
quality of life and are more likely to show improvement with new interventions. The generic 
instruments are needed because Health Technology Authorities often require use of these 
instruments for cost-effectiveness modeling.
The Functional Assessment of HIV (FAHI) is the disease specific instrument that will be used. 
The FAHI evaluates physical well-being, functional and global well-being, emotional 
well-being/living with HIV, social well-being and cognitive functioning. It yields a total score 
and individual subscale scores.
The EQ-5D-3L is the generic instrument that will be used. The EQ-5D-3L includes two parts: the 
EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L 
descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some 
problems, extreme problems. The EQ VAS records the respondents’ self-rated health on a 
100 point, vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable health 
state’ and ‘Worst imaginable health state.’
5.8
Other Assessments 
We will obtain back-up plasma and serum samples for current/future evaluation of the efficacy, 
safety and tolerability of BMS-955176. 
Should any new safety signal develop during the course of the ongoing analysis of the Phase 2a 
trial, appropriate measures for evaluation and management will be incorporated into the design 
of the Phase 2b trial via a protocol amendment.
5.9
Results of Central Assessments
The following describes the centrally assessed parameters and the timing with which they will be 
shared with investigators, if pertinent. Some parameters are relevant to ongoing subject 
management during the study and will be provided to the site for such purpose, while others are 
not relevant to subject management during the study and results may only be shared in a 
summarized way at the end of the study.

Samples sent to the central lab vendors for safety and efficacy assessments and that are tested 
real time will be provided to the sites as soon as results are available

The results of the read of each ECG will be sent to the site by the central ECG vendor as 
soon as results are available

Samples collected on-treatment for resistance testing will be tested if deemed clinically 
relevant (eg, if the development of resistance is suspected). If tested, results will be reported 
to the site

Other samples (including but not limited to biomarker assessments, exploratory resistance, 
pharmacodiagnostics) may not be tested immediately, and may only be tested if deemed 
clinically relevant. Results may be suppressed from laboratory reports and may not be 
provided to the sites
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
Individual PK results will not be reported to the site; the overall PK assessments will be 
included in the CSR

Individual assessments of the Outcomes research will not be reported to the site; the overall 
Outcomes assessments will be included in the CSR
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning,
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs).
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above).
Examples of such events include, but are not limited to, intensive treatment in an emergency 
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room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization). Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must
be handled as
SAEs. 
(See Section 6.1.1 for reporting pregnancies).
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies:

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason)

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing.
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
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SAEs, whether related or not related to study drug, and pregnancies, must be reported to BMS 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on 
a Pregnancy Surveillance Form (electronic or paper forms). The preferred method for SAE data 
reporting collection is through the eCRF. The paper SAE/pregnancy surveillance forms are only 
intended as a back-up option when the eCRF system is not functioning. In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
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
Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours and in accordance with SAE reporting procedures 
described in Section 6.1.1.
The study drug will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for subject safety).
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important.
All occurrences of overdose must be reported as an SAE (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury in HIV-1 mono-infected subjects is defined as:
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
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2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic
6.7
Other Safety Considerations
Any 
significant 
worsening
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
6.7.1
Toxicity Management
The link to the current grading system for specific AEs and laboratory abnormalities is located in 
Appendix 3 (DAIDS; See Appendix 3).
6.7.1.1
Management of Elevations in Liver Transaminases
The following Table 6.7.1.1-1 summarizes the management of elevations in liver transaminases:
Table 6.7.1.1-1:
Management of Elevations in Liver Transaminases Grade Level of 
AST or ALT Recommendationsa
Grade
Recommendation
Grade1
None
Grade 2
none
Grade 3
Confirm elevation, evaluate for potential causes (including but not limited to alcohol or other 
substance abuse, concomitant medications, reactivation of existing or de novo infection with 
hepatitis viruses) consult with BMS Medical Monitor or designate as soon as possible.
Grade 4
Interrupt all study medications, evaluate for potential causes (including but not limited to alcohol 
or other substance abuse, concomitant medications, reactivation of existing or de novo infection 
with hepatitis viruses), monitor values frequently and consult with BMS Medical Monitor or 
designate as soon as possible. If Grade 4 is deemed related to study medication the subject must 
be discontinued from the study. Otherwise, if reinstitution of study therapy is considered, please 
obtain approval from the BMS Medical Monitor or designate.
a If persisting (> Grade 1/2), evaluate for alternative etiologies, including alcohol use and viral hepatitis
6.7.1.2
Management of Renal Toxicity
Serum phosphate levels and creatinine clearance (CrCl; CCL: as calculated by the Cockcroft 
Gault Equation [see Appendix 4] or eGFR) should be monitored and managed as described in the 
Viread local package insert/label.28 Dose interval adjustments of TDF (Viread) are permitted, as 
described in Section 4.5.2.
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6.7.1.3
Management of Hyperbilirubinemia
Most patients taking ATV experience asymptomatic elevations in indirect (unconjugated) 
bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). Hepatic transaminase 
elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. Dose 
modification of ATV is not permitted. Subjects who experience unacceptable jaundice/scleral 
icterus should be discussed with the BMS Medical Monitor or designate to determine if subjects 
are to be discontinued from study. The investigator must contact the BMS Medical Monitor or 
designate prior to discontinuing any subject due to hyperbilirubinemia.
6.7.1.4
Gastrointestinal Toxicity Evaluation and Management Plan
Pre-clinical toxicology studies in rats and dogs (see Section 1.4.1.2) have suggested a potential 
for GI related toxicity with BMS-955176. This section provides general guidance to the 
Investigator on the evaluation and management of primarily upper gastrointestinal symptoms. 
The Investigator may contact the Medical Monitor to discuss evaluation and management 
(including interruption of ARVs or discontinuation of a subject) of any GI symptoms throughout 
the trial.
Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the foundation of proper 
evaluation and management. The following are potential manifestations of some GI 
clinical syndromes that may occur (possibly in combination) during the clinical 
trial. 
Nausea and Vomiting
The investigator should attempt to identify the etiology of these symptoms (and whether 
it is intraperitoneal, extraperitoneal, medication related, infection related, or due to a 
metabolic disorder).33 Medications can cause nausea and vomiting acutely. 
Dyspepsia
The Investigator should identify the presence of red flags (odynophagia, unexplained 
weight loss, recurrent vomiting, GI bleeding, jaundice, palpable mass or adenopathy, or 
family history of GI malignancy). Symptoms of dyspepsia could include early satiety, 
bloating, or belching. Additionally, atypical symptoms of dyspepsia could include: 
pharyngitis, asthma, bronchitis, hoarseness, chest pain, or abdominal pain. 
Ulcerative Disease
Symptoms suggestive of ulceration often are intermittent over a period of weeks to 
months and may be relieved by eating or antacid use;34 penetrating ulcers become more 
acute with localized pain and may not improve with food.35 The development of 
perforation may be indicated by severe diffuse abdominal pain. 
Other Clinical 
Syndromes
Additional diagnostic criteria for other GI disorders potentially encountered in the 
clinical trial are available elsewhere.36
PHYSICAL 
EXAMINATION
Physical examination should complement elements obtained from the history34
Acutely, the investigator may assess for signs of intravascular volume depletion 
(eg, orthostasis) and/or aspiration of vomitus as appropriate. Abdominal 
tenderness and guarding may indicate inflammation. The presence of fecal blood 
can indicate mucosal damage (eg, from an ulcer). Complete evaluation of dyspepsia 
should include an oral examination (poor dentition or pharyngeal erythema) and 
lungs for wheezing. 
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Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the foundation of proper 
evaluation and management. The following are potential manifestations of some GI 
clinical syndromes that may occur (possibly in combination) during the clinical 
trial. 
DIAGNOSTIC 
EVALUATION 
AND 
MANAGEMENT
A major goal in the diagnostic evaluation of a subject with upper GI symptoms is 
to quickly arrive at a final diagnosis without exposing the subject to unnecessary 
(invasive) testing; Investigators should exercise good clinical judgment35 in this 
regard. A major goal of therapy is directed at correcting the underlying 
identifiable medical or surgical abnormalities. Consultation (eg, gastroenterologist) 
is recommended as clinically indicated.
Grade 1 symptoms
Subjects may be treated symptomatically. If subjects develop dyspepsia alone, generally 
only limited and direct diagnostic testing should be performed.34 If the subject has 
dyspepsia they should limit alcohol, caffeine, chocolate, tobacco, other contributing 
concomitant medications (eg, NSAIDs) and eating directly before bedtime. A variety of 
OTC medications are available to address constipation and diarrhea as indicated. Please 
refer to Appendix 1 for Prohibited and Precautionary Therapies.
Grade 2 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

Serum chemistries and assessment of hemoglobin if not recently performed. 

Testing for Helicobacter pylori

Serologies (eg, celiac disease) 

PCR for viruses (eg, CMV)

Iron panel or Vitamin B12 level
For subjects who develop dyspepsia or are infected with H. pylori the use of H2 
antagonists, PPIs, Sucralfate, and antacids are prohibited (see Appendix 1 Prohibited 
Medications). If such therapy is required, discontinuation from the trial is necessary. 
The use of antiemetic’s (eg, Prochlorperazine) can be utilized as indicated. Management 
should be targeted at addressing the underlying pathology.
Grade 3 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

The testing outlined above in Grade 2

A fasting serum gastrin level can be obtained in cases of known ulcers refractory to 
therapy, a family history of the disease, or when surgery is required; of note, H. 
pylori can increase gastrin levels.35

A barium swallow to detect ulcers 

CT to identify gastrointestinal inflammation and a penetrating or perforated ulcer. 

Upper endoscopy with biopsy as indicated in order to evaluate dyspepsia further 
(eg, mucosal injury, new onset unexplained dyspepsia in subjects > 55 y/o, or the 
presence of red flags).
Management should be targeted at addressing the underlying pathology.
Grade 4 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):
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Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the foundation of proper 
evaluation and management. The following are potential manifestations of some GI 
clinical syndromes that may occur (possibly in combination) during the clinical 
trial. 

The testing outlined above in Grade 2 and Grade 3

An acute abdominal series

If a perforated ulcer is clinically suspected, surgical consultation may be necessary
Initial management can include correction of hemodynamic and electrolyte 
abnormalities as clinically indicated. After stabilization, management should be targeted 
at addressing the underlying pathology.
a For Grade 2-4 symptoms if any ARV is thought to have a direct causal relationship to the patient’s 
gastrointestinal symptoms, the Investigator should consider discontinuing the subject from the study and 
performing an evaluation/management plan incorporating elements above. The Investigator can consider 
interruption of the potential offending ARV(s) but must balance this with the increased probability of 
development of viral resistance/lack of efficacy. As stated above, prior to discontinuing the subject from the 
study, attempts should be made to discuss with the BMS Medical Monitor unless the safety of the subject is 
acutely at risk.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This is an estimation study, without statistical testing, and hence there are no power 
considerations.
It is expected that response rate for the primary endpoint for all five arms will be somewhere 
around 80%. With this response rate, and 40 subjects per arm, an exact 95% confidence interval 
would run from roughly 64% to 91%.
8.2
Populations for Analyses
The following definitions are used in this document:

Enrolled subjects: Subject who signed an informed consent form and were assigned a 
Patient Identification number (PID);

Randomized subjects: Enrolled subjects who received a treatment assignment from the 
IVRS;

Treated subjects: Randomized subjects who received at least 1 dose of BMS-955176 or 
TDF. (Also referred to as the mITT analysis set)
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8.3
Endpoints
8.3.1
Primary Endpoint(s)Stage 1 and Stage 2
The primary endpoint for Stage 1 and Stage 2 is the proportion of subjects with plasma HIV-1 
RNA < 40 c/mL at Week 24. This will be assessed with the FDA snapshot algorithm. This uses 
the last on-treatment plasma HIV-1 RNA measurement, within an FDA-specified visit window, 
to determine response. 
8.3.2
Secondary Endpoint(s)

The antiviral efficacy will be determined by the proportion of subjects with plasma HIV-1 
RNA < 40 c/mL at Weeks 48 and 96 using the FDA snapshot algorithm

The antiviral efficacy will also be assessed by the proportion of subjects with plasma HIV-1 
RNA < 200 c/mL at Weeks 24, 48 and 96 using the FDA snapshot algorithm approach with 
positive response defined as HIV-1 RNA < 200 c/mL

The emergence of HIV drug resistance among samples sent for drug resistance testing will be 
assessed using the most recent version of the IAS-USA list of HIV-1 drug resistance 
mutations

Changes from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the 
percentage of CD4+ T-cells will be assessed using on-treatment laboratory results, and 
pre-specified visit windows

The frequency of SAEs and AEs leading to discontinuation (DC) will be tabulated directly 
from the case report forms (CRFs). The summary will count the number of subjects that have 
at least one event

The occurrence of new AIDS defining events (CDC Class C events) will be tabulated from 
the CRFs. The summary will count the number of subjects that have at least one event

The steady-state plasma PK of BMS-955176 will be assessed using the intensive PK data, 
collected at Week 2 from a subset of subjects
8.4
Analyses
In general, categorical variables are tabulated with counts and percents. Continuous variables are 
summarized with univariate statistics (eg, mean, median, standard error).
Longitudinal analyses use pre-defined visit week windows. Unless otherwise specified, windows 
around planned measurement times are constructed based on the midpoint between planned 
study visits (ie, half the duration of time between study visits), and data are summarized at each 
scheduled visit. 
For the calculation of descriptive statistics of observed data, subjects must have a baseline 
measurement to be evaluable for longitudinal tabulations of parameter values and changes from 
baseline. 
Tabulations of the following endpoints present the number of unique subjects with an event: 
protocol deviations; interruptions of study therapy; non-study medications; adverse events; and 
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laboratory abnormalities. Thus, multiple occurrences of the same event are counted only once 
per subject.
8.4.1
Demographics and Baseline Characteristics
The following demographic and baseline characteristics will be summarized by treatment arm
and overall using the treated subjects:

Demographics: age, race, ethnicity, gender, geographic region;

Disease characteristics at baseline: plasma HIV-1 RNA level, CD4+ T-cell counts and 
percentages, CD8+ T-cell counts, HIV-1 subtype;

Laboratory tests at baseline;

Pre-treatment CDC Class C AIDS events;

Prior medications
8.4.2
Efficacy Analyses
The efficacy analyses will be based on the treated subjects.
8.4.2.1
Primary Efficacy Analyses
The primary efficacy endpoint is the proportion of subjects with plasma HIV-1 RNA < 40 c/mL 
at the Week 24 snapshot within each stage. This endpoint is assessed with the FDA snapshot 
algorithm. The primary analysis will be based on a modified ITT (mITT) approach. A sensitivity 
analysis will be conducted using an observed values approach. The two approaches will be 
implemented as follows:

Modified ITT: The numerator will be based on subjects with plasma HIV-1 RNA < 40 c/mL 
at Week 24. The denominator will be based on all treated subjects

Observed values: Similar to the mITT approach, the numerator will be based on subjects with 
plasma HIV-1 RNA < 40 c/mL at Week 24. However, the denominator will be based on the 
treated subjects with plasma HIV-1 RNA at Week 24
Response rates will be tabulated by treatment arm (within the stage) with exact binomial 95% 
confidence intervals.
Subgroup summaries will be provided to examine the impact of baseline viral load. Subgroup
summaries may be provided to examine the impact of other important covariates such as CD4+ 
count, sex, geographic region, etc.
At Week 24, a Time to Loss of Virologic Response (TLOVR) analysis will be conducted as a
sensitivity analysis that compliments the snapshot analysis. The following definition for 
virologic rebound will be used:
“For subjects that have been confirmed as having reached virologic suppression, by 
having two consecutive HIV-1 RNA readings below the assay limit of detection 
(40 copies/mL), virologic rebound is defined as confirmed HIV-1 RNA levels above the 
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limit of detection. For levels above the limit of detection, confirmation consists of either 
two consecutive readings, or a single reading followed by loss to follow-up.”
8.4.2.2
Secondary Efficacy Analyses
The following secondary endpoints will be summarized by treatment arm:

Proportion of subjects with HIV-1 RNA < 40 c/mL at Week 48 and Week 96 using mITT 
and observed values

Proportion of subjects with HIV-1 RNA < 200 c/mL at Week 24, 48 and 96 using mITT and 
observed values

Change from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the 
percentage of CD4+ T-cells over time

Newly emergent genotypic substitutions (using all on-treatment isolates) will be tabulated by 
treatment arm

The newly emergent phenotypic resistance profile (using all on-treatment isolates) will be 
tabulated by treatment arm
8.4.3
Safety Analyses
The investigators will determine the intensity of adverse events (AEs) and the relationship of 
AEs to study therapy. The investigators’ terms will be coded and grouped by system organ class 
using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) in 
production at BMS. AEs will be presented by system organ class and preferred term. 
Presentations will include both non-serious and serious adverse events, unless specified 
otherwise. If a subject had an adverse event with different intensities over time, then only the 
greatest intensity will be reported.
Deaths will be listed for enrolled subjects without regard to onset.
In analyses of fasting lipids over time, values will be excluded after the start of serum lipid 
reducing agents.
The frequency of the following safety events will be summarized by treatment arm for treated 
subjects:

SAEs

AEs leading to discontinuation of study therapy

AEs by intensity

CDC Class C AIDS events

Laboratory abnormalities by toxicity grade
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8.4.4
Pharmacokinetic Analyses
The following PK parameters will be summarized by treatment arm:

Cmax: maximum observed plasma concentration

Tmax: time of maximum observed plasma concentration

Ctau: observed plasma concentration at the end of a dosing interval (eg, concentration at 
24 hours)

C0: observed pre-dose plasma concentration

AUC(TAU) : area under the concentration-time curve in one dosing interval
8.4.4.1
Sparse Pharmacokinetic Analyses
Sparse pharmacokinetic data will be used in population PK, PK/PD and, as available, PK/VK 
analyses.
8.4.4.2
PK/PD and PK/VK Analyses
PK data obtained from this study will be pooled with data from other studies to perform an 
integrated population PK analysis, exposure-response analyses for selected safety and efficacy 
endpoints, and, as available, viral kinetic modeling of BMS-955176 in combination with other 
ARVs to support the on-going development of BMS-955176. These analyses will facilitate 
optimal dose selection for future Phase 3 studies. 
The population PK, exposure-response, and, as available, viral kinetic analyses, will be reported 
separately.
8.4.5
Biomarker Analyses
Details about the biomarker analyses will be provided in the Statistical Analysis Plan (SAP).
8.4.6
Outcomes Research Analyses
Details about the outcomes research analyses will be provided in the SAP.
8.4.7
Other Analyses (including Virologic Futility)
An analysis of virologic futility will be performed at Week 24 when the last randomized subject 
in Stage 1 completes their Week 24 visit. This analysis will be conducted to evaluate whether the 
BMS-955176 arm shows significantly worse antiviral efficacy (HIV-1 RNA < 40 c/mL using the 
FDA snapshot algorithm) than the TDF-containing arm. The comparison of Arms 1 (containing 
BMS-955176) to Arm 2 (containing TDF) will be made with one-sided, Fisher’s exact tests, 
conducted at the 0.01 probability level.
An analysis of virologic futility will be performed at Week 24 when the last randomized subject 
in Stage 2 completes their Week 24 visit. This analysis will be conducted to evaluate whether a 
BMS-955176 arm shows significantly worse antiviral efficacy (HIV-1 RNA < 40 c/mL using the 
FDA snapshot algorithm) than the TDF-containing arm. The comparison of Arms 3-4
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(containing BMS-955176) to Arm 5 (containing TDF) will be made with one-sided, Fisher’s 
exact tests, conducted at the 0.01 probability level.
8.5
Interim Analyses
There are two interim analyses scheduled before the start of Stage 2.
The first interim analysis will be conducted after approximately 50% of the randomized subjects
have completed 24 weeks of therapy in Stage 1. This analysis will use the BMS equivalent of 
SDTM (Study Data Tabulation Model) data (“level 1” data) to facilitate the development of 
models for: population pharmacokinetics; exposure-response relationships; and, as available,
viral kinetics.
A second interim analysis will be conducted after the last subject has completed 24 weeks of 
therapy in Stage 1. This will be an analysis of the available efficacy, safety, resistance and 
pharmacokinetic data.
The schedule for additional analyses will depend upon the decision to initiate the Stage 2, as well 
as the recruiting time frame of Arms 1 & 2 relative to the time frame for Arms 3, 4, and 5. If 
Stage 2 is initiated, and recruiting follows projected timelines, then it is anticipated that analyses 
will be conducted when:

The last subject in Arms 3, 4, and 5 completes the Week 24 visit

The last subject in Arms 1 and 2 completes the Week 96 visit

The last subject in Arms 3, 4, and 5 completes the Week 96 visit
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
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If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the 
source documents:
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS.
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
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9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include the investigational product 
and the non-investigational product(s). Records or logs must comply with applicable regulations 
and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted)

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
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For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
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contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete Abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Female subjects must continue 
to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to 
forego complete abstinence.
If two forms of contraception is required, Complete abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as complete 
avoidance of heterosexual intercourse is an acceptable form of 
contraception for all study drugs. This also means that abstinence is the 
preferred and usual lifestyle of the patient. This does not mean periodic 
abstinence (eg, calendar, ovulation, symptothermal, profession of 
abstinence for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of contraception. Subjects 
who choose complete abstinence are not required to use a second method 
of contraception, but female subjects must continue to have pregnancy 
tests. Acceptable alternate methods of highly effective contraception must 
be discussed in the event that the subject chooses to forego complete 
abstinence
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11
LIST OF ABBREVIATIONS
Term
Definition
3TC
Lamivudine
AE
adverse event
AI
accumulation index
AIDS
Acquired Immunodeficiency Syndrome
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after the 
first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ARV
antiretroviral
AST
aspartate aminotransferase
ATV
atazanavir
ATV/r
atazanavir boosted with ritonavir
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of 
the last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
BID, bid
bis in die, twice daily
BCRP
Breast cancer reactive protein
BDC
Bile duct-cannulated
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BVM
bevirimat
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Term
Definition
c
copies
c/mL
copies per milliliter
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
CA
capsid
cART
Combination antiretroviral therapy
Cavg
average concentration
Cexpected-tau
expected concentration in a dosing interval
CD
Cluster designation (CD4; CD8)
CDC
Centers for Disease Control
CFC
corrected fold change
CFR
Code of Federal Regulations 
CI
confidence interval
CrCl; CCL
creatinine clearance
CLR
renal clearance
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CMV
cytomegalovirus
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Css,avg
average steady-state plasma concentration
CSR
Clinical study report
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
Trough observed plasma concentration
CT
Computed tomography
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Term
Definition
CTA
clinical trial agreement
CTX
Cross-linked C-telopeptide of Type 1 collagen
CYP
cytochrome p-450
D/C
discontinue
DDI
drug-drug interaction
DHHS
Department of Health and Human Services
dL
deciliter
DTG
dolutegravir
EC
Ethics committee
EC
effective concentration
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EFV
efavirenz
eg
exempli gratia (for example)
E-R
exposure-response
ESR
Expedited Safety Report
ET
Early termination or End of Treatment
EU
European Union
FAHI
Functional Assessment of HIV Infection
FDA
Food and Drug Administration
FDC
Fixed dose combination
FSH
follicle stimulating hormone
FTC
emtricitabine
g
gram
GFR
glomerular filtration rate
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
GSH
glutathione
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Term
Definition
h; hr
hour
HAART
Highly active antiretroviral therapy
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
hepatitis C virus
HCO3-
bicarbonate
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
HS
Human serum
HuSA
Human serum albumin
IAS
International AIDS Society
IB
Investigator brochure
IC
Inhibitory concentration
ICD
International Classification of Diseases
ICF
informed consent form
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
INI
Integrase inhibitor
IP
investigational product
IRB
Institutional Review Board
IU
International Unit
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
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Term
Definition
GALT
Gut associated lymphoid tissue
GI
gastrointestinal
kg
kilogram
L
liter
MAD
multiple ascending dose
MC
micronized crystalline
mg
milligram
MI
Maturation inhibitor
MIC
minimum inhibitory concentration
min
minute
mITT
Modified Intent to Treat
mL
milliliter
mmHg
millimeters of mercury
msec
millisecond
MOA
mechanism of action
g
microgram
M
micromolar
N
number of subjects or observations
N/A
not applicable
ng
nanogram
nM
nanomolar
NIMP
non-investigational medicinal products 
NNRTI
Non- nucleoside reverse transcriptase inhibitor
NOAEL
No observed adverse effect level
NOEL
No observed effect level
NRTI
nucleoside reverse transcriptase inhibitor
NSAID
nonsteroidal anti-inflammatory drug
pDILI
potential drug induced liver injury
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
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Term
Definition
PD
pharmacodynamics
PI
protease inhibitor
PDVF
Protocol-defined virologic criteria
PK
pharmacokinetics
PPI
proton pump inhibitor
PR
atrial depolarization to ventricular depolarization
PT
prothrombin time
PTT
partial thromboplastin time
QC
quality control
QD, qd
quaque die, once daily
QRS
interval representing the time for ventricular depolarization
QT
Duration of ventricular electrical activity
QTcF
QT corrected for heart rate using Frederica’s formula
RAL
raltegravir
RBC
red blood cell
RNA
ribonucleic acid
RTV
ritonavir
SAD
single ascending dose
SDD
spray-dried dispersion
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDTM
Study Data Tabulation Model
SOP
Standard Operating Procedures
SP1
spacer peptide 1
Subj
subject
STR
single tablet regimen
t
temperature
T
time
TDF
tenofovir
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Term
Definition
TDF/FTC
Truvada (TDF 300 mg + FTC 200 mg)
TAO
Trial Access Online, the BMS implementation of an EDC capability
TAM
Thymidine analogue mutation
T-HALF
Half life
T-HALFeff_AUC
Effective elimination half life that explains the degree of AUC 
accumulation observed
Tmax, TMAX
time of maximum observed concentration
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UGT
UDP-glucuronosyltransferase
ULN
upper limit of normal
US
United States
VF
virologic failure
VK
Viral kinetics
VLP
Virus-like particles
WBC
white blood cell
WFD
Wallingford, Connecticut, USA
WHO
World Health Organization
Wk or WK
week
WOCBP
women of childbearing potential
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1
WHO HIV Department. Global Summary of the AIDS Epidemic 2013. Available at: 
http://www.who.int/hiv/data/epi_core_dec2014.png?ua=1 Accessed 12/29/14
2
European AIDS Clinical Society. European Guidelines for treatment of HIV-infected adults 
in Europe (Oct 2013). http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf. 
Accessed Nov 30, 2013.
3
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.
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. 
Accessed 
Nov 30, 2013.
4
United States Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research. Guidance for Industry Human Immunodeficiency 
Virus-1 Infection: Developing Antiretroviral Drugs for Treatment. (June 2013). Revision 1.
5
Study AI468001 Randomized, Double-Blinded, Placebo-Controlled, Single and Multiple 
Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
BMS-955176 in Healthy Subjects. Document Control No. 930071044
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Study AI468002 Randomized, Placebo-Controlled, Multiple-Dose Study to Evaluate the 
Pharmacodynamics, Safety and Pharmacokinetics of BMS-955176 (Double-Blinded) and 
BMS-955176 with Atazanavir +/- Ritonavir (Open-Labelled) in HIV-1 Infected Subjects. 
Draft Document Control No. 930087017
7
Min 
S., 
Sloan 
L., 
DeJesus 
E., 
et. 
al. 
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activity, 
safety, 
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pharmacokinetics/pharmacodynamics 
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dolutegravir 
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10-day 
monotherapy 
in 
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8
Walmsley SL., Antela A., Clumeck N., et. al. Dolutegravir plus abacavir-lamivudine for the 
treatment of HIV-1 infection. NEJM 2013 369(19):1807-18.
9
Raffi F., Jaeger H., Quiros-Roland E., et. al. Once-daily dolutegravir versus twice-daily 
raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week 
results from a randomised, double-blind, non-inferiority trial. Lancet ID. 2013 13(11): 
927-35.
10
Cahn P., Pozniak AL., Mingrone H,. et. al. Dolutegravir versus raltegravir in antiretroviral-
experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, 
double-blind, non-inferiority SAILING study. Lancet 2013 382(9893):700-8.
11
Stellbrink HJ., Reynes J., Lazzarin A., Dolutegravir in antiretroviral-naive adults with 
HIV-1: 96-week results from a randomized dose-ranging study. AIDS 2013 27(11):1771-8.
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Eron JJ., Clotet B., Durant J., Safety and efficacy of dolutegravir in treatment-experienced 
subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING 
Study. JID 2013 207(5): 740-748.
13
Sanne I, Piliero P, Squires K, Thiry A, Schnittman S. Results of a phase 2 clinical trial at 48 
weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at 
three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. 
J Acquir Immune Defic Syndr. Jan 1 2003;32(1):18-29.
14
Bertz RJ, Persson A, Chung E, et al. Pharmacokinetics and pharmacodynamics of atazanavir-
containing antiretroviral regimens, with or without ritonavir, in patients who are 
HIV-positive and treatment-naive. Pharmacotherapy. Mar 2013;33(3):284-294.
15
Molto J, Santos JR, Valle M, et al. Monitoring atazanavir concentrations with boosted or 
unboosted regimens in HIV-infected patients in routine clinical practice. Ther Drug Monit. 
Oct 2007;29(5):648-651.
16
Goutelle S, Baudry T, Gagnieu MC, et al. Pharmacokinetic-pharmacodynamic modeling of 
unboosted Atazanavir in a cohort of stable HIV-infected patients. Antimicrob Agents 
Chemother. Jan 2013;57(1):517-523.
17
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. 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed Nov 
30, 2013.
18
Malan DR, Krantz E, David N, Wirtz V, Hammond J, McGrath D. Efficacy and safety of 
atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy 
regimens in antiretroviral-naive patients. J Acquir Immune Defic Syndr. Feb 1 
2008;47(2):161-167.
19
Landman R, Diallo MB, Gueye NF, et al. Efficacy and safety of unboosted atazanavir in 
combination with lamivudine and didanosine in naive HIV type 1 patients in Senegal. AIDS 
Res Hum Retroviruses. May 2010;26(5):519-525.
20
Gianotti N, Seminari E, Guffanti M, et al. Evaluation of atazanavir Ctrough, atazanavir 
genotypic inhibitory quotient, and baseline HIV genotype as predictors of a 24-week 
virological response in highly drug-experienced, HIV-infected patients treated with 
unboosted atazanavir. New Microbiol. Apr 2005;28(2):119-125.
21
Giuntini R, Martinelli C, Ricci E, et al. Efficacy and safety of boosted and unboosted 
atazanavir-containing antiretroviral regimens in real life: results from a multicentre cohort 
study. HIV Med. Jan 2010;11(1):40-45.
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22
Two Drug Combination Studies with BMS-955176 and HIV Antiviral Agents. Version 1.0. 
June 2013. DCN 930071469
23
Song I., Borland J., Chen S. Effect of atazanavir and atazanavir/ritonavir on the 
pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572. Br. J. 
Pharm. 2011 72(1):103-108
24 BMS-955176 Investigator Brochure, Version 2.0, July 2013 DCN 930056146
25 BMS-955176 Investigator Brochure, Version 3.0, April 17, 2014 DCN 930056146
26 Partial response to FDA “May Proceed” Letter dated 27 Sep 2013 for IND 118,936. Bristol-
Myers Squibb Company; Jan 2014. Document Control No. 930076507 2.0. Insert this 
additional reference: “Evaluation of cross-resistance of HIV-1 Maturation Inhibitor 
BMS-955176 toward HIV-1 protease inhibitor resistant viruses. Bristol-Myers Squibb 
Company; 30-Sept-2014. Document Control No. 930083565.”
27 Evaluation of Cross Resistance of HIV-1 Maturation Inhibitor BMS-955176 Toward HIV-1 
Protease Inhibitor Resistant Viruses. Document Control No. 930083565
28 Gilead 
Sciences. 
Prescribing 
Information 
for 
TDF. 
Available 
at: 
http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/viread/viread_pi.pdf.
Accessed Dec 31, 2014
29
ViiV 
Healthcare. 
Prescribing 
Information 
for 
DTG. 
Available 
at: 
https://www.viivhealthcare.com/media/58599/us_tivicay.pdf. Accessed Dec 31, 2014.
30 BMS. 
Prescribing 
Information 
for 
ATV. 
Available 
at: 
http://packageinserts.bms.com/pi/pi_reyataz.pdf. Accessed Dec 31, 2014
31 AbbVie. 
Prescribing 
Information 
for 
RTV. 
Available 
at: 
http://www.rxabbvie.com/pdf/norvirtab_pi.pdf. Accessed Dec 31, 2014
32 Evaluation of Cross-Resistance of HIV-1 Maturation Inhibitor BMS-955176 Toward HIV-1 
Protease Inhibitor Resistant Viruses. DCN 930083565
33
Hasler WL Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrisons 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill
34
Hasler WL and Owyang C Approach to the Patient with Gastrointestinal Disease. Chapter 
290. Harrisons Principles of Internal Medicine 18th edition. 2012. McGraw Hill
35
Soll AH and Graham DY. Peptic Ulcer Disease. Chapter 40. Textbook of Gastroenterology. 
5th edition. 2009. Blackwell Publishing
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Rome Foundation. Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders. 
Available: http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed 
Dec 22 2014
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APPENDIX 1
LISTINGS OF PROHIBITED AND PRECAUTIONARY
THERAPIES
General Notes: 

Guidelines for the use of drugs with established or other potentially significant drug 
interactions listed in the Package Inserts of the marketed ARV agents used by subjects 
participating in this study (Reyataz, Norvir, Viread, Tivicay) should be followed. 

Medications listed in the Package Inserts as contra-indicated with the other marketed ARV 
agents used by subjects participating in this study are not permitted. 

Any immunizations deemed appropriate by the subject’s physician are permitted provided 
that the immunization is given > 4 weeks from any HIV-1 RNA measurement.

A subject may not be co-enrolled in a concomitant trial unless it is approved by the Medical 
Monitor prior to randomization.
Prohibited Therapies
Drugs that should not be administered throughout the duration of the study:
Anticonvulsants: Carbamazepine, 
Phenobarbital, Phenytoin
Use with ATV may result in decreased ATV concentrations. Use of 
Carbamazepine may result in decreased DTG concentrations.
Oral Antifungals: Itraconazole, 
Posaconazole, and Voriconazole
Use with ATV can result in increased ATV concentrations
Antimycobacterials: Rifampin, 
Rifapentine, Rifabutin
These antimycobacterials decrease ATV plasma concentrations and 
may decrease BMS-955176 plasma concentrations.
St. John’s wort
Use with ATV or DTG may result in loss of antiviral therapeutic effect
GI motility agent: Cisapride
Potential for serious and/or life threatening reactions such as cardiac 
arrhythmias
Pimozide
Potential for serious and/or life threatening reactions such as cardiac 
arrhythmias
Zetia (ezetimibe)
Ezetimibe is a substrate of OATP1B1 (of which BMS-955176 is an 
inhibitor in vitro).
Dofetilide
Use with DTG may result in the potential for increased Dofetilide 
plasma concentrations and the risk for serious and/or life threatening 
events
Alfuzosin
ATV increases Alfuzosin concentrations which can result in 
hypotension
Benzodiazepines: Triazolam and 
Midazolam
ATV can increase the concentration of these Benzodiazepines with the 
potential to increase sedation or respiratory depression
Ergot derivatives: 
Dihydroergotamine, ergotamine, 
ergonovine, methylergonovine
ATV can increase potential for ergot toxicity (e.g. peripheral 
vasospasm)
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HMG-CoA Reductase Inhibitors: 
Lovastatin, Simvastatin, Atorvastatin, 
Pitavastatin, Rosuvastatin, Pravastatin
Use with ATV may result in increased levels of HMG-CoA Reductase 
Inhibitors and potential for serious reactions such as myopathy
Antacids, H2 receptor angatonists, 
Proton Pump Inhibitors, Sucralfate
Use with ATV may result in decreased plasma concentrations of ATV. 
Use of Antacids containing Aluminium, Magnesium, or Calcium may 
result in decreased levels of DTG.
Macrolides: Clarithromycin
Use with ATV may result in increased Clarithromycin levels and QTc 
prolongation
Buprenorphine
Use with ATV may increase levels of Buprenorphine
Quetiapine
Use with ATV may increase levels of Quetiapine
Salmeterol
Use with ATV may result in increased levels of Salmeterol
Avanafil
Use with ATV may result in increased Avanafil levels
All drugs with antiretroviral activity 
other than those considered study 
therapy
Any drugs with antiretroviral activity not considered study therapy 
may interfere with the assessments of the study.
Precautionary Therapies
Drugs that should be administered with caution during the study:
Hormonal Contraceptives
Hormonal Contraceptives cannot be relied upon as a highly effective 
method of contraception. 
See Protocol Section 3.3.1, for more information on Highly Effective 
Methods of Contraception.
Antidepressants: Trazodone, Tricyclic 
Antidepressants (TCA)
Use with ATV/r may result in increased plasma concentrations of 
trazodone and TCA
Antimalarials: Atovaquone/Proguanil, 
Mefloquine
Use with ATV/r may result in decreased Atovaquone/Proguanil levels. 
The effect of Mefloquine on ATV/r is unknown.
Benzodiazepines: Alprazolam and 
Diazepam
ATV can increase the concentration of these Benzodiazepines 
Calcium Channel Blockers
Use with ATV may result in increased concentrations of CCB’s. 
Non-topical Corticosteroids: 
Budesonide, Fluticasone, Prednisone, 
Methylprednisolone, Prednisolone, 
Triamcinolone
Use with ATV/r may result in increased levels of glucocorticoids and 
adrenal insufficiency
Dexamethasone
Use with ATV may result in reduced levels of ATV.
Colchicine
Use with ATV may result in increased Colchicine levels
Metformin
Use with DTG may result in increased levels of metformin. 
A cation-containing (e.g. Magnesium) 
laxative
If used with DTG the laxative should be taken 2 hours before or 6 
hours after taking concomitant laxatives.
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APPENDIX 2
AIDS-DEFINING DIAGNOSES
I.
PARASITIC INFECTIONS
Pneumocystis carinii (PC)
1011
PC pneumonia histologically proven.
1012
PC pneumonia, clinical diagnosis by the following specifications and confirmed HIV 
infection:
A history of dyspnea on exertion or non-productive cough of recent onset (within the past 
3 months).
AND
Chest X-ray evidence of diffuse bilateral interstitial or gallium scan evidence of diffuse 
bilateral pulmonary disease;
AND
Arterial blood gas analysis showing an arterial pO2 of < 70 mmHg or a low respiratory 
diffusing capacity (< 80% of predicted values) or an increase in the alveolar-arterial 
oxygen tension gradient;
AND
Successful response to appropriate therapy and no evidence of pneumonias of other 
etiologies.
1013
Pneumocystis carinii, histologically proven, at a site other than lungs.
Toxoplasmosis (in patients > 1 month old)
1021
Toxoplasmosis, clinical diagnosis (of brain only) by the following specifications and 
confirmed HIV infection:
Recent onset of a neurologic disease consistent with toxoplasmosis;
AND
Brain imaging evidence of a mass lesion (on computed tomography, nuclear magnetic 
resonance of radiography enhanced by injection of contrast medium);
AND
Serum antibody to toxoplasmosis and successful response to therapy for toxoplasmosis.
1022
Toxoplasmosis, of brain or internal organs other than liver, spleen or lymph nodes. 
Proven by microscopy.
Isosporiasis
1031
Isosporiasis causing chronic diarrhea of > 1 month. Proven by microscopy.
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Cryptosporidiosis
1041
Cryptosporidiosis causing chronic diarrhea of > 1 month. Proven by microscopy.
II.
FUNGAL INFECTIONS
Candidiasis
2011
Candidiasis, Esophageal, definitive diagnosis by the following specifications:
Gross inspection by endoscopy or autopsy or by microscopy (histology or cytology) on a 
specimen obtained directly from the tissues affected (including scrapings from the 
mucosal surface), not from a culture.
2012
Candidiasis, Esophageal, presumptive diagnosis by the following specifications and 
confirmed HIV infection:
Recent onset of retrosternal pain on swallowing:
AND
Oral candidiasis diagnosed by the gross appearance of white patches or plaques on an 
erythematous base OR by the microscopic appearance of fungal mycelial filaments in an 
uncultured specimen scraped from the oral mucosa;
AND
Response to appropriate therapy.
2013
Candidiasis, Bronchial/Pulmonary, definitive diagnosis by the following specifications; 
Gross inspection by endoscopy or autopsy or by microscopy (histology or cytology) on a 
specimen obtained directly from the tissues affected (including scrapings from the 
mucosal surface), not from a culture.
Cryptococcosis
2022
Cryptococcosis, Extra-pulmonary, proven by microscopy (histology or cytology), culture 
or detection of antigen in a specimen obtained directly from the tissues affected or a fluid 
from those tissues.
Histoplasmosis
2031
Histoplasmosis, Disseminated (at a site other than or in addition to lungs or cervical or 
hilar lymph nodes), proven by microscopy (histology or cytology), culture or detection of 
antigen in a specimen obtained directly from the tissues affected or a fluid from those 
tissues.
Coccidioidomycosis
2041
Coccidioidoidomycosis, Disseminated (at a site other than or in addition to lungs or 
cervical or hilar lymph nodes), proven by microscopy (histology or cytology), culture or 
detection of antigen in a specimen obtained directly from the tissues affected or a fluid 
from those tissues.
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Coccidioidomycosis, clear reactivation of prior infection, proven by microscopy 
(histology or cytology), culture or detection of antigen in a specimen obtained directly 
from the tissues affected or a fluid from those tissues.
III.
BACTERIAL INFECTIONS
Mycobacterium
3001
Mycobacterium (unidentified species). Presumptive diagnosis, by the following 
specifications and confirmed HIV infection.
Acid fast bacilli (AFB) positive stain of specimen obtained from endoscopic biopsy or 
from a normal sterile site other than lungs, skin or cervical or hilar lymph nodes. Species 
NOT identified by culture.
Mycobacterium tuberculosis
3011
Mycobacterium tuberculosis, Pulmonary, definitive diagnosis proven by culture, without 
evidence of upper respiratory infection symptoms of Mycobacterium tuberculosis that 
could account for the positive culture.
3012
Mycobacterium tuberculosis, definitive diagnosis proven by culture, of at least one extra 
pulmonary site regardless of concurrent pulmonary involvement.
3013
Mycobacterium tuberculosis, Disseminated, definitive diagnosis proven by culture.
Mycobacterium avium intracellulare
3022
MAI in Blood, proven by culture.
3023
MAI Colitis, proven by histology and culture. (This does not include MAI of the stool 
alone).
3024
MAI, Disseminated, at a site other than or in addition to lungs or cervical or hilar lymph 
nodes, proven by culture.
Mycobacterium Kansasii, Mycobacterium Scrofulaceum and Other Atypical 
Mycobacterium
3032
M. Kansasii, in Blood, proven by culture.
3033
M. Kansasii Colitis, proven by histology and culture. (NOT including positive M. 
Kansasii of stool alone).
3034
M. Kansasii, Disseminated, at a site other than or in addition to lungs, or cervical or hilar 
lymph nodes, proven by culture.
3035
M. Scrofulaceum or other Atypical Mycobacterium, proven by culture.
Salmonella
3041
Salmonella, recurrent Bacteremia (non-typhoid), proven by culture.
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IV.
VIRAL INFECTIONS
Cytomegalovirus
4011
CMV, Pneumonitis, pathologically or histologically confirmed. Serum antibody titer and 
culture alone is not sufficient for the diagnosis.
4012
CMV, Esophagitis, as diagnosed by histology, pathology or culture of an esophageal 
lesion. Serum antibody titer and culture of other than esophageal tissue is not sufficient 
for the diagnosis.
4013
CMV, Retinitis as evidenced by a characteristic appearance on serial ophthalmoscopic 
examinations (eg, discrete patches of retinal whitening with distinct borders, spreading in 
a centrifugal manner, following blood vessels, progressing over several months, 
frequently associated with retinal vasculitis, hemorrhage, and necrosis). Resolution of 
active disease leaves retinal scarring and atrophy with retinal pigment epithelial mottling.
4014
CMV, Colitis, as diagnosed by histology, pathology or culture of a colonic lesion. Serum 
antibody titer and culture of other than colonic tissue is not sufficient for the diagnosis.
4015
CMV, Encephalitis, as diagnosed by histology, pathology or culture of brain tissue or 
CSF. Serum antibody titer and culture of other than brain tissue or CSF is not sufficient 
for the diagnosis.
Herpes Simplex (in patients > 1 month old).
4021
HSV, Disseminated (but not encephalitis alone), proven by microscopy (histology or 
cytology), culture or detection of antigen in a specimen obtained directly from affected 
tissues.
4022
HSV, Esophagitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for the diagnosis.
4023
HSV, Bronchitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for the diagnosis.
4024
HSV, Pneumonitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for diagnosis.
4025
HSV, GI, other than mouth, throat, or peri-rectal, as diagnosed by microscopy (histology 
or cytology), culture or detection of antigen in a biopsy specimen obtained directly from 
affected tissue. Serological measurement and culture from other than the affected tissue is 
not sufficient for diagnosis.
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HSV, Mucocutaneous, ulcers persisting for 1 month despite appropriate therapy, as 
diagnosed by microscopy (histology or cytology), culture or detection of antigen in a 
biopsy specimen obtained directly from affected tissue. Serological measurement and 
culture from other than the affected tissue is not sufficient for the diagnosis.
Progressive Multifocal Leukoencephalopathy
4041
Progressive Multifocal Leukoencephalopathy, proven by microscopy.
VI.
NEOPLASTIC DISEASES
Kaposi’s Sarcoma
6011
Kaposi’s sarcoma, Mucocutaneous, proven by microscopy.
6012
Kaposi’s sarcoma. Mucocutaneous, presumptive diagnosis with characteristic gross 
appearance and confirmed HIV infection.
6013
Kaposi’s sarcoma, Visceral.
6014
Kaposi’s sarcoma, other than above.
Lymphoma of the Brain
6021
Primary Lymphoma of the brain at any age, proven by microscopy.
Non-Hodgkins Lymphoma
6031
Small Non-cleaved lymphoma (either Burkitt or non-Burkitt type).
6032
Immunoblastic sarcoma, equivalent to any of the following, although not necessarily all 
in combination: Immunoblastic lymphoma, large-cell lymphoma, diffuse histocytic 
lymphoma.
Cervical Carcinoma
6041
Histologically proven invasive carcinoma of the cervix.
VII.
OTHER CONDITIONS
HIV Dementia/Motor Defects
7011
HIV Dementia, clinical findings of disabling cognitive and/or motor dysfunction 
interfering with occupation or activities of daily living progressing over weeks to months, 
in the absence of a concurrent illness or condition other than HIV infection that could 
explain the findings. Method to rule out such concurrent illnesses and conditions must 
include cerebrospinal fluid examination and either brain imaging (computed tomography 
or magnetic resonance) or autopsy.
Slim Disease or HIV Wasting Syndrome
7021
HIV Wasting Syndrome, findings of profound involuntary weight loss > 10% of baseline 
body weight plus either chronic diarrhea (at least two loose stools per day for 30 days) 
or chronic weakness and documented fever (for 30 days, intermittent to constant) in the 
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absence of a concurrent illness or condition other than HIV infection that could explain 
the findings (eg, cancer, tuberculosis, cryptosporidiosis, or other specific enteritis).
7061
Recurrent pneumonia, acute onset within 12 months of most recent episode.
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APPENDIX 3
DAIDS TOXICITY GRADES
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events
Version 2.0 - November 2014
http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx
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APPENDIX 4
COCKCROFT-GAULT EQUATION TO CALCULATE SERUM 
CREATINE CLEARANCE
Online calculator:
http://nephron.com/cgi-bin/CGSI.cgi
Manual calculation:
Male:
Estimated Creatinine Clearance =
(140-age in years) x Body Weight (kg)
72 x Serum Creatinine (mg/dL)
Female:
Estimated Creatinine Clearance =
(140-age in years) x Body Weight (kg) x 0.85
72 x Serum Creatinine (mg/dL)
1 pound = 0.4536 kilograms
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APPENDIX 5
LABORATORY ASSESSMENTS
HEMATOLOGY
WBC
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
RBC
Hemoglobin
Hematocrit
Platelets
Absolute Differential
CHEMISTRY
Glucose
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
Total Protein
Albumin
CK
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin
AST
ALT
Alkaline Phosphatase
LDH 
Amylase
Lipase
Electrolytes (Sodium, 
Potassium, Chloride, 
Bicarbonate)
Calcium
Phosphorous
Creatinine + eGFR
Uric Acid
BUN
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LIPIDS
Cholesterol
Screening
Day 1, Week 4, Week 12, Week 24
HDL
LDL Calculated
Triglycerides
OTHER SERUM TESTS
FSH
Screening
Optional; upon request
HCG
Optional; upon 
request
Optional; upon request
P1NP
Day 1, Week 12, Week 24, Early Term
CTX
Day 1, Week 12, Week 24, Early Term
URINE
Urine Pregnancy test (if 
positive, request serum HCG)
Screening
Every 4 weeks (either done at in-clinic 
visits, or at home)
Urine Toxicology (drugs of 
abuse)
Screening
Urine Creatinine
Day 1, Week 48, Week 96, Early Term
Urine Phosphorous
2 microglobulin
Macroscopic Urinalysis (no 
microscopic)
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
SEROLOGY
HIV-1 RNA
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
HbSAg
Screening
Week 48, Week 96, Early Term
HCV Ab (if positive, reflex to 
HCV RNA)
Screening
Week 48, Week 96, Early Term
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RESISTANCE
Specimens for HIV 
Resistance testing at 
Monogram
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
Specimens for HIV 
Exploratory Resistance 
testing at BMS
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
PHARMACOKINETICS
Intensive PK
Week 2 (optional)
Sparse PK
Week 4, Week 8, Week 12, Week 16, 
Week 24
IMMUNE PANEL
%CD3+/CD4+
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
%CD3+/CD8+
Absolute CD3/CD4
Absolute CD3/CD8
OTHER
Pharmacodiagnostic (PDx)
Screening
Plasma & Serum Back-ups 
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
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PPD

Page:
1
Protocol Number:
AI468048
IND Number:
118,936
Ex-US
Non-IND
EUDRACT Number
N/A
Date:
28-Jan-2015
Revised Date:
17-Mar-2016
CLINICAL PROTOCOL AI468048
A Phase 2b Randomized, Active-Controlled, Staged, Open-Label Trial to Investigate Safety and 
Efficacy of BMS-955176 in Combination with Dolutegravir and Atazanavir (with or without 
Ritonavir) in Treatment-Experienced HIV-1 Infected Adults
Revised Protocol Number: 03
Incorporates Amendment(s): 07
Study Director/Central Medical Monitor
 DO, MPH
5 Research Parkway
Office 201D
Wallingford, CT  06492 USA
Telephone (office): 
Fax: 
24-hr Emergency Telephone Number
USA:
International: 
Bristol-Myers Squibb Research and Development
Virology Clinical Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
5 Research Parkway
Wallingford, CT 06492
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
PPD
PPD
PPD
PPD
PPD

Clinical Protocol
AI468048
BMS-955176
HIV Maturation Inhibitor
Revised Protocol No.: 03
Date: 17-Mar-2016
2
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.

Clinical Protocol
AI468048
BMS-955176
HIV Maturation Inhibitor
Revised Protocol No.: 03
Date: 17-Mar-2016
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 03
17-Mar-2016
Incorporates Amendment 07
Amendment 07
17-Mar-2016
The primary purpose of this amendment is to broaden the study population 
to reflect the general, treatment experienced HIV-1 infected adults based 
upon feedback from global Principal Investigator participation in 
AI468048. Thus, the study population for AI468048 will now include HIV-
1 infected adults who have documented evidenced of having failed at least 
1 ARV treatment regimen (with or without documented resistance). This 
definition remains consistent with the current overall clinical understanding 
of treatment experienced adults.
In addition, corrections, and modifications have been made to the 
Reproductive Status relative to Inclusion. Previously, two methods of 
contraception were required: one chosen from a list of highly effective 
methods, and a second method that could be highly effective or chosen 
from a list of methods identified as less effective. It is now required that 
male study subjects and WOCBP (females who are either a study subject or 
the sexual partner of a male study subject) must use one highly effective 
method of contraception. Male study subjects must use a condom, not for 
contraceptive purposes, but to prevent potential secondary exposure to 
BMS-955176 from seminal fluid to a WOCBP during any stage of 
pregnancy, even in the very earliest stages of a pregnancy that has not yet 
been positively confirmed. These changes are consistent with the European 
Union 
Clinical 
Trials 
Facilitation 
Group 
(CTFG) 
Guidance, 
“Recommendations related to contraception and pregnancy testing in 
clinical trials.” The contraceptive requirements have also been corrected to 
reduce the length of time during which contraceptive requirements should 
be followed, and to allow the use of IUDs that are either hormonal or 
nonhormonal.
The screening window has been modified to allow for an extension up to 60 
days, but only if awaiting the report of the PhenoSenseGT + Integrase 
resistance results. All other results should be on file by Day 42.
Prior exposure to BMS-955176 has been added to the list of exclusion 
criteria.
Revised 
Protocol 02
03-Jun-2015
Incorporates Amendment 05
Amendment 05
03-Jun-2015
To mitigate the risk of randomizing subjects infected with HIV-1 with an 
unknown efficacy profile, exclusion criteria have been modified to now 
exclude subjects with Clade AE as well as those subjects who have failed a 
previous boosted PI- or Integrase strand transfer inhibitor (INSTI)-
containing regimen for which resistance analyses were not conducted at the 
time of failure. 
To remove “male condoms with spermicide” as a highly effective method 
of contraception (moved to the list of less effective methods) and require 
the use of a highly effective method of contraception as specified in the 
Clinical 
Trials 
Facilitation 
Group 
Recommendations 
Related 
to 

Clinical Protocol
AI468048
BMS-955176
HIV Maturation Inhibitor
Revised Protocol No.: 03
Date: 17-Mar-2016
4
Document
Date of Issue
Summary of Change
Contraception and Pregnancy Testing in Clinical Trials.  Most 
contraception methods were more clearly defined, including the removal of 
any text relative to hormonal methods used by female study subjects who 
are WOCBP, since they can’t be counted among the methods used at all.
Pregnancy was added as a reason to be discontinued from the study, and the 
practice of Rescreening was more clearly defined, an administrative change 
was made to clearly indicate that AIDS History will be taken at Screening,
In addition, at Week 24, a Time to Loss of Virologic Response analysis will 
be conducted as a sensitivity analysis that compliments the snapshot 
analysis, and a definition of virologic rebound was added.
A table of the laboratory assessments in detail was added as an appendix, 
and the appendix of the DAIDS Toxicity Table (updated 2009) was 
removed to include a link to the more current 2014 version of the table. In 
addition, and a table of laboratory assessment was added as a new appendix
Other changes, more administrative in nature, have been included.
Revised 
Protocol 01
19-Mar-2015
Incorporates Amendment 04
Amendment 04
19-Mar-2015
Incorporated information that more clarify the Week 24 data (consisting of 
efficacy, safety, and pharmacokinetic data) to be used to confirm the doses 
for Stage 2 and to trigger the start of Stage 2 of the study relative to other 
analyses conducted under the protocol for other purposes.
Removed the requirement that all Sparse PK samples need to be collected 
as pre-AM dose samplings.  Only one visit Weeks 4- 24 (as opposed to all 
visits Weeks 4 - 24) needs to be performed in the morning and to have the 
blood collected as a pre-AM dose sampling; (includes the deletion of 
Table 5.5.2-1).
Administrative changes.
Original 
Protocol
28-Jan-2015
Not applicable

Clinical Protocol
AI468048
BMS-955176
HIV Maturation Inhibitor
SYNOPSIS
Clinical Protocol AI468048
Protocol Title: A Phase 2b Randomized, Active-Controlled, Staged, Open-label Trial to Investigate Safety and 
Efficacy of BMS-955176 in Combination with Dolutegravir and Atazanavir (with or without Ritonavir) in 
Treatment-Experienced HIV-1 Infected Adults
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Subjects in each arm and per stage will begin QD dosing (in the morning, with a meal) with 
BMS-955176 in combination with atazanavir (ATV) [with or without ritonavir (RTV)] and dolutegravir (DTG), or 
tenofovir (TDF) in combination with atazanavir boosted with ritonavir (ATV/r) and DTG, for a duration of 
96 weeks.
Stage 1:

Arm 1: BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, OR

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Study Phase: 2b
Research Hypothesis: This Phase 2b study will evaluate whether the combination of BMS-955176 with ATV (with 
or without RTV) and DTG is efficacious, safe, and well-tolerated in HIV-1 infected treatment-experienced adults.
Objectives:
Primary Objective Stage 1

To assess the antiviral efficacy of BMS-955176 120 mg and a TDF 300 mg-containing arm, each when given in 
combination with ATV/r 300/100 and DTG 50 mg by determining the proportion of treatment-experienced 
subjects with plasma HIV-1 RNA < 40 c/mL at Week 24 in Stage 1.
Primary Objective Stage 2

To assess the antiviral efficacy of two doses (120 and 180 mg) of BMS-955176, each when given in 
combination with unboosted ATV 400 mg and DTG 50 mg, and to assess the antiviral efficacy of TDF 300 mg 
when given in combination with and ATV/r 300/100 mg and DTG 50 mg by determining the proportion of 
treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at Week 24 in Stage 2. 
Secondary Objectives

To assess the antiviral efficacy of BMS-955176 Arms, and TDF-containing regimens (TDF + ATV/r + DTG), 
by determining the proportion of treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at 
Weeks 48 and 96

To assess the antiviral efficacy of BMS-955176 Arms, and TDF-containing regimens, by determining the 
proportion of treatment-experienced subjects with plasma HIV-1 RNA < 200 c/mL at Weeks 24, 48, 96

To assess the emergence of HIV drug resistance in samples selected for drug resistance testing (according to 
criteria outlined in Protocol Section 5.4.1)
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Clinical Protocol
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
To assess efficacy of BMS-955176 Arms, and TDF-containing regimens, by using the mean changes from 
baseline in log10 HIV-1 RNA, CD4+ T-cell counts, and percentage of CD4+ T-cells

To assess the safety and tolerability of BMS-955176 in treatment-experienced subjects by measuring frequency 
of SAEs and AEs leading to discontinuation

To assess disease progression as measured
by the occurrence of new AIDS defining events 
(CDC Class C events)

To characterize the pharmacokinetics of BMS-955176 when co-administered with ATV (with or without 
ritonavir) and DTG in treatment-experienced HIV-1 infected subjects
Study Design: This is a randomized, active-controlled, staged, open-label clinical trial. Approximately 
200 treatment-experienced subjects total will be randomized into the study. In Stage 1, approximately 80 subjects 
will be randomized 1:1 (approximately 40 per arm) to either of the treatment arms containing BMS-955176 or TDF 
in combination with boosted atazanavir (ATV/r) and DTG. In Stage 2, approximately 120 subjects will be 
randomized 1:1:1 (approximately 40 per arm) to either of the two BMS-955176 treatment arms containing
unboosted ATV and DTG, or to the TDF-containing Arm containing ATV/r and DTG.
Stage 1:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, OR

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, OR

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
A Continuation Dose of BMS-955176 will be selected based on Week 24 data from Stage 1 and from study 
AI468038 (BMS-955176 in ARV treatment-naive HIV-1 infected subjects) with which subjects in Stage 1, Arm 1 
may transition to for the remainder of the study. The transition may occur on or after Week 48.
The data from the Week 24 analysis for AI468038 and Stage 1, including safety, efficacy and pharmacokinetics, will 
be examined to trigger the start of Stage 2 (utilizing unboosted ATV in the experimental arms) and confirm the two 
doses of BMS-955176 (in the experimental arms) for study in Stage 2.
After the Stage 2 Week 24 endpoint, a Continuation Dose of BMS-955176 will be selected based on data from 
Stages 1 and 2, and study AI468-038 with which subjects in Stage 2, Arms 3 and 4 will transition to for the 
remainder of the study. The switch in Stage 2 may occur sooner, between Week 24 and Week 48, or it may be after 
Week 48.
The assigned backbone for each arm, ATV and DTG, or ATV/r and DTG, will remain unaltered throughout the 
study.
All subjects in both stages are expected to receive study treatment for 96 weeks.
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Clinical Protocol
AI468048
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HIV Maturation Inhibitor
Arm 2
TDF
300 mg QD
+ ATV/r + DTG
Day 1
Begin dosing
Arm 3
BMS-955176 
120 mg QD
+ ATV + DTG
1 Virologic Futility will be evaluated at Week 24 
(see Section 8.4.7).  
Results of Week 24 Stage 1 AI468-048 & AI468-038 
Confirm the Start of Stage 2   
Arm 4
BMS-955176 
180 mg QD
+ ATV + DTG
40
40
Week 2
Week 24
Week 24 Analysis1
Intensive PK subset
4 Based on totality of data from both studies the 
Continuation Dose for Arms 3 & 4 may be 
identified.  
Number
Randomized
STAGE 2
Week 96
Week 96 Analysis/End of Study
Week 48
Week 48 Analysis
The Switch to the Continuation Dose4,3     
is expected to occur on or after Week 48, 
but could occur sooner.
Arm 1
BMS-955176 
120 mg QD
+ ATV/r + DTG
Week 2
Number
Randomized
Week 24
Week 24 Analysis1
Day 1
Begin dosing
Intensive PK subset
40
40
Week 48
Week 96
Week 48 Analysis
Week 96 Analysis/End of Study
The Switch to             
the Continuation Dose2,3
may occur on or after 
Week 48 
STAGE 1
BMS-955176
Continuation Dose QD 
+ ATV/r + DTG
Arm 5
TDF
300 mg QD
+ ATV/r + DTG
40
3 The actual switch of subjects of BMS-955176 
subjects to that Continuation Dose may occur when 
all of the subjects have reached at least Week 48 
(though it could occur sooner in Stage 2).
BMS-955176
Continuation Dose QD
+ ATV + DTG
2 Based on Week 24 data from Arms 1 & 2 and 
from AI468-038, the Continuation Dose for 
Arm 1 may be identified.  
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Clinical Protocol
AI468048
BMS-955176
HIV Maturation Inhibitor
Study Population:
Key Inclusion Criteria:

Men and non-pregnant women, at least 18 years of age (or minimum age as determined by local regulatory or as 
legal requirements dictate)

Antiretroviral treatment-experienced, defined as having documented evidence of having failed at least 1 
treatment regimen (with or without documented resistance)

Failure could be due (but is not limited) to cART intolerance, sub-optimal adherence, or an adverse 
event

Screening Plasma HIV-1 RNA 400 copies/mL (An initial, pre-screening value from Investigator must 
demonstrate HIV-1 RNA > 40 c/mL)

CD4+ T-cell count > 50 cells/mm3

Screening genotype/phenotype indicating susceptibility to study drugs (unboosted ATV, FC < 2.2; DTG; TDF)
Key Exclusion Criteria:

Antiretroviral treatment-experienced adults who have failed < 1 ARV regimen

Antiretroviral treatment-experienced adults infected with Clade AE

Subjects who have failed a previous boosted PI- or Integrase strand transfer inhibitor (INSTI)-containing 
regimen for which resistance analyses were not conducted at the time of failure

Resistance or partial resistance to any study drug

Three or more of the following PI mutations, historical or documented: M36I/V, M46I/L/T, G48M/V, 
I54V/L/T/M/A, G73S/A/C/T, V82A/F/T/S/I, or L90M

Any major ATV mutations, historical or documented: I50L, I84V/A, N88D/S

Any major TDF mutation, historical or documented: K65R or T69ins

Three or more of the following non-accessory thymidine analogue mutations (TAMs): M41L, D67N, K70R, 
L210W, T215Y/F, K219Q/E

Any major mutations for raltegravir (RAL), elvitegravir (or clinically suspected INI resistance), historical or 
documented: T66IAK, E92Q, S147G, N155H, Q148H/K/R, Y143C/H/R, E157Q

Chronic HBV/HCV (Positive blood screen for HBsAg; Positive blood screen for HCV Ab and HCV RNA)

ALT or AST > 3 × ULN

Alkaline Phosphatase > 5 × ULN

Bilirubin 1.5 × ULN

History of decompensated cirrhosis or active decompensated cirrhosis

Hemoglobin < 8.0 g/dL

Platelets < 50,000 cells/mm3

Prior exposure to BMS-955176
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for AI468048
Medication 
Potency 
IMP/Non-IMP 
BMS-955176 
60 mg or 120 mga
IMP
Revised Protocol No.: 03
Date: 17-Mar-2016
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Clinical Protocol
AI468048
BMS-955176
HIV Maturation Inhibitor
Study Drug for AI468048
Medication 
Potency 
IMP/Non-IMP 
Tenofovir (TDF)
300 mg
Non-IMP
Atazanavir (ATV)
200 mg and 300 mg
IMP
Ritonavir (RTV)
100 mg
Non-IMP
Dolutegravir (DTG)
50 mg
IMP and Non-IMP, based on country
approval status
a The 180 mg dose of BMS-955176 will be constructed with BMS-955176 60 mg + BMS-955176 120 mg
Study Assessments: Efficacy assessments will include plasma HIV-1 RNA measurements. Safety Assessments will 
include blood chemistry and hematology, ECGs, Physical Exams and Vital Signs, and assessment of non-serious 
AEs, SAEs and AEs leading to discontinuation.
Statistical Considerations:
Sample Size:
This is an estimation study, without statistical testing, and hence there are no power considerations.
It is expected that response rate for the primary endpoint for all five arms will be somewhere around 80%. With this 
response rate, and 40 subjects per arm, an exact 95% confidence interval would run from roughly 64% to 91%.
Endpoints:
Primary Endpoint(s) for Stage 1 and Stage 2
The primary endpoint for Stage 1 and Stage 2 is the proportion of subjects with plasma HIV-1 RNA < 40 c/mL at 
Week 24. This will be assessed with the FDA snapshot algorithm. This uses the last on-treatment plasma HIV-1 
RNA measurement, within an FDA-specified visit window, to determine response
Secondary Endpoint(s)

The antiviral efficacy will be determined by the proportion of subjects with plasma HIV-1 RNA < 40 c/mL at 
Weeks 48 and 96 using the FDA snapshot algorithm

The antiviral efficacy will also be assessed by the proportion of subjects with plasma HIV-1 RNA < 200 c/mL 
at Weeks 24, 48 and 96 using the FDA snapshot algorithm approach with positive response defined as HIV-1 
RNA < 200 c/mL

The emergence of HIV drug resistance among samples sent for drug resistance testing will be assessed using the 
most recent version of the IAS-USA list of HIV-1 drug resistance mutations

Changes from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the percentage of 
CD4+ T-cells will be assessed using on-treatment laboratory results, and pre-specified visit windows

The frequency of SAEs and AEs leading to discontinuation (DC) will be tabulated directly from the case report 
forms (CRFs). The summary will count the number of subjects that have at least one event.

The occurrence of new AIDS defining events (CDC Class C events) will be tabulated from the CRFs. The 
summary will count the number of subjects that have at least one event.

The steady-state plasma PK of BMS-955176 will be assessed using the intensive PK data, collected at Week 2 
from a subset of subjects.
Revised Protocol No.: 03
Date: 17-Mar-2016
9

Clinical Protocol
AI468048
BMS-955176
HIV Maturation Inhibitor
Analyses:
There are two interim analyses scheduled before the start of Stage 2.
The first interim analysis will be conducted after approximately 50% of the randomized subjects have completed 
24 weeks of therapy in Stage 1. This analysis will use the BMS equivalent of SDTM (Study Data Tabulation Model) 
data (“level 1” data) to facilitate the development of models for: population pharmacokinetics; exposure-response 
relationships; and, as available, viral kinetics.
A second interim analysis will be conducted after the last subject has completed 24 weeks of therapy in Stage 1. 
This will be an analysis of the available efficacy, safety, resistance and pharmacokinetic data.
The schedule for additional analyses will depend upon the decision to initiate the Stage 2, as well as the recruiting 
time frame of Arms 1 & 2 relative to the time frame for Arms 3, 4, and 5. If Stage 2 is initiated, and recruiting 
follows projected timelines, then it is anticipated that analyses will be conducted when:

The last subject in Arms 3, 4 and 5 completes the Week 24 visit

At Week 24, a Time to Loss of Virologic Response (TLOVR) analysis will be conducted as a sensitivity 
analysis that compliments the snapshot analysis

The last subject in Arms 1 and 2 completes the Week 96 visit

The last subject in Arms 3, 4 and 5 completes the Week 96 visit
Revised Protocol No.: 03
Date: 17-Mar-2016
10

TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale to support study design ............................................................ 
1.1.2 Rationale to support the dose selection ................................................... 
1.1.3 Rationale to support drug combinations.................................................. 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
1.4.1 Background Information BMS-955176 .................................................... 
1.4.1.1 Mechanism of Action....................................................................... 
1.4.1.2 Nonclinical studies .......................................................................... 
1.4.1.3 Clinical studies................................................................................ 
1.4.2 Background Information on TDF ............................................................ 
1.4.3 Background Information on DTG ............................................................ 
1.4.4 Background Information on ATV ............................................................. 
1.4.5 Background Information on RTV ............................................................. 
1.4.6 Drug-Drug Interactions ........................................................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Screening.................................................................................................. 
3.1.2 Day 1/Baseline Visit ................................................................................. 
3.1.2.1 Day 1/Baseline Visit for Arms 1 and 2 - Stage 1 ............................ 
3.1.2.2 Day 1/Baseline Visit for Arms 3, 4 and 5 - Stage 2 ........................ 
3.1.3 Week 2 Intensive PK Visit ........................................................................ 
3.1.4 Visits Week 4 - 96 ..................................................................................... 
3.1.5 Selection of the Continuation Dose of BMS-955176 ............................... 
3.1.5.1 Selection of the Continuation Dose, and the Switch for Stage 1 .... 
3.1.5.2 Selection of the Continuation Dose, and the Switch for Stage 2 .... 
3.1.6 End of the study ........................................................................................ 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
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3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Instructions for Dose Administration ...................................................... 
4.5.1.1 General Instructions ....................................................................... 
4.5.1.2 Specific Dosing Instructions for Initial Treatment Arm Assignment
...............................................................................................................
4.5.2 Dose Modifications .................................................................................. 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Vital Signs and Physical Examinations ................................................... 
5.3.2 Adverse Events ......................................................................................... 
5.3.3 Concomitant Medication Assessment ...................................................... 
5.3.4 Electrocardiograms ................................................................................. 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.1.1 Guidelines for Confirmatory Testing of Plasma HIV-1 RNA and 
Resistance testing .................................................................................. 
5.4.1.2 Protocol Defined Virologic Failure ................................................ 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.4.2.1 CD4+ and CD8+ T-Cells ............................................................... 
5.4.2.2 Drug Resistance Testing ................................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Intensive Pharmacokinetic Assessment .................................................... 
5.5.2 Sparse Pharmacokinetic Assessments ...................................................... 
5.6 Biomarker Assessments .................................................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
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5.8 Other Assessments ............................................................................................ 
5.9 Results of Central Assessments ........................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
6.7.1 Toxicity Management ............................................................................... 
6.7.1.1 Management of Elevations in Liver Transaminases ....................... 
6.7.1.2 Management of Renal Toxicity ....................................................... 
6.7.1.3 Management of Hyperbilirubinemia ............................................... 
6.7.1.4 Gastrointestinal Toxicity Evaluation and Management Plan ......... 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s)Stage 1 and Stage 2 ................................................. 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Efficacy Analyses .............................................................. 
8.4.2.2 Secondary Efficacy Analyses .......................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.4.1 Sparse Pharmacokinetic Analyses .................................................. 
8.4.4.2 PK/PD and PK/VK Analyses .......................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses (including Virologic Futility) ......................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
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9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 LISTINGS OF PROHIBITED AND PRECAUTIONARY 
THERAPIES ........................................................................................................... 
APPENDIX 2 AIDS-DEFINING DIAGNOSES.......................................................... 
APPENDIX 3 DAIDS TOXICITY GRADES .............................................................. 
APPENDIX 4 COCKCROFT-GAULT EQUATION TO CALCULATE SERUM 
CREATINE CLEARANCE .................................................................................... 
APPENDIX 5 LABORATORY ASSESSMENTS ....................................................... 
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1
INTRODUCTION AND STUDY RATIONALE
1.1
Study Rationale
Despite advances in prevention and care, HIV/AIDS remains a significant epidemic in both the 
US and worldwide. AIDS remains the 6th leading cause of death, internationally. Globally, 
approximately 35 million people were living with HIV infection in 2013.1 A number of these 
patients include those who are treatment-experienced. Note: the use of the term 
“treatment-experienced” herein refers to subjects who have failed at least one or two 
antiretroviral (ARV) regimens and who may be harboring drug resistant virus (current or 
archived) to at least one drug class.
In contrast to current HIV treatment guidelines for treatment-naïve patients, the recommended 
composition of combination
antiretroviral therapy (cART) is far less uniform for 
treatment-experienced subjects.2,3 The level of detail in the DHHS and EACS guidelines leads to 
a lack of uniformity in treatment for patients in later lines of therapy. Moreover, drug related 
toxicities (both short and longer term) in treatment-experienced subjects necessitate vigilance 
and continued monitoring. Thus, there is a need for new and efficacious agents with novel 
mechanisms of action (MOA) and favorable safety/tolerability profiles. Given the aging HIV-1 
infected population and overall fewer number of ARV options for treatment-experienced 
patients, there is a need for a more simplified regimen that may have a better long-term safety 
profile such as that of a nucleoside- and booster-sparing cART regimen. As discussed below, this 
study 
evaluates 
the 
merits 
of 
a 
nucleoside-sparing 
cART 
regimen 
and 
a 
nucleoside/booster-sparing cART regimen in Stage 1 and 2, respectively.
Given the aforementioned challenges with existing treatment in ARV treatment-experienced 
adults, the two primary objectives of this two stage, Phase 2b study are to: 1) To study the 
efficacy of one dose (120 mg) of BMS-955176 (a novel HIV-1 maturation inhibitor) when given 
in combination with atazanavir boosted with ritonavir (ATV/r) 300/100 mg and dolutegravir 
(DTG) 50 mg in Stage 1, and 2) to study the efficacy of two doses (120 and 180 mg) of 
BMS-955176 when given in combination with unboosted ATV 400 mg and dolutegravir (DTG) 
50 mg in Stage 2.
Ultimately this Phase 2b clinical trial will provide supportive data in the context of a therapeutic 
dose of BMS-955176 and the clinical safety/efficacy/resistance of the proposed component(s) of 
a single tablet regimen (STR, that is also a nucleoside/ritonavir sparing ARV strategy) for 
Phase 3 trial development in HIV-1 infected treatment-experienced subjects. Specifically, two 
arms in Stage 2 will contain the individual ARV components of a potential STR: BMS-955176, 
ATV, and DTG.
1.1.1
Rationale to support study design
This Phase 2b open-label clinical trial design is in general agreement with published Food and 
Drug 
Administration 
(FDA)
guidance.4
Initially,
in 
Stage 
1, 
approximately 
80 treatment-experienced HIV-1 infected subjects will be randomized 1:1 (approximately 40 per 
treatment group) to one experimental arm (Arm 1) and a TDF-containing arm (Arm 2). Stage 1
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(see Figure 3.1.6-1) will study the efficacy of one dose (120 mg) of BMS-955176 when given in 
combination with ATV/r (300/100 mg) and DTG (50 mg). At the Week 24 primary endpoint of 
Stage 1, Bristol-Myers Squibb (BMS) will conduct an analysis of efficacy, safety, and 
pharmacokinetics. Combined with the Week 24 primary endpoint of AI468038 (see below), this 
analysis will be used to 1) select a continuation dose for BMS-955176 in Arm 1 of study 
AI468048, 2) trigger the start of Stage 2 (utilizing unboosted ATV in the experimental arms) of 
study in AI468048, and 3) confirm the two doses of BMS-955176 (in the experimental arms) for 
study in Stage 2 of study AI468048 (see below for further details).
AI468038 is a concurrent Phase 2b study in HIV-1 infected treatment naive adults; the primary 
objective is to evaluate three doses of BMS-955176 (60, 120, and 180 mg) and EFV when given 
in combination with TDF/FTC by determining the proportion of subjects with HIV-1 RNA < 40 
c/mL at Week 24.
To mitigate the clinical concerns of a potential subtherapeutic regimen and the subsequent 
development of virologic failure/resistance, the clinical trial design will contain a second stage. 
Specifically in Stage 2, approximately 120 additional treatment-experienced HIV-1 infected 
subjects will begin randomization 1:1:1 (approximately 40 per treatment group) to Arms 3, 4,
and 5 based upon the results of two concurrent analyses:

Results of the Week 24 analysis in Stage 1, including an analysis for virologic futility (see 
Section 8.4.7)

Results of the Week 24 analysis in AI468038 (treatment-naïve HIV-1 infected adults)
Thus, Stage 2 (Arms 3, 4, and 5) will not enroll if the likelihood of a subtherapeutic regimen 
(in Arms 3 and 4) is high based upon the results of the Week 24 analyses from either AI468038 
or Stage 1 of AI468048. Note, subjects in Arm 5 (Stage 2) will receive the same ARV regimen 
as subjects in Arm 2 (Stage 1); Arm 5 in Stage 2 exists to maintain similar baseline demographic 
and clinical characteristics among subjects who are randomized to the three Arms in Stage 2. 
This staged design allows Stage 2 (Arms 3, 4, and 5) to begin recruitment in a clinically 
de-risked fashion and accomplish this study’s Stage 2 primary study objective: to study the 
efficacy of two doses (120 mg and 180 mg) of BMS-955176 when given in combination with 
unboosted ATV 400 mg and DTG 50 mg. Ultimately, the totality of data from the Week 24 
primary endpoint of Stage 2 (Arms 3, 4, and 5), Stage 1 (Arms 1 and 2), and all arms in the 
AI468038 study will be used to select a continuation dose for BMS-955176 in Arms 3 and 4 of 
study AI468048. Across all five arms of this study, subjects will receive treatment with three 
fully-active ARVs (see Section 1.1.3, Rationale to support any drug combinations). Ultimately, 
subjects in experimental Arms 1, 3, and 4 will be given a continuation dose of BMS-955176 
which has acceptable efficacy, safety, and tolerability (see Figure 3.1.6-1) for subsequent 
development in HIV-1 treatment-experienced adults. 
Since the Phase 2a study AI468002 did not include any subjects infected with HIV-1 clade AE
(see Section 1.4.1.3), this multinational Phase 2b trial will not include Clade AE subjects. The 
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study duration is expected to be 96 weeks in length to assess durability of response and longer 
term safety and tolerability.
1.1.2
Rationale to support the dose selection
Phase 1 and Phase 2a clinical trials (AI4680015 and AI4680026) investigating BMS-955176 
utilized a spray-dried dispersion (SDD) suspension. However, this Phase 2b study will utilize a 
micronized crystalline (MC) tablet.
In the concomitant dose-finding Phase 2b study in HIV-1 infected treatment naive adults for 
BMS-955176 (AI468038), doses of BMS-955176 of 60 mg, 120 mg, and 180 mg MC tablet are 
proposed for assessment. These doses are based upon modeling and simulation and formulation 
considerations. A population pharmacokinetic model was developed using single dose 
(10 mg - 120 mg SDD) and multiple dose (10 mg to 80 mg SDD) data in healthy subjects 
(AI468001) as well as multiple dose data in HIV-1 clade B-infected subjects (5 mg to 120 mg
SDD for 10 days, AI468002). An exposure-response analysis was conducted using data from 
Part A of the Phase 2a clinical trial where HIV-1 clade B infected subjects received 
BMS-955176 monotherapy (Dose range: 5 - 120 mg) for 10 days. The exposure-response 
relationship was assessed via an Emax model using observed BMS-955176 steady state Cmin. The 
primary endpoint was predicted maximum viral load decline from baseline.
Steady state BMS-955176 Cmin values in HIV-infected subjects administered MC tablet with 
food were projected according to the following data and assumptions:

Exposures in HIV-infected subjects are 35% less than normal healthy volunteers based on 
observations from AI468001 and AI468002 study

Single dose data projected to multiple dose using accumulation index from AI468001 study

BMS-955176 exposures from the MC tablet formulation with food were projected based on 
studies AI468001 and AI468034. The impact of food on the 60 mg MC tablet dose was 
assumed to be that observed for the 40 mg MC suspension formulation in AI468001. 
Exposures to BMS-955176 120 mg MC tablet with food were determined from observed data 
in Study AI468034, where BMS-955176 C24 increased approximately 70% when 120 mg 
MC tablet was given with a high fat meal, relative to fasted conditions. Finally, exposures to 
BMS-955176 180 mg MC tablet with food were assumed to be 1.5-times that of 120 mg MC 
tablet with food
Figure 1.1.2-1 depicts the simulated maximum viral load decline in HIV-infected subjects 
administered BMS-955176 MC tablet under fed conditions.
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Figure 1.1.2-1:
Simulated Maximum Viral Load Decline from Baseline Under Fed 
Conditions1
1 Solid lines are 10th and 90th percentiles and the median of simulated data, shaded area is the 90% confidence 
interval of simulated data, vertical solid lines are the 25th to 75th percentile of the simulated steady state 
BMS-955176 Cmin for the 60 mg MC tablet dose, vertical dotted lines are the 25th to 75th percentile of the 
simulated steady state BMS-955176 Cmin for the 120 mg MC tablet dose, and vertical dashed and dotted lines 
are the 25th to 75th percentile of the simulated steady state BMS-955176 Cmin for the 180 mg MC tablet dose.
While baseline EC90 was not a covariate included in the model due to the lack of significance; 
this covariate, among others, was considered marginally significant and it is possible this 
covariate will become important with additional data.
Although data from AI468002 Part C (in HIV-1 clade C infected subjects) were not included in 
the exposure-response assessment described above, BMS-955176 doses 40 mg SDD once daily 
demonstrated median maximal reductions in HIV-1 RNA > 1 log10 in both clade B and clade C 
HIV-1-infected subjects (see Section 1.4.1.3); thus, doses of BMS-955176 60 mg, 120 mg, and 
180 mg are expected to yield a similar response in HIV-1 infected subjects of either clade.
Because the lowest dose assessed in AI468038 (BMS-955176 60 mg) has the potential for a 
suboptimal antiviral response and possible development of resistance, BMS-955176 120 mg in 
combination with ATV/r and DTG will be assessed in Stage 1 of this study. Based on previous 
data that demonstrated exposures to BMS-955176 increase approximately 50% when given in 
combination with RTV, exposures to BMS-955176 120 mg given in combination with ATV/r are 
expected to result in exposures similar to BMS-955176 180 mg given without RTV. Finally, 
BMS-955176 180 mg will not be used in Stage 1 because exposures (when administered with 
RTV) are expected to exceed those previously studied in clinical trials.
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Table 1.1.2-1 depicts the projected exposure multiples of BMS-955176 60 mg, 120 mg, and 
180 mg MC tablet with food at the NOAEL for pre-clinical findings of interest.
Table 1.1.2-1:
Exposure Multiples of BMS-955176 at NOAELa
Species/ Study 
NOAEL
Multiples
Dose 
(mg/kg/d)
Exposure
PK 
Parameter
60 mg
120 mg
180 mg
Rat/6-month (stomach 
histologic changes) 
No NOAEL
AUC
---
---
---
Dog/9-month (stomach 
histologic changes) 
1
AUC:
64.9 gh/mL
AUC 
3
2
1
Dog/1-month (heart rate)
20
Cmax:
17.8 g/mL 
Cmax
19
10
5
Dog/ Cardiovascular 
telemetry (heart rate) 
2
Cp:
1.93 g/mL 
Cmax
2
1
0.5
Mouse/EFD 
45
AUC:
197 gh/mL 
AUC
10
6
3
a Exposure multiple = animal value ÷ human value. Projected human Cmax values are 0.94, 1.79, and 3.61 g/mL 
and steady state AUC values are 19.3, 35.8, and 69.2 g•h/mL at 60, 120, and 180 mg in HIV-1 subjects 
receiving BMS-955176 MC tablets with high fat meal, respectively. High fat meal provides the highest exposure 
relative to other meal types or fasted state.
With regard to heart rate and the NOAEL of 1.93 g/mL observed in the cardiovascular 
telemetry study in dogs (N = 2), it is noted that the projected exposure multiple is 1 at a dose of 
120 mg MC tablet in HIV-infected subjects. However, to date, there have been no clinically 
meaningful changes in heart rate observed in subjects treated with BMS-955176 up to 28 days
(in Part B of the Phase 2a study). With regard to stomach histologic changes, no NOAEL could 
be established based on the 6-month rat study and the projected exposure multiples from the 
9-month dog study are relatively low (eg, 2-fold at the 120 mg MC tablet dose). Despite these 
preclinical findings, a dose of BMS-955176 120mg MC tablet will provide exposures in this 
study which are expected to be generally safe and well tolerated based on existing clinical data 
(see Section 1.4.1).
Data from Study AI468034 demonstrated that BMS-955176 120 mg MC tablet AUC increased 
53% when given with a high fat meal, relative to fasted conditions. Furthermore, preliminary 
data from Study AI468049 demonstrated that a light meal, a standard meal, and a high fat meal 
increased BMS-955176 180 mg MC tablet AUC 1.8-, 2.1-, and 2.5-fold, respectively, relative to 
fasted conditions. Taken together, these data suggest that exposures to BMS-955176 MC tablet 
at doses up to 180 mg increase in a linear fashion when given with food and that similar 
exposures are observed regardless of meal type.
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In total, BMS-955176 120 mg is expected to be safe, well-tolerated, and efficacious in Stage 1 
and will inform the selection of a Stage 1 continuation dose and aspects of Stage 2 (as described 
in detail within Section 1.1.1).
The doses of BMS-955176 in Stage 2 will be confirmed based upon the Week 24 analyses
(efficacy, safety, and pharmacokinetics) of both Stage 1 and Study AI468038. As described in 
this protocol, the doses in Stage 2 are proposed to be BMS-955176 120 mg and 180 mg in Arms 
3 and 4, respectively.
1.1.3
Rationale to support drug combinations
This study co-administers BMS-955176, with unboosted ATV 400 mg QD or ATV/r 300/100 mg
QD, and DTG 50 mg. The drug combinations within this clinical trial design will provide 
supportive data in the context of a therapeutic dose of BMS-955176 and the clinical 
safety/efficacy/resistance of the proposed components (Stage 2, Arms 3 and 4) of a single tablet 
regimen (STR) for Phase 3 trial development. Ultimately, BMS will seek approval of 
BMS-955176 for use in treatment-experienced HIV-1 infected adults (including either a STR; 
FDC; and/or monoentity). 
The rationale for using a backbone of ATV and DTG in this treatment-experienced patient 
population is based upon established safety, efficacy, and tolerability of the individual 
components. DTG alone provides a 2.46 log10 c/mL reduction in HIV-1 RNA when administered 
as monotherapy for 10 days.7 Furthermore, DTG has been recently approved and is generally 
safe.8,9,10,11,12 Lastly, ATV/r is often used in treatment-experienced adults’ second-line therapies 
or beyond (for example, in individuals who may have failed an non-nucleoside reverse 
transcriptase inhibitor (NNRTI) and/or integrase inhibitor (INI) based regimen).2,4
This Phase 2b design allows treatment-experienced adults in the experimental arms to be 
exposed to three fully active ARVs (from three classes). Subjects will benefit from each ARV 
(except RTV) independently providing a > 1 log10
c/mL decrease in HIV-1 RNA
(see Section 1.4.1.3 for details on Phase 2a results [AI468002]). BMS expects the combination of 
two agents (unboosted ATV and DTG) with one investigational agent (BMS-955176) to provide 
a generally improved safety/tolerability profile relative to the respective arm containing ATV/r 
(Arms 3 and 4 relative to Arm 1, respectively) or TDF (Arms 3 and 4 relative to Arm 5, 
respectively).
There is a potential risk of a subtherapeutic regimen to treatment-experienced subjects enrolled 
in Arms 3 and 4 since unboosted ATV is only approved for use in treatment-naïve HIV infected 
adults (within the US) and the therapeutic dose of BMS-955176 has not been established.
Unboosted ATV (400 mg) in treatment-naïve adults results in a 1.41 log10 c/mL reduction in 
HIV-1 RNA after two weeks of monotherapy.13 Despite the monotherapy based reduction in 
HIV-1 RNA, pharmacokinetic data of unboosted ATV in prospective clinical trials,14
cross-sectional,15 and retrospective analyses16 generally supports the finding of DHHS defined 
subtherapeutic ATV levels (< 150 ng/mL) in patients.17
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In a randomized, open-label clinical trial, ATV/r has demonstrated non-inferiority to unboosted 
ATV (TLVOR: 75% vs 70% VR-OC: 87% vs 76%, respectively), similar declines in HIV-1 
RNA (approx -3.1 log10 c/mL), and increase in CD4 cell counts within treatment-naïve adults. 
However, the unboosted ATV arm had an increased number of subjects with emerging ATV and 
lamivudine (3TC) resistance. In particular, the difference in nucleoside/nucleotide reverse 
transcriptase inhibitor (NRTI) resistance was markedly greater in the unboosted ATV compared 
to RTV boosted ATV arm.18 Of note, in this clinical trial (AI468048) NRTIs are not used in the 
experimental Arms 1, 3, and 4. Similar single arm, prospective studies have replicated the viral 
efficacy and immunologic response using unboosted ATV in treatment-naïve HIV infected 
adults.19
Insights from limited data regarding the use of unboosted ATV in treatment-experienced adults 
have demonstrated a viral decay ranging from -1.4 to -2.7 log10 c/mL over 24 weeks of therapy 
in combination with NRTIs (such as TDF, 3TC, and didanosine).20 Also, observational data 
(mean: 24 months of follow-up) has shown similar percentages of subjects with their last HIV 
RNA being undetectable (80% vs 83%) after receiving unboosted and RTV boosted ATV, 
respectively.21
Taking the key findings from studies of ATV in both treatment-naïve and treatment-experienced 
HIV infected adults, Arms 3 and 4 containing unboosted ATV may have the potential for 
increased resistance (relative to Arm 1 containing RTV boosted ATV) and the development of 
virologic failure. However, several other factors must be taken into consideration. First, these 
Arms will use three potent (> 1 log10
c/mL) ARVs in combination. Moreover, 
treatment-experienced subjects who have failed one or two prior regimens are likely to be either 
naïve to ATV treatment (prior NNRTI- and/or INI-class failure) or will need to be fully 
susceptible to approved ARVs (including unboosted ATV, see Section 3.3.2). Second, both the 
combination of ATV and DTG with BMS-955176 independently have demonstrated additivity to 
synergy in-vitro22 (see Section 1.4.1.3 for clinical data on the combination of ATV and 
BMS-955176). Third, unboosted ATV increases the geometric mean ratio of Ctrough for DTG by 
a factor of 2.8.23 Fourth, in normal healthy volunteers, multiple dose administration of 
BMS-955176 40 mg (SDD suspension formulation) with ATV 400 mg for 14 days resulted in an 
approximate 25% increase in the AUC(TAU) of BMS-955176 administration alone24 and 
preliminary PK data from the Phase 2a (AI468002) demonstrated that BMS-955176 AUC(TAU) 
increased approximately 37% and 52% when ATV was combined with BMS-955176 40 and 
80 mg (SDD suspension formulation), respectively, relative to administration of BMS-955176 
alone. It is clinically unclear whether higher exposures of DTG and BMS-955176 would lead to 
a decreased incidence of unboosted ATV resistance in the context of Arms 3 and 4 
(BMS-955176 120 and 180 mg + ATV + DTG). Combined with these factors, BMS proposes to 
mitigate the potential risk of increased resistance by 1) studying two doses of BMS-955176 
(120 and 180 mg) in combination with unboosted ATV and DTG, and 2) using a two stage 
clinical trial design with Stage 2 (Arms 3, 4, and 5) enrolling after the Week 24 analysis
(efficacy, safety, and pharmacokinetics) of Stage 1 (Arms 1 and 2) and AI468038 are completed, 
and 3) only enrolling subjects who are susceptible to study medication (including unboosted 
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ATV), (see Section 1.1.1, Rationale to support study design). This risk mitigation is employed to 
decrease the probability of exposure to a subtherapeutic regimen and increase the probability of 
establishing clinical efficacy (number of responders at the Week 24) in treatment-experienced 
HIV-1 infected adults.
BMS expects BMS-955176 120 and 180 mg given with unboosted atazanavir to be generally 
safe and well-tolerated. Subjects in Arms 3 and 4 treated with unboosted ATV would potentially 
benefit from a more favorable lipid profile, fewer gastrointestinal (GI) side effects, and 
decreased indirect hyperbilirubinemia. In total, the potential clinical risks for subjects 
randomized to Arms 3 and 4 in Stage 2 do not outweigh the potential benefits of a Nucleoside-
and Booster-sparing cART regimen that may offer both efficacy and long-term safety (including 
but not limited to improved bone mineral density, improved renal function, and improved lipid 
profile). Please see Section 1.5 for further details on the overall risk/benefit assessment.
1.2
Research Hypothesis 
This Phase 2b study will evaluate whether the combination of BMS-955176 with ATV (with or 
without RTV)
and DTG
is efficacious, safe, and well-tolerated
in HIV-1 infected 
treatment-experienced adults.
1.3
Objectives(s)
1.3.1
Primary Objective
Primary Objective Stage 1

To assess the antiviral efficacy of BMS-955176 120 mg, and a TDF 300 mg-containing arm,
each when given in combination with ATV/r 300/100 mg and DTG 50 mg by determining 
the proportion of treatment-experienced subjects with plasma HIV-1 RNA < 40 c/mL at 
Week 24 in Stage 1.
Primary Objective Stage 2

To assess the antiviral efficacy of two doses (120 and 180 mg) of BMS-955176, each when 
given in combination with unboosted ATV 400 mg and DTG 50 mg, and to assess the 
antiviral efficacy of TDF 300 mg when given in combination with ATV/r 300/100 mg and 
DTG 50 mg by determining the proportion of treatment-experienced subjects with plasma 
HIV-1 RNA < 40 c/mL at Week 24 in Stage 2. 
1.3.2
Secondary Objectives

To assess the antiviral efficacy of BMS-955176 arms, and TDF-containing regimens (TDF + 
ATV/r + DTG), by determining the proportion of treatment-experienced subjects with plasma 
HIV-1 RNA < 40 c/mL at Weeks 48 and 96

To assess the antiviral efficacy of BMS-955176 arms, and TDF-containing regimens, by 
determining the proportion of treatment-experienced subjects with plasma HIV-1 RNA 
< 200 c/mL at Weeks 24, 48, 96
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
To assess the emergence of HIV drug resistance in samples selected for drug resistance 
testing (according to criteria outlined in Sections 5.4.1.1 and 5.4.1.2)

To assess efficacy of BMS-955176 arms, and TDF-containing regimens, by using the mean 
changes from baseline in log10 HIV-1 RNA, CD4+ T-cell counts, and percentage of CD4+ 
T-cells

To assess the safety and tolerability of BMS-955176 in treatment-experienced subjects by 
measuring frequency of SAEs and AEs leading to discontinuation

To assess disease progression as measured by the occurrence of new AIDS defining events 
(CDC Class C events)

To characterize the pharmacokinetics of BMS-955176 when co-administered with ATV 
(with or without ritonavir) and DTG in treatment-experienced HIV-1 infected subjects
1.3.3
Exploratory Objectives

To determine the effect of BMS-955176 arms, and TDF-containing regimens, on renal 
clinical parameters and biomarkers through Weeks 48 and 96

To determine the effect of BMS-955176 arms, and TDF-containing regimens, on bone 
biomarkers through Weeks 12 and 24

To assess the impact of baseline (pre-therapy) Gag polymorphisms on the efficacy of 
BMS-955176 by determining the proportion of treatment-experienced subjects with plasma 
HIV-1 RNA < 40 c/mL, HIV-1 RNA < 200 c/mL, and the changes from baseline in log10
HIV-1 RNA at Weeks 24, 48 and 96, by baseline polymorphisms

To characterize the steady-state plasma PK of DTG when co-administered with BMS-955176 
and ATV (with or without RTV) in treatment-experienced subjects. The effect of 
BMS-955176 on DTG PK in the presence of ATV (without RTV) may be assessed relative to 
historical data

To compare steady-state exposures of DTG when co-administered with BMS-955176 and 
ATV/RTV to DTG when co-administered with TDF and ATV/RTV

To characterize the PK of ATV when co-administered with DTG and BMS-955176, with or 
without RTV

To explore PK/PD and PK/viral kinetic (VK) relationships between BMS-955176, ATV, 
and/or DTG exposure and both efficacy and safety endpoints

To assess the impact of the study therapies on health-related quality of life measures
1.4
Product Development Background
1.4.1
Background Information BMS-955176
1.4.1.1
Mechanism of Action
BMS-955176 is an HIV-1 maturation inhibitor (MI), a novel class of anti-HIV-1 drugs that 
prevents the maturation of HIV-1 virions by binding near a key structural element within the Gag 
polyprotein that is required for virion maturation and assembly. Maturation inhibitors block the 
last protease cleavage event between Gag protein segments designated as capsid (CA) protein 
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p24 (p24) and spacer peptide 1 (SP1), resulting in the release of immature noninfectious virus 
particles. BMS-955176 has excellent potency and broad spectrum activity, and mechanism of 
action studies indicate that BMS-955176 is a true MI, with a mechanism of action distinct from 
current antiretroviral agents.25 Development of BMS-955176 could potentially lead to novel 
HIV-1 treatment regimens in treatment-experienced HIV-1 patients.
1.4.1.2
Nonclinical studies
Nonclinical Pharmacology and Microbiology
BMS-955176 specifically inhibits HIV-1 protease cleavage at the CA(p24)/SP1 junction within 
the Gag protein in both HIV-1-infected cells and purified HIV-1 Gag virus-like particles (VLPs). 
Radiolabeled BMS-955176 specifically binds to purified HIV-1 Gag VLPs, and its binding is 
dose-dependently inhibited by related MIs and is reversible. BMS-955176 does not directly 
inhibit HIV-1 protease nor bind to a small HIV-1 protease peptide substrate. These results 
indicate that BMS-955176 inhibits late in the HIV-1 life cycle by specific binding to immature 
capsid structures at or near the CA(p24)/SP1 junction, thereby inhibiting cleavage at that 
particular site. In cell culture, the range of values for the concentration producing 50% effect 
(EC50) of BMS-955176 against 7 common laboratory strains of HIV-1 was 1.6 to 10.5 nM 
(mean = 6.0 3.5 nM). Using a reverse transcriptase readout, a phenotyping analysis of 
93 subtype B viruses whose genotypes are representative of 96% of the diversity (found in the 
Los Alamos National Laboratory [LANL] database) in Gag sequences indicates that the mean 
EC50 of this cohort was 2.7 1.9 nM, with a median value of 2.2 nM and a range between 0.6 to 
12 nM. A similar analysis of 23 isolates of subtype C viruses found a mean EC50 of 
6.1 3.1 nM, a median value of 5.6 nM, and a range from 2.5 to 16 nM. When evaluated against 
clinical isolates in peripheral blood mononuclear cells (PBMCs), BMS-955176 exhibited a mean 
EC50 of 24 24 nM against a cohort (N = 22) of subtype B viruses. Activity was also observed 
against viruses from subtypes A, C, D, F, and G, with average EC50 values for 96% of tested 
isolates (N = 41) between 5.9 and 87 nM. Clinical isolates from the CRF01_AE subtype were 
approximately 2- to 3-fold less susceptible to BMS-955176 (average EC50 77 nM, N = 7) 
viruses. BMS-955176 was active against 1 of 3 human immunodeficiency virus type-2 (HIV-2)
isolates (EC50 = 15 nM). BMS-955176 retains complete activity against reverse transcriptase 
(RT), protease, and integrase inhibitor-resistant viruses, with EC50 values similar to wild-type 
(wt) viruses, while the potency of currently approved nucleotide/nucleoside reverse transcriptase 
inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors 
(PIs), and integrase inhibitors (INIs) was undiminished when tested against viruses with reduced 
susceptibility to BMS-955176. BMS-955176 maintained activity against a panel of PI-resistant 
isolates from PI-treated subjects harboring a variety of major and minor PI-resistance
determinants in both protease and Gag.26,27 Protein binding to 100% human serum (HS) was 
86%, and in the presence of 40% HS supplemented with additional human serum albumin 
(HuSA) to match physiologic concentrations, BMS-955176 exhibited an approximately 4-fold 
reduction of antiviral activity. Selection for resistance to BMS-955176 in cell culture identified
changes that map to amino acids adjacent to the CA(p24)/SP1 cleavage site. These include an 
amino acid substitution of A364V or a combination of V362I with secondary changes (V370A, 
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A374P or I376V). In vitro, virus with the A364V change exhibited a drastic loss of susceptibility 
to BMS-955176 (>100-fold), while the V362I plus secondary change-containing viruses were 
generally less sensitive to BMS-955176 (median EC50 25 nM, range 7.1 to 167 nM). In 2-drug 
combination studies with representative drugs from NRTI, NNRTI, PI, and INI classes, all 
combinations produced additive to synergistic effects, suggesting that BMS-955176 should be 
amenable for use in combination with any of these agents.
Bevirimat (BVM), a first-generation MI, demonstrated proof of concept and dose-dependent 
anti-HIV-1 potency in both Phase 1 and Phase 2 clinical studies. Patients infected with HIV-1 
sensitive to BVM demonstrated an approximate 1.2 log10 decline in HIV-1 RNA. However, 
approximately 50% of patients harboring naturally occurring polymorphisms located close to the 
CA(p24)/SP1 cleavage site showed a significantly reduced response to BVM treatment. In 
addition, BVM exhibited a large reduction in antiretroviral activity in the presence of human 
serum. BMS-955176 was developed to address the key flaws of BVM by providing improved 
coverage of BVM-resistant polymorphic variants and improved potency in serum. BMS-955176 
has been shown to be active against viruses with resistance from all marketed ARVs, and to 
possess a low serum effect. Development of BMS-955176 could potentially lead to novel HIV-1 
treatment regimens in treatment-experienced HIV-1 patients.
Nonclinical Pharmacokinetics
The absolute oral bioavailability of BMS-955176 was low (3.89% to 26.8%) in all preclinical 
species (mice, rats, dogs, and monkeys). In the dog, though there was a positive food effect and 
no pH dependent absorption, upon repeat dosing a less than dose-proportional increase in 
exposure was observed. BMS-955176 distributed preferentially into the duodenum, liver, and 
lymph nodes with little penetration into the brain. Protein binding was 86.1% in human serum 
and 78% to 94% in animal sera
In human in vitro systems, the metabolism of BMS-955176 was primarily mediated via 
cytochrome P450 (CYP)3A4. In vivo in rats, dogs, and monkeys, BMS-955176 was the 
predominant drug-related component in plasma following a single oral dose of BMS-955176. 
BMS-955176 was eliminated principally via metabolism followed by excretion in bile with little 
renal excretion. 
In vitro, BMS-955176 was an inhibitor of CYP2C8 (concentration at which 50% inhibition 
observed [IC50] = 28.5 M), CYP3A4 (IC50 = 32 M), and uridine diphosphate 
glucuronosyltransferase (UGT)1A1 (IC50 = 20 M) enzymes. No P-gp inhibition or 
time-dependent inhibition of CYPs was observed. BMS-955176 was not an inducer of CYP1A2, 
CYP2B6, or CYP3A4. The steady state Cmax of BMS-955176 180 mg tablet in HIV-infected 
patients with food is projected to be approximately 5.2 M. Thus, the potential exists for 
BMS-955176 to inhibit CYP2C8, CYP3A4, and/or UGT1A1 in vivo and increase exposures to 
co-administered drugs that are metabolized by these enzymes. Furthermore the potential exists 
for drug-drug interactions (DDI) if BMS-955176 is co-administered either with an inhibitor or 
inducer of CYP3A4 or P-gp.
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BMS-955176 was a substrate of mouse P-glycoprotein (P-gp) based on higher bioavailability in 
P-gp knock-out mice when BMS-955176 was co-administered with elacridar, a potent inhibitor 
of P-gp and breast cancer resistance protein (BCRP). BMS-955176 could not be reliably assessed 
as a substrate for human P-gp due to nonspecific binding and low solubility. In vitro, 
BMS-955176 inhibited organic anion transporting polypeptide (OATP)1B1 and OATP1B3 
(IC50 5.3 and 4 M, respectively), but was not an inhibitor of P gp, sodium taurocholate 
cotransporting polypeptide (NTCP), organic anion transporter (OAT)1, OAT3, multiple 
drug-resistance protein (MRP)2, and bile salt export pump (BSEP). These findings suggest a 
potential for DDI between BMS-955176 (as the perpetrator) and substrates of OATP1B1 and 
OATP1B3, but not with those of P-gp, NTCP, OAT1, OAT3, MRP2, and BSEP. Furthermore, 
the potential exists for drug-drug interactions (DDI) if BMS-955176 is co-administered either 
with an inhibitor or inducer of CYP3A4 or P-gp. Preliminary data indicate that BMS-955176 
does not inhibit OCT2, a transporter that is inhibited by dolutegravir (DTG), a drug with which
BMS-955176 is planned to be co-administered.
Nonclinical Toxicology
The toxicity profile of BMS-955176 was evaluated in single- and repeat-dose toxicity, 
genotoxicity, phototoxicity, safety pharmacology, sensitization, reproductive toxicity and 
embryo-fetal development studies. The scope of the toxicologic evaluation for BMS-955176
supports its proposed clinical use for HIV-1 infection. Unless otherwise mentioned, all animal 
studies were dosed by the oral route with an aqueous methylcellulose suspension of a 
BMS-955176 spray-dried dispersion (SDD). 
BMS-955176 was not phototoxic, mutagenic, or clastogenic in vitro and was not genotoxic in a 
rat micronucleus assay at 300 mg/kg/day (AUC 279 g·h/mL). BMS-955176 was not a skin 
sensitizer in the local lymph node assay in the mouse. BMS-955176 had a low potential (IC50 or 
EC50 > 5 M [> 3.45 µg/mL]) for in vitro off-target interactions on a broad range of enzymes, 
transporters, and receptors, including cardiac ion channels. 
In safety pharmacology evaluations in rats, there were no respiratory findings and no direct 
central nervous system (CNS) findings. Decreases in motor activity, arousal, and rearing were 
considered secondary to general toxicity (ie, body weight decreases).
Cardiovascular safety pharmacology evaluations were conducted in rabbits, rats, and dogs. In the 
definitive oral single-dose cardiovascular safety study in conscious telemeterized dogs, blood 
pressure and electrocardiogram were was unaffected at 20 mg/kg; however, increases in heart 
rate (mean 33% to 57% of pretest vehicle) were observed at 8 and 20 mg/kg. The increase in 
heart rate at these doses was primarily due to increases in 2 dogs at each dose that had higher 
plasma concentrations (12.83 g/mL) relative to the dogs without effects on heart rate 
(6.81 g/mL). The no-observed-effect level (NOEL) for cardiovascular effects in dogs was 
2 mg/kg (plasma concentration of 1.93 µg/mL). Importantly, there was no change in heart rate at 
20 mg/kg/day at higher plasma concentrations (Cmax 17.8 µg/mL) in the 1-month study in 
dogs (below). 
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Taken together, BMS-955176 has low potential for respiratory, CNS, and cardiovascular effects 
and no cardiovascular effects have been observed in humans to date.
Two-week, 1-month, and 6-month studies were conducted in rats. As the 2-week study was of 
limited scope, only the 1-month and 6-month studies are presented in this summary. 
BMS-955176 was administered for 1 month at doses of 30, 100, or 300 mg/kg/day. While there 
was no mortality at 100 mg/kg/day, the high dose of 300 mg/kg/day was associated with 
pronounced signs of clinical toxicity and early euthanasia of all the rats at that dose level on 
Days 8 to 9. The dose of 30 mg/kg/day was tolerated. The intermediate dose of 100 mg/kg/day 
(AUC 357 g·h/mL) resulted in dose-limiting toxicity including persistent reduction in food 
consumption and body weights. A number of minor hematology (including red cell parameter 
changes with no consistent effect on the erythron) and serum chemistry changes (including 
increased alkaline phosphatase and alanine aminotransferase) without correlating histologic liver 
findings) occurred at 30 and 100 mg/kg/day; these changes were considered not adverse due to 
small magnitude, occurrence only in 1 sex, and lack of microscopic correlates, and most were 
secondary to decreases in food consumption and body weight. Dose-related gastrointestinal 
toxicity was primarily characterized by morphologic changes in the stomach at 100 mg/kg/day 
and the stomach and small and large intestines at 300 mg/kg/day. At the end of the 2-week 
postdose recovery period, there was complete recovery of all BMS-955176-related findings at 
30 mg/kg/day. At 100 mg/kg/day, all findings recovered with the exception of increased red cell 
distribution width in females, minimally higher (1.94×) ALT activity in 1 male without any 
histologic correlates, and decreased mean prostate gland (with seminal vesicles) weights. The 
low dose of 30 mg/kg/day (AUC 113.5 g·h/mL) was considered the no-observed-adverse-effect 
level (NOAEL) because the body weight and food consumption changes were minimal and 
transient and there were no BMS-955176-related morphologic changes.
In a 6-month oral toxicity study in rats with 1-month recovery period, BMS-955176 was 
administered at doses of 10, 25, or 50 mg/kg/day. BMS-955176-related effects were similar to 
those observed in the 1-month rat study and occurred at all doses (10 mg/kg/day; 
AUC 71 gh/mL). Findings included decreased body weight, food consumption, and in the 
stomach, minimal to marked atrophy involving both parietal and chief cells, minimal to mild 
single-cell necrosis and minimal regeneration in the glandular mucosa, which were partially 
reversible at the end of the 1-month recovery period. A NOAEL was not established in this 
study.
Five-day, 1-month, and 9-month repeat-dose studies were conducted in dogs. As the 5-day 
toxicokinetics and tolerability studies were of limited scope, only the 1-month and 9-month
studies are presented here. In the 1-month study, BMS-955176 was administered at doses of 2, 8, 
or 20 mg/kg/day. Increased incidences of sporadic vomiting and liquid, yellow, and/or mucoid 
feces occurred at all doses, but had no apparent effect on the overall health of these animals. 
At 20 mg/kg/day, additional findings included occasional decreases in food consumption in a 
few animals, loss of body weight (up to 8%) in 2 females, a minimal increase in serum ALT 
activity (2.10× pretest) in 1 female with no microscopic correlates, and minimal single-cell 
necrosis of stomach glandular epithelium. All BMS-955176-related changes were fully 
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reversible by the end of the 2-week recovery period. The dose of 8 mg/kg/day was considered a 
NOAEL (AUC 219.5 g·h/mL) since the sporadic clinical observations had no adverse effects 
on the general health of the animals and there were no BMS-955176-related morphologic 
changes. 
In a 9-month oral toxicity study in dogs with 1-month recovery period, BMS-955176 was 
administered at 0 (vehicle), 1, 3, or 10 mg/kg/day. BMS-955176-related effects were similar to 
those observed in the 1-month dog
study
and
occurred at doses 3 mg/kg/day 
(AUC 135 gh/mL). Findings included salivation (only males at 10 mg/kg/day), fur thinness 
(males), thin appearance, and abnormal feces (yellow, liquid, pale and/or mucoid) that occurred 
sporadically throughout the study; increases in mean food consumption; minimal to marked chief 
cell depletion in the glandular stomach. Additional findings at 10 mg/kg/day included thin 
appearance that correlated with decreases in body weight in food consumption; occasional 
vomitus in males; in the stomach, minimal to moderate mucous cell hyperplasia (often associated 
with glandular dilatation) correlating with increased thickness macroscopically (males only) and 
minimal to marked parietal cell depletion and single-cell necrosis of glandular epithelial cells; 
and increases in serum gastrin values (1.31 to 4.56× highest control value) for several dogs that
may have reflected the reductions in gastric parietal cells. The NOAEL was 1 mg/kg/day 
(AUC 64.9 gh/mL).
The embryo-fetal development (EFD) studies were conducted in 3 species (rabbits, rats, and 
mice) instead of the standard 2 species due to poor maternal tolerability and inability to achieve 
adequate systemic exposures in rabbits.
In a definitive EFD study in pregnant mice, BMS-955176 was administered at doses of 15, 45, or 
150 mg/kg/day from gestation day (GD) 6 through 15. BMS-955176 was a selective 
developmental toxicant in mice. Dose of 100 mg/kg/day was associated with an increase in 
embryo-fetal lethality (cumulative postimplantation losses of 11.5%, relative to 3.9% in control 
litters, attributed to increased incidences of dead fetuses, early resorptions and late resorptions). 
Cleft palate and exencephaly were observed in a few fetuses; additionally, marginal reductions in 
fetal body weight (5% relative to control values) were observed. There was no maternal toxicity 
at any dose tested. The developmental NOAEL was 45 mg/kg/day (AUC 213 g·h/mL).
In a definitive EFD study in pregnant rats, BMS-955176 was administered at doses of 10, 30, or 
100 mg/kg/day from GD 6 through 15. BMS-955176 was not a selective developmental toxicant. 
Developmental toxicity (reduced fetal body weights, increases in fetal alterations, and reduced 
fetal ossification) occurred only at 100 mg/kg/day; whereas, maternal toxicity (clinical 
observations, reduced body weights, and reduced food consumption) was observed at 
30 mg/kg/day. The developmental NOAEL was 30 mg/kg/day (AUC 114 gh/mL). 
In an EFD study in pregnant rabbits, BMS-955176 was administered at a dose of 80 mg/kg/day 
from GD 7 through 19. BMS-955176 was not a developmental toxicant in rabbits at 
80 mg/kg/day (AUC 3.26 gh/mL), at which reductions in maternal food consumption and 
weight gain were observed.
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In the fertility and early embryonic development study in rats, BMS-955176 was evaluated at 
doses of 10, 30, or 100/60 mg/kg/day in males and females. BMS-955176 did not affect 
reproduction or early embryonic development at doses 100 mg/kg/day that produced overt 
toxicity. The reproductive NOAEL was 100/60 mg/kg/day (AUC 210 g•h/mL) in male rats and
100 mg/kg/day (AUC 458 g•h/mL) in female rats.
Overall, results from the nonclinical toxicology studies demonstrate that BMS-955176 has a low 
potential for cardiovascular effects, is toxic to the gastrointestinal tract, and is a selective 
developmental toxicant. Clinical monitoring of vital signs (heart rate, systolic and diastolic blood 
pressure) and for gastrointestinal adverse events (AEs) (eg, nausea, vomiting, diarrhea, or fecal 
changes), along with screening for potential renal tubular injury, have not indicated any potential 
for these AEs in Phase 1 or proof of concept (POC) studies in humans. Clinical protocols will 
ensure that appropriate contraceptive measures will be followed to minimize the risk of 
pregnancy while enrolling women of child-bearing potential (WOCBP) males subjects who are 
sexually active with (see Section 3.3.1 Inclusion Criteria).
1.4.1.3
Clinical studies
Phase 1
The safety, tolerability, and PK of BMS-955176 were evaluated in a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD, 10-120 mg) and multiple ascending 
dose (MAD, 10-80 mg QD for 14-28 days) study in healthy subjects (AI468001). No SAEs, 
deaths, or discontinuations related to study drug occurred. No clinically meaningful trends were 
observed in vital signs, physical exam findings, laboratory values, or ECGs. Following 
single-dose and multiple-dose administration of BMS-955176, a slightly less than 
dose-proportional increase in Cmax and AUC(INF) was observed over the dose ranges studied. 
Steady state was reached in approximately 7 days following multiple-dose once daily 
administration of BMS-955176. The half life (T-HALF) of BMS-955176 is approximately 
35 hours. 
Study AI468034 assessed the relative bioavailability and dose proportionality of BMS-955176 
MC tablet - the formulation that will be used in the current study. Relative to 80 mg SDD 
suspension, the bioavailability of BMS-955176 120 mg MC tablet was approximately 23% 
lower. Furthermore, consistent with the low solubility of BMS-955176, considerable overlap in 
exposures was observed between 60 mg, 120 mg and 180 mg MC tablet, when given under 
fasted conditions. The impact of food on exposures to BMS-955176 120 mg MC tablet was 
assessed in Study AI468034 as well; a high fat meal increased BMS-955176 AUC approximately 
50% with negligible impact on BMS-955176 Cmax.
Study AI468049 assessed the impact of a light meal, a standard meal, and a high fat meal on the 
PK of BMS-955176 180 mg MC tablet. Preliminary results demonstrate that, relative to fasted 
conditions, BMS-955176 Cmax is increased approximately 2-fold with all three meal types, while 
BMS-955176 AUC increased approximately 1.8-, 2.1-, and 2.5-fold with a light meal, a standard 
meal, and a high fat meal, respectively. These results, taken together with those from AI468034 
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described above, demonstrate that the impact of food on exposures to BMS-955176 is 
dose-dependent with the degree of impact increasing with increasing dose. Preliminary safety 
results from AI468049 indicate that GI adverse events (eg, nausea, vomiting, loose stools) only
occurred in the fed arms (where the BMS-955176 exposures were higher) relative to the fasted 
arms.
Study AI468049 assessed the impact of a light meal, a standard meal, and a high fat meal on the 
PK of BMS-955176 180 mg MC tablet. Preliminary results demonstrate that, relative to fasted 
conditions, BMS-955176 Cmax is increased approximately 2-fold with all three meal types, while 
BMS-955176 AUC increased approximately 1.8-, 2.1-, and 2.5-fold with a light meal, a standard 
meal, and a high fat meal, respectively. These results, taken together with those from AI468034 
described above, demonstrate that the impact of food on exposures to BMS-955176 is 
dose-dependent with the degree of impact increasing with increasing dose.
Phase 2a
A randomized, double-blind, placebo-controlled proof of concept study in HIV subjects has 
completed enrollment and is undergoing analysis (AI468002). The three parts of this study were: 
1) Part A evaluated doses of 5, 10, 20, 40, 80, and 120 mg of BMS-955176 (SDD suspension) 
given for 10 days in HIV-1 clade B infected subjects, 2) Part B compared the antiviral activity of 
BMS-955176 (SDD suspension) administered with ATV (with or without RTV) against standard 
of care (TDF + FTC + ATV/r) for 28 days in HIV-1 clade B infected subjects, and 3) Part C 
evaluated BMS-955176 40 and 120 mg (SDD suspension) given for 10 days in HIV-1 clade C 
infected subjects. See Table 1.4.1.3-1 for baseline demographics. 
Preliminary results from the Phase 2a study (AI468002) in HIV-1 (clade B and C only) infected 
adults showed that at effective doses, a maximum median reduction in HIV-1 RNA ranging from 
1.3 to 1.7 log10 was observed. In the Phase 2b study BMS-955176 doses estimated to provide 
similar exposure to effective doses in the Phase 2a study will be used. Moreover, when 
BMS-955176 was combined with ATV RTV, these combinations resulted in maximum median 
declines in HIV-1 RNA ranging from 1.9 to 2.2 log10 (see Table 1.4.1.3-2). These results are 
generally similar to the antiviral effect demonstrated by other classes of ARVs in short-term
monotherapy trials, and thus BMS-955176 should contribute substantially with other ARVs to 
form an effective cART regimen. Lastly, preliminary safety data show acceptable safety and 
tolerability across all Phase 2a arms. Most AEs were Grade 1-2 and were most frequently due to 
an indirect hyperbilirubinemia; the levels seen with BMS-955176 and ATV/r were similar to 
those seen with ATV/r combined with TDF/FTC. The arms containing BMS-955176 and 
unboosted ATV had bilirubin levels that were approximately half of those observed in the arms
containing ATV/r. Last, arms containing BMS-955176 alone did not show elevated bilirubin
levels. Many of these events occurred in subjects who were randomized to an arm containing 
BMS-955176 and ATV. Of the Grade 2-4 related AEs, many were due to headache and an 
increase in hyperbilirubinemia. Many of the AEs of hyperbilirubinemia occurred in subjects also 
receiving ATV.
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Table 1.4.1.3-1:
Phase 2a Baseline Demographics and Characteristics of Subjects 
(Preliminary Results)
Treatment Arm
Subjects
(n)
Median 
age
Male
White
Median 
HIV 
RNA 
(log10
c/ml)
Median 
CD4 
(cells/mm3)
Part A (Clade B, 10 days 
monotherapy)
BMS-955176 5 mg
8
43.5
8 (100)
6 (75.0)
4.09
437
BMS-955176 10 mg
8
39
7 (87.5)
7 (87.5)
4.02
539
BMS-955176 20 mg
8
33
8 (100)
8 (100)
3.59
512
BMS-955176 40 mg
8
38
8 (100)
8 (100)
4.03
536
BMS-955176 80 mg
8
31.5
8 (100)
8 (100)
3.82
504
BMS-955176 120 mg
8
37.5
8 (100)
8 (100)
3.84
498
Placebo
12
36
12 
(100)
12 
(100)
3.98
458
Part B (Clade B, 28 days therapy)
BMS-955176 40 mg + ATV 400 mg
8
32.5
8 (100)
6 (75)
4.04
581
BMS-955176 40 mg + ATV 300 mg + 
RTV 100 mg
8
34
8 (100)
8 (100)
4.45
480
BMS-955176 80 mg + ATV 400 mg
8
31.5
8 (100)
7 (87.5)
4.15
549
Truvada® + ATV 300 mg + RTV 
100 mg
4
32.5
4 (100)
4 (100)
4.12
427.5
Part C (Clade C, 10 days 
monotherapy)
BMS-955176 40 mg
7
35
4 (57.1)
2 (28.6)
4.53
554
Placebo
2
38.5
2 (100)
0 (0)
3.78
304
Table 1.4.1.3-2:
Maximum Decline Log10 HIV-1 RNA (Preliminary Results)
Treatment 
Mean 
S.D. 
Median 
Max
Min
Part A (Clade B, 10 days monotherapy)
BMS-955176 5 mg
-0.49
0.217
-0.498
-0.78
-0.22
BMS-955176 10 mg
-1.05
0.351
-0.976
-1.76
-0.64
BMS-955176 20 mg
-1.17
0.645
-1.115
-2.12
-0.13
BMS-955176 40 mg
-1.55
0.352
-1.701
-1.88
-0.93
BMS-955176 80 mg
-1.52
0.257
-1.555
-1.82
-1.04
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Table 1.4.1.3-2:
Maximum Decline Log10 HIV-1 RNA (Preliminary Results)
Treatment 
Mean 
S.D. 
Median 
Max
Min
BMS-955176 120 mg
-1.53
0.478
-1.654
-2.07
-0.83
Placebo
-0.48
0.581
-0.381
-1.46
0.56
Part B (Clade B, 28 days therapy)
BMS-955176 40 mg + ATV 400 mg
-1.89
0.273
-1.858
-2.37
-1.49
BMS-955176 40 mg + ATV 300 mg + RTV 100 
mg
-2.22
0.676
-2.202
-3.52
-1.24
BMS-955176 80 mg + ATV 400 mg
-2.3
0.307
-2.228
-2.68
-1.87
Truvada® + ATV 300 mg + RTV 100 mg
-2.41
0.495
-2.39
-3.04
-1.83
Part C (Clade C, 10 days monotherapy)
BMS-955176 40 mg
-1.5
0.439
-1.285
-2.03
-1.04
Placebo
0.12
0.141
0.12
0.02
0.22
The pharmacokinetics of BMS-955176 were assessed in HIV-1 infected subjects in AI468002. 
Overall, exposures to BMS-955176 are approximately 30% to 35% lower in HIV-1-infected 
subjects compared to healthy subjects administered the same doses and formulation of 
BMS-955176. Furthermore, exposures to BMS-955176 increased in a generally linear fashion up 
to 40 mg, with a less than dose proportional increase in exposures between 40 mg and 80 mg, 
and considerable overlap in exposures between 80 mg and 120 mg.
1.4.2
Background Information on TDF
Tenofovir disoproxil fumarate (TDF) is an analog of the nucleotide adenosine 
5’-monophosphate. TDF inhibits HIV-1 reverse transcriptase and is indicated in combination 
with other ARVs for the treatment of HIV-1 infection. The most common adverse reactions 
include rash, diarrhea, headache, pain, depression, asthenia, and nausea. Clinicians are warned 
about new onset or worsening renal impairment, decreases in bone density, and immune 
reconstitution syndrome. For more information concerning TDF, please refer to the 
TDF/Viread® SmPC or TDF/Viread® USPI.28
1.4.3
Background Information on DTG
Dolutegravir (DTG) is a HIV-1 integrase strand transfer inhibitor indicated in combination with 
other ARVs for the treatment of HIV-1 infection. The most common adverse reactions of 
moderate to severe intensity include insomnia, fatigue, and headache. Clinicians are warned 
about immune reconstitution syndrome. For more information concerning DTG, please refer to 
the DTG/Tivicay SmPC or the DTG/Tivicay USPI.29
1.4.4
Background Information on ATV 
Atazanavir is a protease inhibitor indicated for use in combination with other ARVs for the 
treatment of HIV-1 infection. The most common adverse reactions include nausea, 
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jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral 
neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. Clinicians are warned 
about hyperbilirubinemia, nephrolithiasis, and cholelithiasis. For more information concerning 
ATV please refer to the ATV/Reyataz® SmPC or ATV/Reyataz® USPI.30
1.4.5
Background Information on RTV
Ritonavir is a protease inhibitor indicated in combination with other ARVs for the treatment of 
HIV-1 infection. The most frequently reported adverse drug reactions with RTV alone or in 
combination with other ARVs include diarrhea, nausea, vomiting, abdominal pain, paresthesia, 
rash, and fatigue/asthenia. Clinicians are warned about total cholesterol and triglyceride 
elevations. For more information concerning RTV please refer to the RTV/Norvir® SmPC or 
RTV/Norvir® USPI.31
1.4.6
Drug-Drug Interactions
In AI468001, coadministration of BMS-955176 as a single dose following two doses of 100 mg 
RTV resulted in an approximate 48% increase in BMS-955176 AUC(INF), consistent with 
inhibition of CYP3A4 and/or P-gp. Multiple-dose administration of BMS-955176 with daily 
400 mg ATV and a standard meal for 14 days resulted in a modest (~25%) increase in the 
BMS-955176 AUC(TAU).
Study AI468005 assessed the two-way interaction between BMS-955176 40 mg (administered as 
an SDD suspension) and TDF at steady state in healthy subjects. Relative to administration of 
each drug alone, neither BMS-955176 nor TDF exposures were meaningfully impacted upon 
coadministration.
Study AI468041 assessed the impact of BMS-955176 80 mg (administered as an SDD 
suspension) on the pharmacokinetics of the components of a combined oral contraceptive 
containing ethinyl estradiol (EE) and norgestimate (NGM). Exposures to both EE and 
norelgestromin (NGMN), the active metabolite of NGM were reduced in the presence of 
BMS-955176. Furthermore, one subject had a serum progesterone level > 300 ng/dL while 
BMS-955176 and the oral contraceptive were concomitantly administered, indicative of 
ovulation and contraceptive failure.
Finally, in vitro data suggest that BMS-955176 may inhibit OATP1B1 and OATP1B3 and 
exposures to substrates of these transporters, such as HMG-CoA reductase inhibitors, may 
increase when co-administered with BMS-955176.
1.5
Overall Risk/Benefit Assessment
The preclinical and clinical safety data demonstrate that BMS-955176 administered at doses in 
this Phase 2b study (120, and 180 mg) should be well tolerated without a major clinically 
relevant impact on safety. Moreover, there have been no identified safety risks from 
completed/ongoing clinical studies to date.
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The preclinical toxicology studies demonstrate two potential risks to subjects:
First, BMS-955176 is a selective developmental toxicant. Developmental toxicity (skeletal 
alterations in rats; cleft palate and reduced fetal body weights in mice) were observed in 
embryofetal development studies. In order to address this concern, subjects will be required to 
use two methods of contraception (as described in Section 3.3.1 Inclusion Criteria) and undergo 
routine urine pregnancy testing (as described in the T&E Tables in Section 5.1). Furthermore, 
due to results from Study AI468041 that demonstrates reduced exposures to the components of a 
combination oral hormonal contraceptive containing ethinyl estradiol and norgestimate when 
given concomitantly with BMS-955176, oral hormonal contraceptives cannot be used as a 
method of contraception by WOCBP in this study.
Second, single or repeat oral doses of BMS-955176 were associated with sporadic vomiting in 
dogs and unformed and/or liquid feces in rats and dogs. In rats at 10 mg/kg/day there were 
decreases in body weight and food consumption; in the stomach there was atrophy involving 
both parietal and chief cells, single-cell necrosis and regeneration in the glandular mucosa, and 
modest increases in serum gastrin values. At higher doses (100 mg/kg/day) in rats there were 
additional findings in the intestines (distended jejunum, ileum, and cecum; hyperplasia of the 
crypt epithelium in the jejunum; ulcers and erosions in the cecum; and decreased mucosal cell 
extrusion and increased mucus in the colon). 
Similar gastric changes were seen in dogs. At 20 mg/kg/day there was single-cell necrosis of the 
stomach glandular epithelium. At 3 mg/kg/day gastric changes showed chief cell depletion. 
At 10 mg/kg/day changes in the stomach included: mucous cell hyperplasia correlating with 
increased thickness macroscopically, parietal cell depletion, single-cell necrosis of glandular 
epithelial cells, and modest increases in serum gastrin values. Unlike the rats, no changes were 
observed elsewhere in the alimentary canal including the gastroesophageal junction and the 
duodenum. There was no evidence of macrocytosis. Measurement of Total Protein and Albumin 
revealed no clinically relevant changes. The stomach histologic findings were BMS-955176 
dose- and duration dependent. In the 1-month studies, vomiting and fecal changes stopped soon 
after dosing cessation, and microscopic lesions in the stomach and/or intestines reversed 
completely within a 2-week treatment-free period. In the 6 month study in rats and the 9-month 
study in dogs, microscopic lesions in the stomach partially recovered after a 1 month treatment 
free period. The NOAEL was 1 mg/kg/day (AUC 64.9 mg•h/mL) in the 9-month study in dogs, 
and was not established in the 6-month study in rats. Investigative studies for gastric toxicity in 
rats and dogs indicated similar findings with both SDD and MC forms, and with no clear 
evidence that the gastric toxicity is a direct local effect of BMS-955176. The mechanism and 
clinical relevance of these gastrointestinal findings is unknown at present (see below).
A Phase 1 study (AI468001) in healthy volunteers evaluated single and multiple doses of 
BMS-955176 for 14-28 days both alone and in certain arms, in combination with ATV or RTV. 
Overall the safety data demonstrated that BMS-955176 was generally safe and well tolerated. 
A Phase 2a (AI468002) study in HIV-1 infected adults evaluated several doses of BMS-955176 
given alone or in combination with ATV RTV for 10-28 days. The preliminary results show 
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acceptable safety and tolerability across all arms. There were no deaths, SAEs, or AEs leading to 
discontinuation. There were no clinically relevant changes in vital signs, lab parameters, or 
EKGs. Most of the AEs were Grade 1-2 and were most frequently due to hyperbilirubinemia 
(primarily observed in treatment arms with ATV). Of the GI AEs, most were attributable to 
diarrhea or loose/watery stools. Many of these events occurred in subjects who were randomized 
to an arm containing BMS-955176 and ATV. Of the Grade 2-4 related AEs, many were due to 
headache and an increase in hyperbilirubinemia. Many of the AEs of hyperbilirubinemia 
occurred in subjects also receiving ATV; moreover, the three arms with the highest average total 
bilirubin occurred in subjects receiving both BMS-955176 and ATV. Clinical changes/symptoms 
consistent with the GI findings from dogs and rats (described above) were not seen in the 
preliminary data set from short-term therapy with BMS-955176 in HIV-1 infected adults. 
In this treatment-experienced study population, we estimate GI safety multiples of 2× and 1×, 
(based on NOAEL in 9-month dog study), corresponding to projected human exposures at 
BMS-955176 doses of 120 and 180 mg.
While no clinically relevant GI safety signals have been observed in AI468001 or AI468002, in 
this clinical trial, subjects will undergo routine targeted and complete history/physical exams in 
addition to regular laboratory measurements (including CBC and chemistries). This will initially 
occur more frequently than in standard clinical practice and allow for increased vigilance for any 
potential GI toxicity. Guidance on the evaluation and management of potential GI toxicity is 
outlined in Section 6.7.1.4.
Subjects in this clinical study will benefit from receiving cART potentially containing 
BMS-955176. Preliminary data from the Phase 2a (Part A, B and C) study show a maximum 
median reduction in HIV-1 RNA (clades B and C) ranging from 1.3 to 1.7 log10 in the dose arms 
estimated to provide similar exposure to those in this current study. When BMS-955716 was 
combined with ATV RTV (Part B) this resulted in maximum median declines in HIV-1 RNA 
ranging from 1.9 to 2.2 log10. These results are generally similar to the antiviral effect 
demonstrated by other classes of ARVs. Thus, BMS-955176 should contribute with other ARVs 
substantially to form an effective cART regimen.
As with any antiretroviral study in HIV-1-infected subjects, there is a risk for the development of 
treatment failure and the development of drug resistance associated mutations to BMS-955176 
and/or other antiretrovirals. However, drug resistance to the maturation inhibitor would not be 
anticipated to result in cross-resistance to any other ARV class, including protease inhibitors.32
Ongoing analysis of preliminary data from the Phase 2a study is evaluating both emergent 
genotypic and phenotypic changes after short term monotherapy with BMS-955176. The use of 
three fully susceptible agents as a part of cART is expected to decrease the probability of 
virologic failure and drug resistance. Initially in this clinical trial, measurement of HIV-1 RNA 
will occur more frequently than in standard clinical practice which will allow for increased 
vigilance for the development of lack of efficacy/resistance. Finally, an analysis for virologic 
futility will occur at Week 24 (see Section 8.4.7).
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As described earlier, treatment-experienced adults enrolled in Arms 3-4 may be exposed to a 
subtherapeutic regimen and may be at higher risk for virologic failure and the development of 
resistance. In order to decrease this probability, this clinical trial uses a two-stage design 
whereby enrollment in Arms 3-5 will be dependent upon the results of the Week 24 analyses
(efficacy, safety, and pharmacokinetics) in Stage 1 and Study AI468038. This will minimize the 
risk of virologic failure and resistance to subjects enrolled in Arms 3-4 because clinical data will 
already have been generated using BMS-955176 with ATV/r (Arm 1) in Stage 1.
Of note, the other ARVs used in this clinical trial have a known and acceptable risk benefit ratio 
and are frequently prescribed to HIV-1 infected adults as a part of standard of care.
Taken together, the clinical data to date show that BMS-955176 has potent antiretroviral activity 
and is generally safe and well tolerated in healthy volunteers and HIV-1 infected adults. These 
factors should allow subjects to benefit from achieving viral suppression whilst taking a 
generally safe and well-tolerated new antiretroviral; additionally subjects in Arms 1, 3, and 4 
may benefit from a cART regimen that is nucleoside and nucleoside/booster sparing, 
respectively. Specifically, these subjects may benefit from improved bone mineral density, renal 
function, and lipid profiles. The risks, including teratogenicity, GI toxicity, and drug resistance, 
will be appropriately managed by following guidance in the study protocol.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
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investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion.
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented.
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The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a randomized, active-controlled, staged, open-label clinical trial. Approximately 
200 treatment-experienced HIV-1 subjects will be randomized to one of five treatment arms
(approximately 40 per arm) in a staged fashion.
The data from the Week 24 analysis of Stage 1 and AI468038, including safety, efficacy and 
pharmacokinetics, will be examined to trigger the start of Stage 2 and confirm the two doses of 
BMS-955176 for study in Stage 2.
Stage 1:
In Stage 1, subjects will be randomly assigned 1:1 to one of two treatment arms and on Day 1 
will begin dosing with:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:
In Stage 2, subjects will be randomly assigned 1:1:1 to one of three treatment arms and on Day 1 
will begin dosing with: 

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
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3.1.1
Screening
The screening period begins with the subject’s signature on the informed consent form (ICF).
The subject is then enrolled via the Interactive Voice Response System IVRS (or its web-based 
equivalent) See Section 4.4.
If the subject meets all eligibility criteria, the subject must be randomized within the 42 day 
screening period.*
* If, within the 42-day screening window, the resistance results have not yet been reported, the 
screening window may be extended up to 60 days for only these results.
3.1.2
Day 1/Baseline Visit
3.1.2.1
Day 1/Baseline Visit for Arms 1 and 2 - Stage 1
In Stage 1, approximately 80 subjects will be randomized 1:1 (approximately 40 per arm) to 
either of the treatment arms containing boosted atazanavir (ATV/r).
On the Day 1 Visit, subjects in Arms 1 and 2 will begin QD dosing with BMS-955176 or TDF, 
each in combination with ATV/r and DTG (see Section 4.5 for additional details of Selection and 
Timing of Dose).

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
3.1.2.2
Day 1/Baseline Visit for Arms 3, 4 and 5 - Stage 2
In Stage 2, approximately 120 subjects will be randomized 1:1:1 (approximately 40 per arm) to 
either of the two BMS-955176 treatment arms containing ATV, or to the TDF Arm.
On the Day 1 Visit, subjects will begin QD dosing with BMS-955176 in combination with ATV 
and DTG, or TDF in combination with ATV/r and DTG (see Section 4.5 for additional details of 
Selection and Timing of Dose).

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r QD 300/100 mg + DTG 50 mg QD
3.1.3
Week 2 Intensive PK Visit
Subjects with anemia, defined as Hemoglobin < 11.0 g/dL, should be excluded from 
participation in the Week 2 Intensive PK Substudy.
Subjects in all arms will have the opportunity to participate in an elective Intensive PK Substudy 
visit at Week 2 (window for visit: Day 12-16). Approximately 60 subjects, 12 subjects from each 
arm, are expected to participate in the substudy; BMS may allow the substudy to over-enroll in 
an effort to have a sufficient number of complete datasets.
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The series of 12 blood draws begins with pre-dose (0-hour) blood samples to be collected
approximately 24 hours (20-28 hrs) after the morning doses of study drugs that were taken on the 
day before. Ten more samplings are drawn through the 12-hr time point, with one final sampling 
collected at the 24-hr time point, requiring the subject to either remain overnight in the clinic, or 
to return the next morning; the final 24-hr sample will be collected prior to administration of the 
morning doses of study drugs (See Section 5.5.1).
PK Tools/Job Aids will be provided to assist with the proper sequencing of dosing and blood 
sample collections, as well as the collection of required data.
3.1.4
Visits Week 4 - 96
Subjects are expected to be treated for the duration of 96 weeks. In each Stage, after Day 1 and 
the optional Intensive PK visit at Week 2, subjects will be required to attend 12 more in-clinic 
study visits over the 96-week treatment period, as follows:

Visits are conducted every 4 weeks from Week 4 through Week 16

Visits are conducted every 8 weeks from Week 24 through Week 48

Visits are conducted every 12 weeks from Week 60 through Week 96
Visits should be scheduled as an interval from the Day 1/Randomization date, and within a 
window of 5 days earlier or later.
One of the visits Week 4 - 24 should meet the very specific timing requirements as outlined in 
Section 5.5.2 for a pre-AM dose blood collection.
Telephonic visits will be conducted with each subject at visit Weeks 20, 28, 36, 44, 54, 66, 78,
and 90 to conduct an adherence assessment and to continue retention efforts
3.1.5
Selection of the Continuation Dose of BMS-955176
3.1.5.1
Selection of the Continuation Dose, and the Switch for Stage 1
Once all subjects in Stage 1 have reached Week 24*, BMS will conduct an interim analysis of 
efficacy, safety, resistance and pharmacokinetics.
As described in Section 8.4.7, an analysis of Virologic Futility will also occur. If Arm 1 meets 
criteria for Virologic Futility at Week 24, the clinical trial will be terminated.
The Week 24 analysis of Arms 1 and 2, combined with the Week 24 analysis of all Arms in the 
AI468038 study, will be used to select a Continuation Dose of BMS-955176 for Arm 1 in this 
study. Subjects in the BMS-955176 Treatment Arm 1 may subsequently be transitioned to a
selected Continuation Dose.
Subjects in the Arm containing TDF will continue with the TDF treatment regimen.
The assigned backbone will not change.
The Week 24 efficacy, safety, and pharmacokinetic analyses from Stage 1 and study AI468038 
will also trigger the start of Stage 2.
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* If the Continuation Dose cannot be clearly identified using the Week 24 data, the study 
will continue in original fashion until an analysis of the Week 48 data can be performed 
and the Continuation Dose is selected. If a Continuation Dose cannot be selected based 
upon the Week 24 data, this does not preclude the ability to start recruitment of Stage 2.
After the Continuation Dose is selected, and once all of the logistics (eg, distribution of clinical 
drug supplies, activation of the new portion of the IVRS) have been completed globally, the 
transition of the subjects in Arm 1 to the Continuation Dose will occur. It is anticipated that this 
transition will occur on or after all subjects have reached Week 48 (the earliest subjects to begin 
study treatment could be well beyond Week 48 when the switch to the Continuation Dose 
occurs).
3.1.5.2
Selection of the Continuation Dose, and the Switch for Stage 2
Once all subjects in Stage 2 have reached Week 24, BMS will conduct an analysis of efficacy, 
safety, resistance and pharmacokinetics.
As described in Section 8.4.7, an analysis of Virologic Futility will also occur. If a BMS-955176 
dose arm meets criteria for Virologic Futility at Week 24, subjects in said arm will begin dosing 
with the next highest available remaining dose of BMS-955176.
The data from AI468038 and AI468048 (Stages 1 and 2) will be used to select a Continuation 
Dose of BMS-955176 for Arms 3 and 4. Subjects in the BMS-955176 Treatment Arms 3 and 4 
will subsequently be transitioned to a selected Continuation Dose. It is anticipated that this 
transition may occur on or after all subjects have reached Week 48, or it could occur sooner after 
Week 24.
The assigned backbone will not change.
Subjects in the arm containing TDF will continue with this assigned treatment regimen.
3.1.6
End of the study
The end of the study will occur when the last study visit has been completed, defined as the final 
subject completing their final study visit (expected to be a Week 96 or Early Termination visit).
The study design schematic is presented in Figure 3.1.6-1.
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Figure 3.1.6-1:
Study Design Schematic
Arm 2
TDF
300 mg QD
+ ATV/r + DTG
Day 1
Begin dosing
Arm 3
BMS-955176 
120 mg QD
+ ATV + DTG
1 Virologic Futility will be evaluated at Week 24 
(see Section 8.4.7).  
Results of Week 24 Stage 1 AI468-048 & AI468-038 
Confirm the Start of Stage 2   
Arm 4
BMS-955176 
180 mg QD
+ ATV + DTG
40
40
Week 2
Week 24
Week 24 Analysis1
Intensive PK subset
4 Based on totality of data from both studies the 
Continuation Dose for Arms 3 & 4 may be 
identified.  
Number
Randomized
STAGE 2
Week 96
Week 96 Analysis/End of Study
Week 48
Week 48 Analysis
The Switch to the Continuation Dose4,3     
is expected to occur on or after Week 48, 
but could occur sooner.
Arm 1
BMS-955176 
120 mg QD
+ ATV/r + DTG
Week 2
Number
Randomized
Week 24
Week 24 Analysis1
Day 1
Begin dosing
Intensive PK subset
40
40
Week 48
Week 96
Week 48 Analysis
Week 96 Analysis/End of Study
The Switch to             
the Continuation Dose2,3
may occur on or after 
Week 48 
STAGE 1
BMS-955176
Continuation Dose QD 
+ ATV/r + DTG
Arm 5
TDF
300 mg QD
+ ATV/r + DTG
40
3 The actual switch of subjects of BMS-955176 
subjects to that Continuation Dose may occur when 
all of the subjects have reached at least Week 48 
(though it could occur sooner in Stage 2).
BMS-955176
Continuation Dose QD
+ ATV + DTG
2 Based on Week 24 data from Arms 1 & 2 and 
from AI468-038, the Continuation Dose for 
Arm 1 may be identified.  
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3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug. Study drug will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee 
or through another mechanism at the discretion of BMS. BMS reserves the right to terminate 
access to BMS supplied study drug if any of the following occur: a) the marketing application is 
rejected by responsible health authority; b) the study is terminated due to safety concerns; c) the 
subject can obtain medication from a government sponsored or private health program; or 
d) therapeutic alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Ability to understand and sign a written informed consent form
2. Target Population
a) Antiretroviral treatment-experienced, defined as having documented evidence of having
failed at least 1 ARV regimen (with or without documented resistance)
i)
Failure could be due (but is not limited) to cART intolerance, sub-optimal adherence, 
or an adverse event
b) Screening Plasma HIV-1 RNA 400 copies/mL (An initial, pre-screening value from 
Investigator must demonstrate HIV-1 RNA > 40 c/mL)
c) CD4+ T-cell count > 50 cells/mm3
d) Screening genotype/phenotype indicating susceptibility to study drugs (unboosted ATV, 
FC < 2.2; DTG; TDF)
e) Estimated Life expectancy 1 year
Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued 
the study as a pre-treatment failure (ie, subject has not been randomized / has not been treated). 
If re-enrolled, the subject must be re-consented and assigned a new PID. (See Section 5.5.1 for 
additional details.)
3. Age and Reproductive Status
a) Males and non-pregnant females
b) At least 18 years of age, (or minimum age as determined by local regulatory or as legal 
requirements dictate)
c) Willingness to use approved highly effective methods of contraception (see below) to 
avoid pregnancy (female subjects who are WOCBP or female partners of male subjects 
who are sexually active with WOCBP)
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d) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
e) Women must not be breastfeeding
f)
WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug BMS-955176 plus 5 half-lives of the study drug 
BMS-955176 (8 days) plus 30 days (38 days) post-treatment completion.
g) Males who are sexually active with WOCBP must agree to use a condom for the duration 
of treatment with study drug BMS-955176 plus 5 half-lives of the study drug 
BMS-955176 (8 days) post-treatment completion.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. 
All subjects must agree to the use of a highly effective method of contraception as listed below.
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION FOR FEMALE SUBJECTS 
WHO ARE WOCBP, MALE SUBJECTS AND THEIR FEMALE PARTNERS (WHO 
ARE WOCBP)
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to 
use one of the highly effective methods of contraception listed below. 
Study subjects who are WOCBP cannot use hormonal methods of contraception as one of the 
highly effective methods of contraception because there are data to show a lack of effectiveness 
of systemic hormonal contraceptives in women taking BMS-955176. However, WOCBP can 
continue to use hormonal contraceptives, if necessary, in addition to one other non-hormonal 
highly effective methods of contraception.  
Male subjects must inform their female partners who are WOCBP of the contraceptive 
requirements of the protocol and are expected to adhere to using contraception with their partner. 
Relevant exposure of BMS-955176 in female partners of male participants in the study is 
expected to be negligible. Female partners of male subjects participating in the study may use 
hormone based contraceptives as one of the acceptable methods of contraception because 
exposure to the investigational product would be too small to alter exposure of hormonal 
contraceptives.
1. IUDs
2. Bilateral tubal occlusion
3. Vasectomised partner with documented azoospermia 90 days after procedure
o
Vasectomised partner is a highly effective birth control method provided that partner is 
the sole sexual partner of the WOCBP trial participant and that the vasectomised partner 
has received medical assessment of the surgical success.
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4. Complete abstinence
o
Complete abstinence is defined as the complete avoidance of heterosexual intercourse 
when this is the preferred lifestyle of the patient.
o
Complete abstinence is an acceptable form of contraception for all study drugs and must 
be used throughout the duration of study and for the duration of time as specified above.
o
It is not necessary to use any other method of contraception when complete abstinence is 
elected.
o
Subjects who choose complete abstinence must continue to have pregnancy tests. 
o
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Antiretroviral treatment-experienced adults who have failed < 1 ARV regimen
b) Resistance or partial resistance to any study drug
c) Three or more of the following PI mutations, historical or documented: M36I/V, 
M46I/L/T, G48M/V, I54V/L/T/M/A, G73S/A/C/T, V82A/F/T/S/I, or L90M
d) Any major ATV mutations, historical or documented: I50L, I84V/A, N88D/S
e) Any major TDF mutation, historical or documented: K65R or T69ins
f)
Three or more of the following non-accessory thymidine analogue mutations (TAMs): 
M41L, D67N, K70R, L210W, T215Y/F, K219Q/E
g) Any major mutations for raltegravir (RAL), elvitegravir (or clinically suspected INI 
resistance), historical or documented: T66IAK, E92Q, S147G, N155H, Q148H/K/R, 
Y143C/H/R, E157Q
h) Antiretroviral treatment-experienced adults infected with Clade AE
i)
Patients who have failed a previous boosted PI- or Integrase strand transfer inhibitor 
(INSTI)-containing regimen for which resistance analyses were not conducted at the time 
of failure
j)
Prior exposure to BMS-955176
2. Medical History and Concurrent Diseases
a) A new AIDS defining condition diagnosed within the 30 days prior to screening
(see Appendix 2)
b) Any other clinical condition (including but not limited to active substance use) or prior 
therapy that, in the opinion of the Investigator, would make the subject unsuitable for the 
study; unable to comply with dosing requirements; or unable to comply with study visits; 
or a condition that could affect the absorption, distribution, metabolism or excretion of 
the drug.
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3. Physical and Laboratory Test Findings
a) Chronic HBV/HCV (Positive blood screen for HBsAg; Positive blood screen for HCV 
Ab and HCV RNA)
b) ALT or AST > 3 × ULN
c) Alkaline Phosphatase > 5 × ULN
d) Bilirubin 1.5 × ULN
e) History of decompensated cirrhosis or active decompensated cirrhosis
f)
Hemoglobin < 8.0 g/dL
g) Platelets < 50,000 cells/mm3
h) Estimated eGFR < 60 mL/min (CKD-EPI formula)
i)
Confirmed QT value > 500 msec at Screening or Day 1
j)
Confirmed QTcF value > 470 msec for women and > 450 msec for men at Screening or 
Day 1
k) Confirmed PR Interval > 260 msec (severe first degree AV block) at Screening or Day 1
l)
Confirmed second or third degree heart block at Screening or Day 1
4. Allergies and Adverse Drug Reaction
a) Medications contraindicated for use with investigational/non-investigational study drugs 
(ATV, RTV, DTG, TDF);
or subjects with any known allergies to the 
investigational/non-investigational study drugs (ATV, RTV, DTG, TDF)
b) Current or anticipated treatment with any of the medications listed in Appendix 1, in 
addition to any medications that are contraindicated with ATV, RTV, DTG or TDF
c) Participation in an experimental drug and/or HIV-1 vaccine trial(s) within 30 days prior 
to Screening
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A woman of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/mL to confirm menopause.
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Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is > 40 mIU/mL at any time 
during the washout period, the woman can be considered postmenopausal:

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
Refer to Appendix 1 which details prohibited and precautionary therapies during the study, 
including specifics about the use of antacids and hormonal methods of contraception.
3.4.2
Other Restrictions and Precautions
None.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Pregnancy (subjects should be discontinued in an appropriate manner)

Repeat non-adherence by the subject with the requirements of the protocol or treatment
(as determined by Investigator in consultation with the BMS Medical Monitor)

Evidence of Hepatitis B or C infection

Failure to achieve > 1 log10 c/mL decrease in HIV-1 RNA by Week 8

Confirmed plasma HIV-1 RNA 1000 c/mL after Week 24

Confirmed plasma HIV-1 RNA 200 c/mL after Week 48

Emergence of genotypic and/or phenotypic resistance to any component of the study 
treatment regimen at any time after Screening

Subject requires switching to any other ARV
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
Development of pDILI (potential drug induced liver injury)

Confirmed QTcB or QTcF value > 500 msec

Confirmed second degree (Type II) or third degree AV block at any time during the study
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. The study drug will be permanently discontinued in an 
appropriate manner.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5 (ie, perform an Early Termination [ET] visit). The only 
exception to this requirement is when a subject withdraws consent for all study procedures 
including post-treatment study follow-up (no such period exists in this study) or loses the ability 
to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
Subjects who discontinue study drug may continue to be followed.
Subject’s contact information will be collected/confirmed throughout the study so that subjects 
who discontinue study drug may continue to be followed for resolution of a pregnancy or SAE.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
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All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for AI468048:
Product Description / 
Class and Dosage Form
Potency
IMP/Non-IMP
Blinded or 
Open Label
Packaging/ Appearance
Storage Conditions
(per label)
BMS-955176 
60 mga
IMP
Open Label
Bottle/
A white to off-white, biconvex, 
oval shaped film coated tablet
Store at 2 - 30°C
Protect from light.
Store in a tightly closed container.
BMS-955176
120 mga
IMP 
Open Label
Bottle/
A white to off-white, biconvex, 
capsule shaped film coated tablet
Store at 2 - 30°C
Protect from light.
Store in a tightly closed container.
Tenofovir (TDF)
300 mg
Non-IMP
Open Label
Various packaging configurations
Refer to label on
container or package insert.
Atazanavir (ATV)
200 mg
IMP
Open Label
Bottle/
Blue cap and blue body
printed with white ink
Store at 15 - 30°C
Store in a tightly closed container.
Atazanavir (ATV)
300 mg
IMP
Open Label
Bottle/
Red cap and blue body,
printed with white ink
Store at 15 - 30°C
Store in a tightly closed container.
Ritonavir (RTV)
100 mg
Non-IMP
Open Label
Various packaging configurations
Refer to label on
container or package insert.
Dolutegravir (DTG)
50 mg
Non-IMP or 
IMP,
depending on 
country 
approval status.
Open Label
Various packaging configurations
Refer to label on
container or package insert.
a The 180 mg dose of BMS-955176 will be constructed with BMS-955176 60 mg + BMS-955176 120 mg
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, investigational product(s) is/are: BMS-955176, ATV, and DTG (in countries 
where DTG has not been approved for use). These products will be supplied.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products.
In this protocol, noninvestigational product(s) is/are: TDF, RTV, and DTG (in countries where 
DTG is approved for use). These products will be supplied.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
4.4
Method of Assigning Subject Identification
At the start of the screening period, the investigative staff will call the Assignment Center via an 
Interactive Voice Response System ([IVRS], or its web-based equivalent) designated by the 
sponsor to enroll the subject and to obtain a subject patient identification number (PID).
For subjects who meet the protocol eligibility criteria, the investigative staff will call the IVRS 
and subjects will start treatment.
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Subjects will be randomly assigned in the staged fashion to one of the treatment arms, as
described in Section 3 and as outlined in the AI468048 Study Schematic Figure 3.1.6-1.
Note: All efforts should be made to limit the possibility of randomizing subjects that do not start 
treatment. If a subject is randomized but does not receive study medication, the BMS study team 
must be notified immediately.
4.5
Selection and Timing of Dose for Each Subject
Subjects will be randomized into the treatment arms in a staged fashion described in Section 3.1.
Stage 1:
In Stage 1, subjects will be randomly assigned 1:1 to one of two treatment arms and on Day 1 
will begin dosing with:

Arm 1 : BMS-955176 120 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD, or

Arm 2: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
Stage 2:
In Stage 2, subjects will be randomly assigned 1:1:1 to one of three treatment arms and on Day 1 
will begin dosing with:

Arm 3: BMS-955176 120 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 4: BMS-955176 180 mg QD + ATV 400 mg QD + DTG 50 mg QD, or

Arm 5: TDF 300 mg QD + ATV/r 300/100 mg QD + DTG 50 mg QD
4.5.1
Instructions for Dose Administration
4.5.1.1
General Instructions

Subjects should administer doses of each drug from only one bottle at a time, until that bottle 
is empty, before another bottle may be opened. 

Subjects will be required to complete Dosing Diaries so that drug administration can be 
accurately accounted. It is important that sites provide instructions to subjects for completion 
and obtain their acknowledgment that doing so provides critical information for the clinical 
trial.

Dosing times (and study appointment times) must be carefully considered through Week 24 
due to the requirements of the PK collection outlined in Section 5.5.
4.5.1.2
Specific Dosing Instructions for Initial Treatment Arm Assignment
In the morning, with a meal, subjects will take the following:

Arm 1: One pill each from bottles BMS-955176 120 mg, ATV, RTV, and DTG

Arm 2: One pill each from bottles TDF, ATV, RTV and DTG
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BMS-955176
HIV Maturation Inhibitor

Arm 3: One pill each from bottles BMS-955176 120 mg, DTG, and two pills from bottle
ATV (the unboosted dose of ATV is 400 mg, achieved by 200 mg x 2)

Arm 4: One pill each from bottles BMS-955176 60 mg, BMS-955176 120 mg and DTG, and 
two pills from bottle ATV (the unboosted dose of ATV is 400 mg, achieved by 200 mg x 2)

Arm 5: One pill each from bottles TDF, ATV, RTV and DTG
4.5.2
Dose Modifications
No dose adjustments or changes in intake frequency are allowed for any of the assigned study 
drugs in the protocol, except for the unique case of treatment-limiting renal toxicity which limits 
the use of the TDF. In the event of treatment-limiting renal toxicity, dose interval adjustments for 
TDF are permitted according to the local package insert/label, and only after the completion of 
the Week 2 Intensive PK optional Visit, if the subject is inclined to participate.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment Adherence to the treatment regimen will be critical to the conduct of this study. 
Adherence will be evaluated by the investigative staff at every treatment visit (including 
telephone contact visits) through interviews with the subjects and through examination of 
returned medication. It is expected that site staff attempt to have subjects maintain 90% 
treatment compliance or greater. Subjects should be instructed to bring all unused study 
medication back in the original container to each visit. Site staff are required to review Dosing 
Diaries completed by the subject, and to reinforce their use.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request
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HIV Maturation Inhibitor

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
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HIV Maturation Inhibitor
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (AI468048)
Procedure
Screening Visit
(42-day screening period)a
Notes
Eligibility Assessments
Informed Consent
X
Call IVRS to Enroll the subject; PID assigned
X
Inclusion/Exclusion Criteria
X
Medical History
X
AIDS History
X
Non-Laboratory Safety Assessments
Full Physical Examination
X
See Section 5.3.1 for requirements
Vital Signs & Physical Measurements
X
See Section 5.3.1 for requirements
Pre-treatment events
X
Only CDC Class C events with onset during the Screening period
Serious Adverse Events Assessment
X
All SAEs that occur after the ICF has been signed should be reported
ECG
X
See Section 5.3.4 for requirements
Pregnancy Test
X
WOCBP
For females under age 55, an FSH level must be on record to confirm she 
is not a WOCBP if pregnancy testing is not being performed.
If positive urine, request serum hCG quant. on lab requisition.
Laboratory Assessments (See Appendix 5 for full details)
Fasting Chemistry and Lipid Panel
X
Fasting overnight
Hematology
X
Urinalysis
X
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HIV Maturation Inhibitor
Table 5.1-1:
Screening Procedural Outline (AI468048)
Procedure
Screening Visit
(42-day screening period)a
Notes
Plasma HIV-1 RNA
X
This is the confirmatory HIV-1 RNA
(The first value is provided by the PI)
CD4+ and CD8+ T-cell count
X
HBV Surface Antigen
X
HCV Serology
X
Urine toxicology (drugs of abuse)
X
Could aid in the selection of appropriate study candidates.
Pharmacodiagnostic (PDx) sampleb
X
Plasma collection to be banked for potential future use in development of 
novel predictive assay(s)
Resistance Testing
(HIV-1 Drug Resistance)
PhenoSense GT Plus Integrase
X
Proper collection of the full volume of plasma outlined in the lab manual 
will allow for repeat testing of the sample if assay steps fail during 
testing.a
Gag assays are not performed in real-time, and Gag results are not used to 
assess eligibility
PhenoSense Gag
X
Next Generation Seq. - Qs Gag
X
Exploratory Resistance
(HIV-1 Drug Resistance)
X
Molecular analysis at BMS WFD Discovery of baseline resistant samples 
and baseline sensitive controls in cases of subsequent on-treatment 
virologic failure
a If the PSGT + Integrase resistance assay cannot be resulted within 42 days, the Screening window can be extended up to 60 days, and solely for this procedure 
to allow time for Monogram to complete the testing.  
b By definition, a pharmacodiagnostic sample (PDx) is a pre-treatment test to determine whether or not a patient is likely to respond to a drug (ie, a predictive 
test). Based on the results of clinical studies with BMS-955176, BMS may have to develop a PDx assay. Thus, PDx samples obtained at Screening in this 
study would be used for that sole purpose.
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HIV Maturation Inhibitor
Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Eligibility Assessments
Inclusion/Exclusion Criteria
X
Non-Laboratory Safety Assessments
Full Physical Examination
WK 12, 24, 48, 96/ET
See Section 5.3.1 for requirements
Targeted Physical Examination
X
WK 4, 8, 16, 32, 40, 60, 72, 84
See Section 5.3.1 for requirements
Vital Signs & Physical 
Measurements
X
X
See Section 5.3.1 for requirements
Adherence Assessments
X
X
Including review of Dosing Diaries
Pre-treatment Events
X
See Table 5.1-1
Adverse Events Assessments
X
X
X
Serious and Non-serious AEs
Concomitant Medications
X
X
X
See Section 5.3.3
ECG
X
WK 4, 12, 24, 48, 96/ET
See Section 5.3.4 for requirements
Pregnancy Test
X
X
X
For females under age 55, an FSH 
level must be on record to confirm 
she is not a WOCBP if pregnancy 
testing is not being performed.
If positive urine, request serum 
hCG quant. on lab requisition.
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HIV Maturation Inhibitor
Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Provide WOCBP with Home 
Pregnancy test kit(s) to be used 
during the in-clinic visit interval
WK 16, 24, 32, 40,
48, 60, 72, 84
Provide One Kit at Weeks 16 - 40
Provide Two Kits at Weeks 48 - 84
WOCBP subjects perform test Q4 
weeks at home and report results to 
site.
Laboratory Assessments for Safety and Efficacy and Other Endpoints (See Appendix 5 for full details)
Fasting Chemistry
X
X
Fasting overnight
Fasting Lipid Panel
X
WK 4, 12, 24, 48, 96/ET
Fasting overnight
Hematology
X
X
Urinalysis
X
X
Fractional Excretion of Phosphorous 
(FePO4)
(Urine creatinine and phosphorus, 
Serum creatinine and phosphorus)
X
WK 48 and 96/ET
Plasma HIV-1 RNA
X
X
X
If collecting an HIV-1 RNA at an 
UNSCHEDULED visit, also collect 
samples for Resistance and 
Exploratory Resistance Testing
CD4 and CD8 T-cell counts
X
X
HBV Surface Antigen
WK 48 and 96/ET
HCV Serology
WK 48 and 96/ET
Positive HCV Ab will reflex to 
HCV RNA
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BMS-955176
HIV Maturation Inhibitor
Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
Resistance Testing
(HIV-1 Drug Resistance)
PhenoSense GT Plus Integrase
X
X
Samples stored and tested if needed
(ie, analyses of subjects if deemed 
clinically relevant)
See Section 5.4.2.2
PhenoSense Gag
X
X
Next Generation Seq. - Qs Gag
X
X
Exploratory Resistance
(HIV-1 Drug Resistance)
X
X
Samples stored and tested 
retrospectively if needed (ie,
exploratory analyses for subjects if 
deemed clinically relevant)
Intensive PK sample collection
X
Use of PK Tools for data collection 
recommended.
See Section 5.5.1 for requirements
Sparse PK sample collection
WK 4, 8, 12, 16, 24
See Section 5.5.2 for requirements
Bone Biomarkers
(P1NP and CTX)
X
WK 12 and 24/ET
Serum collection
Renal Biomarkers
(2-microglobulin and creatinine)
X
WK 48 and 96/ET
Urine collection
Backup Serum and Plasma Sample
X
X
Samples stored and tested if needed
Outcomes Measures
EQ-5D-3L Form
X
WK 12, 24, 32, 40, 48,
60, 72, 84, 96
Health Outcomes Questionnaire
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AI468048
BMS-955176
HIV Maturation Inhibitor
Table 5.1-2:
Short-term Procedural Outline (AI468048)
Procedure
In-clinic 
Visit
Day 1
In-Clinic Visit 
Optional 
Week 2 for 
Intensive PK
(Day 12-16)
In-Clinic Visits
Weeks 4, 8, 12, 16, 24, 32, 40, 
48, 60, 72, 84, 96, and/or 
Early Termination (ET)
(5 days)
Phone Visits
Weeks 20, 
28, 36, 44, 
54, 66, 78, 90
(5 days)
Notes
FAHI Form
X
WK 12, 24, 32, 40, 48,
60, 72, 84, 96
Functional Assessment of HIV 
Infection
Clinical Drug Supply
Call IVRS to Randomize
X
Dispense Study Drug
X
X
There is no dispensation at Week 96 
or ET.
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HIV Maturation Inhibitor
5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value). The Screening Period for this study is 42 days (see Table 5.1-1, Table Note a, for the 
single parameter for which the screening period may be extended).
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultations 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant (eg, a previously failed inclusion criterion).
Rescreening is different than Retesting. Rescreening is the process of Re-enrollment and requires 
that all procedures be repeated in an entirely new screening period. A one-time Rescreening is 
permitted, if further rescreening is considered for reassessment of enrollment eligibility this 
should be discussed with the Medical Monitor.
The assigned patient identifier (PID) for the subject must be Screen Failed in the IVRS. A new 
call must be made to the IVRS for the assignment of a new PID for the subject, and all Screening 
parameters must be done again in reference to the new PID (See Section 3.3.1, Inclusion 
Criteria 2f). Subject must also be re-consented with the new PID.
5.2
Study Materials
The sponsor will provide each investigative site with the following:

BMS-955176 Investigator Brochure (IB) and any relevant safety addenda or updates

Protocol and any Amendments to the Protocol

Instructions for completing electronic Case Report Forms (eCRFs)

Laboratory Manual from the central laboratory

ECG Machines and manual

IVRS Worksheets to complete when calling the IVRS center to enroll, randomize, and 
discontinue subjects

Patient-reported Outcomes Questionnaires: EQ-5D-3L Health Outcome Questionnaire, FAHI 
(Functional Assessment of HIV Infection)

PK Tools/Job Aids that may be used for detailed instruction about the PK visits, and as a 
comprehensive source for documents of date/times of dosing and blood sampling

Dosing Diaries

Completion by subjects is required

Should include daily dose of study medications administered by subject, modified or 
missed
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HIV Maturation Inhibitor

Site staff should review the diaries with the subject at each visit, and, in combination with 
detailed questioning, should be able to provide comprehensive information in the case 
report form, noting discrepancies in the subject’s file. Dosing Diaries should be 
maintained in the subject’s study file.
5.3
Safety Assessments
The investigative team should follow the protocol-specified scheduled of safety-related 
measurements. Only data for the procedures and assessments specified should be submitted to 
BMS on the case report form. Additional procedures and assessments may be performed as part 
of standard of care, however, data for these assessments should remain in the subject’s medical 
record and should not be submitted to BMS, unless specifically requested (ie, as part of an SAE).
5.3.1
Vital Signs and Physical Examinations
The schedule of vital signs, physical examinations, and targeted physical examinations is 
provided in Section 5.1 (Flow Chart/Time and Events Schedule). Vital signs include heart rate, 
blood pressure, respiration rate, and temperature and should be measured after the subject has 
been sitting/resting for at least 5 minutes. Physical measurements include height and weight. 
Targeted physical examinations will include examination of the heart, lungs, skin, abdomen, any 
symptomatic organ system, and general appearance.
5.3.2
Adverse Events
Subjects will be closely monitored throughout the study for any new or ongoing HIV-related 
diagnoses (Appendix 2) and/or adverse events. CDC Class C events that occur from the 
Screening Visit through Day 1 (prior to dosing), will be recorded as Pre-treatment Events. All 
events that occur after dosing on Day 1 will be recorded on the appropriate Adverse Event eCRF. 
Additional information on Adverse Events is provided in Section 6.
5.3.3
Concomitant Medication Assessment
All medications taken from the Screening Visit throughout the duration of the study will be 
reported. In addition, any prior therapy with antiretroviral drugs will be reported
(See Appendix 1 for Prohibited and Precautionary Therapies).
5.3.4
Electrocardiograms
The schedule of electrocardiograms (ECGs) is provided in Section 5.1 (Flow Chart/Time and 
Events Schedule). ECG machines will be provided by a central vendor who will also perform the
read/interpretation of the output.
5.4
Efficacy Assessments
5.4.1
Primary Efficacy Assessment
The primary assessment for efficacy is HIV-1 RNA at Week 24.
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HIV Maturation Inhibitor
5.4.1.1
Guidelines for Confirmatory Testing of Plasma HIV-1 RNA and 
Resistance testing
A confirmatory HIV-1 RNA viral load should be obtained when:

HIV-1 RNA 40 c/mL if prior suppression 40 c/mL, or

> 1 log10 c/mL increase in HIV-1 RNA at anytime above nadir level where nadir is 
40 c/mL
All efforts should be made to collect this sample within 2-4 weeks from the collection of the 
original sample.
When collecting a blood sample for HIV-1 RNA testing at an Unscheduled visit, samples should 
also be collected for the sets of Resistance and Exploratory Resistance Tests, so that the samples
are available should resistance testing be required or deemed necessary based on the result of the 
HIV-1 RNA test.  
Table 5.4.1.1-1:
Management of Detectable HIV-1 RNA, based on Confirmed 
(2-4 weeks from original sample) or Consecutive HIV-1 RNA 
Resulta
Day 1 through Week 24
40 - 399 c/mL
Reinforce Adherence
400 c/mL
Consider the need for resistance testing, in consultation with BMS Medical Monitor.
Consider possible discontinuation of subject, in consultation with BMS Medical Monitor, 
and/or reinforce adherence.
After Week 24 through Week 48
40 - 399 c/mL
Reinforce Adherence
400 - 999 c/mL
Resistance testing will be performed.
If resistance has developed, subject must be discontinued.
If resistance has not developed, consider possible discontinuation of subject, in consultation 
with BMS Medical Monitor, and/or reinforce adherence.
1000 c/mL
Resistance testing will be performed.
Regardless of result of resistance tests, subject must be discontinued (see Section 3.5).
After Week 48
40 to < 200 
c/mL
Reinforce Adherence
200 c/mL
Subject must be discontinued (see Section 3.5). 
If 400 c/mL, consider the need for resistance testing, in consultation with BMS Medical 
Monitor.
a When discontinuation is required or otherwise warranted and resistance results are needed, subject may continue 
on study medication/on study until resistance testing results are available.
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HIV Maturation Inhibitor
5.4.1.2
Protocol Defined Virologic Failure
Protocol Defined Virologic Failure (PDVF) is defined by a subject meeting one of the following 
criteria:
1) Confirmed > 1 log10 c/mL increase in HIV-1 RNA at anytime above nadir level where nadir 
is 40 c/mL
2) Confirmed HIV-1 RNA 400 c/mL after Week 24
3) Confirmed HIV-1 RNA 40 c/mL if prior suppression to < 40 c/mL
4) Failure to have the last on-treatment HIV-1 RNA to < 400 c/mL within Week 24, 48, or 96 
week snapshot window
5) Failure to achieve > 1 log10 c/mL decrease in HIV-1 RNA by Week 8
In addition to the clinical management outlined in section 5.4.1.1, samples meeting criteria for 
PDVF will also be sent for resistance and exploratory resistance testing.
5.4.2
Secondary Efficacy Assessments
5.4.2.1
CD4+ and CD8+ T-Cells
CD4+ and CD8+ T-cells counts and percentages will be assessed using flow cytometry. The 
schedule of assessments is provided in Section 5.1 (Flow Chart/Time and Events Schedule). 
Procedures for samples collection and processing are provided in the central clinical laboratory 
manual.
5.4.2.2
Drug Resistance Testing
Plasma samples for viral drug resistance testing will be collected at Screening for all subjects and 
the HIV-1 drug resistance genotype will be analyzed to rule out resistance to any component of 
the study regimen or specific resistance mutations as outlined in Section 3.3.2, Exclusionary 
Criteria. At subsequent visits, samples for emergent drug resistance testing (both genotypic and 
phenotypic) will be collected and stored to be as outlined in Section 5.4.1.
5.5
Pharmacokinetic Assessments
It is extremely important to record the exact dose and time of the dose(s) taken the day prior to 
the visit/collection, and the exact date and time of the sample collection, even if drawn slightly 
off-schedule.
5.5.1
Intensive Pharmacokinetic Assessment
A subset of subjects (about 12 subjects per treatment group) will participate in an optional 
Intensive PK assessment at Week 2 (window Day 12-16).
Intensive PK samples collected in this study will provide for the assessment of BMS-955176, 
ATV, RTV, and DTG to support the secondary and exploratory objectives (to characterize the 
PK of BMS-955176, DTG, and ATV (with or without RTV) when given in combination, and to 
compare steady-state exposures of DTG when co-administered with BMS-955176 and 
ATV/RTV to DTG when co-administered with TDF and ATV/RTV).
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HIV Maturation Inhibitor
Intensive PK sampling begins with a morning pre-dose (0 hour) sampling, ie, prior to the 
administration of the morning doses of the study drugs on the day of the visit. The sampling 
should also begin 24 hours (between 20 and 28 hours) after the morning doses of the study drugs 
that were taken the day prior to the visit.
The subsequent 11 time points include samplings through Hour 12, with the last sample collected 
at Hour 24. The subject will either stay overnight or will return to the clinic so that the final 
sample can be collected at Hour 24.
It is critical to capture the exact date and time of each PK sample collection, even if drawn 
slightly off-schedule. There is no specified collection window end for which any one time point 
should be abandoned as the schedule progresses. If a sample collection time point is missed/late 
and the next collection time point has not yet been reached, collect the missed time point, and 
record the exact time of that collection, then get back on track for the next time point/on-time 
collection.
Table 5.5.1-1 lists the sampling schedule to be followed for the assessment of intensive 
pharmacokinetics. Further details of PK blood collection and sample processing will be provided 
in the central clinical laboratory manual.
Table 5.5.1-1:
AI468048 Intensive Pharmacokinetic Sampling Schedule at Week 2
Time 
(Event)
Time 
(Relative to Dosing)
Hour: Min
PK
Blood Sample
Study Week 2
(window Day 12-16)
0 (morning pre-dose)
00:00
X
1 Hr
01:00
X
2 Hr
02:00
X
2.5 Hr
02:30
X
3 Hr
03:00
X
4 Hr
04:00
X
4.5 Hr
04:30
X
5 Hr
05:00
X
6 Hr
06:00
X
8 Hr
08:00
X
12 Hr
12:00
X
24 hr (morning pre-dose)
24:00
X
5.5.2
Sparse Pharmacokinetic Assessments
All subjects will provide Sparse PK samples (as part of the regular blood collection) for the 
assessment of BMS-955176, ATV, RTV and DTG at visit Weeks 4- 24.
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HIV Maturation Inhibitor
Of the five visits (Week 4 - 24), it is requested that the following guidelines are followed:

At any one visit Week 4 through Week 24, the Sparse PK sample must be collected 
approximately 24 hours (between 20 and 28 hours) after the dose that was taken the morning 
before and before the morning dose is taken on the day of the visit

At the remaining four visits Week 4 through Week 24, the blood collections may be done 
without any specific consideration to timing of previous dose administration (taken either the 
day before the visit or on the day of the visit), though it is critical that the date and time of the 
most previous dose of study drug is recorded in the eCRF so that the exact interval between 
dose and blood sampling can be calculated for accurate PK analysis
PK Samples need to be tested on an ongoing basis prior to the Week 24 database lock and 
analysis.
5.6
Biomarker Assessments
In this study, BMS is confirming the safety of BMS-955176 demonstrated in the Phase 2a study 
to date. The proposed sample population of treatment-experienced adults in Arms 3, 4, and 5, 
will provide a representation of the potential benefits of BMS-955176 on nucleoside and RTV 
based toxicities of interest (ie, renal toxicity, bone mineral density, and dyslipidemia): Arms 3 
and 4 relative to Arms 1, 2, and 5.
Specifically, to evaluate for renal toxicity we will evaluate clinically relevant parameters and 
biomarkers for glomerular and tubular toxicity, which may include but are not limited to: 
fractional excretion of phosphorous and urinary β2-microglobulin/creatinine, in all available 
subjects. To evaluate for bone-related toxicity, clinically relevant bone biomarkers for both 
formation and resorption will be evaluated in all available subjects. These may include but are 
not limited to: N-terminal Propeptide of Type 1 procollagen (P1NP) and Cross-linked 
C-telopeptide of Type 1 collagen (CTX). The bone and renal biomarkers will be collected and 
measured at time points specified in Table 5.1-2 Additionally, back-up plasma and serum 
samples (at Baseline, Week 24, and Week 48) will be obtained for potential future evaluation of 
the safety of BMS-955176.
Samples will be collected at the screening visit for HIV-1 Gag sequencing, phenotypic 
susceptibility (PhenoSense Gag) and potential pharmacodiagnostic analysis as specified in Table 
5.1-1. These samples may be analyzed, if deemed clinically relevant, as a predictive marker of 
clinical response.
Any remaining blood and urine specimens that are available after completion of the designated 
analyses may be used in the future for identification of potentially predictive or 
pharmacodynamic markers of study drug activity or to enhance the understanding around disease 
biology, except where prohibited by local laws or regulations.
5.7
Outcomes Research Assessments
Increases in CD4 counts and avoidance of opportunistic infections and other AIDS-defining 
illnesses have been shown in many studies to improve health related quality of life (HRQoL). To 
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HIV Maturation Inhibitor
help assess whether use of BMS-955176 will result in a better quality of life outcome, both a 
disease specific quality of life assessment and a generic quality of life assessment will be 
administered. Disease specific instruments are more sensitive to disease specific changes in 
quality of life and are more likely to show improvement with new interventions. The generic 
instruments are needed because Health Technology Authorities often require use of these 
instruments for cost-effectiveness modeling.
The Functional Assessment of HIV (FAHI) is the disease specific instrument that will be used. 
The FAHI evaluates physical well-being, functional and global well-being, emotional 
well-being/living with HIV, social well-being and cognitive functioning. It yields a total score 
and individual subscale scores.
The EQ-5D-3L is the generic instrument that will be used. The EQ-5D-3L includes two parts: the 
EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L 
descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some 
problems, extreme problems. The EQ VAS records the respondents’ self-rated health on a 
100 point, vertical, visual analogue scale where the endpoints are labeled ‘Best imaginable health 
state’ and ‘Worst imaginable health state.’
5.8
Other Assessments 
We will obtain back-up plasma and serum samples for current/future evaluation of the efficacy, 
safety and tolerability of BMS-955176. 
Should any new safety signal develop during the course of the ongoing analysis of the Phase 2a 
trial, appropriate measures for evaluation and management will be incorporated into the design 
of the Phase 2b trial via a protocol amendment.
5.9
Results of Central Assessments
The following describes the centrally assessed parameters and the timing with which they will be 
shared with investigators, if pertinent. Some parameters are relevant to ongoing subject 
management during the study and will be provided to the site for such purpose, while others are 
not relevant to subject management during the study and results may only be shared in a 
summarized way at the end of the study.

Samples sent to the central lab vendors for safety and efficacy assessments and that are tested 
real time will be provided to the sites as soon as results are available

The results of the read of each ECG will be sent to the site by the central ECG vendor as 
soon as results are available

Samples collected on-treatment for resistance testing will be tested if deemed clinically 
relevant (eg, if the development of resistance is suspected). If tested, results will be reported 
to the site

Other samples (including but not limited to biomarker assessments, exploratory resistance, 
pharmacodiagnostics) may not be tested immediately, and may only be tested if deemed 
clinically relevant. Results may be suppressed from laboratory reports and may not be 
provided to the sites
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
Individual PK results will not be reported to the site; the overall PK assessments will be 
included in the CSR

Individual assessments of the Outcomes research will not be reported to the site; the overall 
Outcomes assessments will be included in the CSR
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs).
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above).
Examples of such events include, but are not limited to, intensive treatment in an emergency 
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room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization). Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must
be handled as
SAEs. 
(See Section 6.1.1 for reporting pregnancies).
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies:

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason)

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing.
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
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SAEs, whether related or not related to study drug, and pregnancies, must be reported to BMS 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on 
a Pregnancy Surveillance Form (electronic or paper forms). The preferred method for SAE data 
reporting collection is through the eCRF. The paper SAE/pregnancy surveillance forms are only 
intended as a back-up option when the eCRF system is not functioning. In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
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
Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours and in accordance with SAE reporting procedures 
described in Section 6.1.1.
The study drug will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for subject safety).
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important.
All occurrences of overdose must be reported as an SAE (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury in HIV-1 mono-infected subjects is defined as:
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
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2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic
6.7
Other Safety Considerations
Any 
significant 
worsening
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
6.7.1
Toxicity Management
The link to the current grading system for specific AEs and laboratory abnormalities is located in 
Appendix 3 (DAIDS; See Appendix 3).
6.7.1.1
Management of Elevations in Liver Transaminases
The following Table 6.7.1.1-1 summarizes the management of elevations in liver transaminases:
Table 6.7.1.1-1:
Management of Elevations in Liver Transaminases Grade Level of 
AST or ALT Recommendationsa
Grade
Recommendation
Grade1
None
Grade 2
none
Grade 3
Confirm elevation, evaluate for potential causes (including but not limited to alcohol or other 
substance abuse, concomitant medications, reactivation of existing or de novo infection with 
hepatitis viruses) consult with BMS Medical Monitor or designate as soon as possible.
Grade 4
Interrupt all study medications, evaluate for potential causes (including but not limited to alcohol 
or other substance abuse, concomitant medications, reactivation of existing or de novo infection 
with hepatitis viruses), monitor values frequently and consult with BMS Medical Monitor or 
designate as soon as possible. If Grade 4 is deemed related to study medication the subject must 
be discontinued from the study. Otherwise, if reinstitution of study therapy is considered, please 
obtain approval from the BMS Medical Monitor or designate.
a If persisting (> Grade 1/2), evaluate for alternative etiologies, including alcohol use and viral hepatitis
6.7.1.2
Management of Renal Toxicity
Serum phosphate levels and creatinine clearance (CrCl; CCL: as calculated by the Cockcroft 
Gault Equation [see Appendix 4] or eGFR) should be monitored and managed as described in the 
Viread local package insert/label.28 Dose interval adjustments of TDF (Viread) are permitted, as 
described in Section 4.5.2.
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6.7.1.3
Management of Hyperbilirubinemia
Most patients taking ATV experience asymptomatic elevations in indirect (unconjugated) 
bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). Hepatic transaminase 
elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. Dose 
modification of ATV is not permitted. Subjects who experience unacceptable jaundice/scleral 
icterus should be discussed with the BMS Medical Monitor or designate to determine if subjects 
are to be discontinued from study. The investigator must contact the BMS Medical Monitor or 
designate prior to discontinuing any subject due to hyperbilirubinemia.
6.7.1.4
Gastrointestinal Toxicity Evaluation and Management Plan
Pre-clinical toxicology studies in rats and dogs (see Section 1.4.1.2) have suggested a potential 
for GI related toxicity with BMS-955176. This section provides general guidance to the 
Investigator on the evaluation and management of primarily upper gastrointestinal symptoms. 
The Investigator may contact the Medical Monitor to discuss evaluation and management 
(including interruption of ARVs or discontinuation of a subject) of any GI symptoms throughout 
the trial.
Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the foundation of proper 
evaluation and management. The following are potential manifestations of some GI 
clinical syndromes that may occur (possibly in combination) during the clinical 
trial. 
Nausea and Vomiting
The investigator should attempt to identify the etiology of these symptoms (and whether 
it is intraperitoneal, extraperitoneal, medication related, infection related, or due to a 
metabolic disorder).33 Medications can cause nausea and vomiting acutely. 
Dyspepsia
The Investigator should identify the presence of red flags (odynophagia, unexplained 
weight loss, recurrent vomiting, GI bleeding, jaundice, palpable mass or adenopathy, or 
family history of GI malignancy). Symptoms of dyspepsia could include early satiety, 
bloating, or belching. Additionally, atypical symptoms of dyspepsia could include: 
pharyngitis, asthma, bronchitis, hoarseness, chest pain, or abdominal pain. 
Ulcerative Disease
Symptoms suggestive of ulceration often are intermittent over a period of weeks to 
months and may be relieved by eating or antacid use;34 penetrating ulcers become more 
acute with localized pain and may not improve with food.35 The development of 
perforation may be indicated by severe diffuse abdominal pain. 
Other Clinical 
Syndromes
Additional diagnostic criteria for other GI disorders potentially encountered in the 
clinical trial are available elsewhere.36
PHYSICAL 
EXAMINATION
Physical examination should complement elements obtained from the history34
Acutely, the investigator may assess for signs of intravascular volume depletion 
(eg, orthostasis) and/or aspiration of vomitus as appropriate. Abdominal 
tenderness and guarding may indicate inflammation. The presence of fecal blood 
can indicate mucosal damage (eg, from an ulcer). Complete evaluation of dyspepsia 
should include an oral examination (poor dentition or pharyngeal erythema) and 
lungs for wheezing. 
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Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
DIAGNOSTIC 
EVALUATION 
AND 
MANAGEMENT
A major goal in the diagnostic evaluation of a subject with upper GI symptoms is 
to quickly arrive at a final diagnosis without exposing the subject to unnecessary 
(invasive) testing; Investigators should exercise good clinical judgment35 in this 
regard. A major goal of therapy is directed at correcting the underlying 
identifiable medical or surgical abnormalities. Consultation (eg, gastroenterologist) 
is recommended as clinically indicated.
Grade 1 symptoms
Subjects may be treated symptomatically. If subjects develop dyspepsia alone, generally 
only limited and direct diagnostic testing should be performed.34 If the subject has 
dyspepsia they should limit alcohol, caffeine, chocolate, tobacco, other contributing 
concomitant medications (eg, NSAIDs) and eating directly before bedtime. A variety of 
OTC medications are available to address constipation and diarrhea as indicated. Please 
refer to Appendix 1 for Prohibited and Precautionary Therapies.
Grade 2 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

Serum chemistries and assessment of hemoglobin if not recently performed. 

Testing for Helicobacter pylori

Serologies (eg, celiac disease) 

PCR for viruses (eg, CMV)

Iron panel or Vitamin B12 level
For subjects who develop dyspepsia or are infected with H. pylori the use of H2 
antagonists, PPIs, Sucralfate, and antacids are prohibited (see Appendix 1 Prohibited 
Medications). If such therapy is required, discontinuation from the trial is necessary. 
The use of antiemetic’s (eg, Prochlorperazine) can be utilized as indicated. Management 
should be targeted at addressing the underlying pathology.
Grade 3 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

The testing outlined above in Grade 2

A fasting serum gastrin level can be obtained in cases of known ulcers refractory to 
therapy, a family history of the disease, or when surgery is required; of note, H. 
pylori can increase gastrin levels.35

A barium swallow to detect ulcers 

CT to identify gastrointestinal inflammation and a penetrating or perforated ulcer. 

Upper endoscopy with biopsy as indicated in order to evaluate dyspepsia further 
(eg, mucosal injury, new onset unexplained dyspepsia in subjects > 55 y/o, or the 
presence of red flags).
Management should be targeted at addressing the underlying pathology.
Grade 4 symptomsa
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

The testing outlined above in Grade 2 and Grade 3

An acute abdominal series

If a perforated ulcer is clinically suspected, surgical consultation may be necessary
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Table 6.7.1.4-1:
GI Toxicity Evaluation and Management
Initial management can include correction of hemodynamic and electrolyte 
abnormalities as clinically indicated. After stabilization, management should be targeted 
at addressing the underlying pathology.
a For Grade 2-4 symptoms if any ARV is thought to have a direct causal relationship to the patient’s 
gastrointestinal symptoms, the Investigator should consider discontinuing the subject from the study and 
performing an evaluation/management plan incorporating elements above. The Investigator can consider 
interruption of the potential offending ARV(s) but must balance this with the increased probability of 
development of viral resistance/lack of efficacy. As stated above, prior to discontinuing the subject from the 
study, attempts should be made to discuss with the BMS Medical Monitor unless the safety of the subject is 
acutely at risk.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This is an estimation study, without statistical testing, and hence there are no power 
considerations.
It is expected that response rate for the primary endpoint for all five arms will be somewhere 
around 80%. With this response rate, and 40 subjects per arm, an exact 95% confidence interval 
would run from roughly 64% to 91%.
8.2
Populations for Analyses
The following definitions are used in this document:

Enrolled subjects: Subject who signed an informed consent form and were assigned a 
Patient Identification number (PID);

Randomized subjects: Enrolled subjects who received a treatment assignment from the 
IVRS;

Treated subjects: Randomized subjects who received at least 1 dose of BMS-955176 or 
TDF. (Also referred to as the mITT analysis set)
8.3
Endpoints
8.3.1
Primary Endpoint(s)Stage 1 and Stage 2
The primary endpoint for Stage 1 and Stage 2 is the proportion of subjects with plasma HIV-1 
RNA < 40 c/mL at Week 24. This will be assessed with the FDA snapshot algorithm. This uses 
the last on-treatment plasma HIV-1 RNA measurement, within an FDA-specified visit window, 
to determine response. 
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8.3.2
Secondary Endpoint(s)

The antiviral efficacy will be determined by the proportion of subjects with plasma HIV-1 
RNA < 40 c/mL at Weeks 48 and 96 using the FDA snapshot algorithm

The antiviral efficacy will also be assessed by the proportion of subjects with plasma HIV-1 
RNA < 200 c/mL at Weeks 24, 48 and 96 using the FDA snapshot algorithm approach with 
positive response defined as HIV-1 RNA < 200 c/mL

The emergence of HIV drug resistance among samples sent for drug resistance testing will be 
assessed using the most recent version of the IAS-USA list of HIV-1 drug resistance 
mutations

Changes from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the 
percentage of CD4+ T-cells will be assessed using on-treatment laboratory results, and 
pre-specified visit windows

The frequency of SAEs and AEs leading to discontinuation (DC) will be tabulated directly 
from the case report forms (CRFs). The summary will count the number of subjects that have 
at least one event

The occurrence of new AIDS defining events (CDC Class C events) will be tabulated from 
the CRFs. The summary will count the number of subjects that have at least one event

The steady-state plasma PK of BMS-955176 will be assessed using the intensive PK data, 
collected at Week 2 from a subset of subjects
8.4
Analyses
In general, categorical variables are tabulated with counts and percents. Continuous variables are 
summarized with univariate statistics (eg, mean, median, standard error).
Longitudinal analyses use pre-defined visit week windows. Unless otherwise specified, windows 
around planned measurement times are constructed based on the midpoint between planned 
study visits (ie, half the duration of time between study visits), and data are summarized at each 
scheduled visit. 
For the calculation of descriptive statistics of observed data, subjects must have a baseline 
measurement to be evaluable for longitudinal tabulations of parameter values and changes from 
baseline. 
Tabulations of the following endpoints present the number of unique subjects with an event: 
protocol deviations; interruptions of study therapy; non-study medications; adverse events; and 
laboratory abnormalities. Thus, multiple occurrences of the same event are counted only once 
per subject.
8.4.1
Demographics and Baseline Characteristics
The following demographic and baseline characteristics will be summarized by treatment arm
and overall using the treated subjects:

Demographics: age, race, ethnicity, gender, geographic region;
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
Disease characteristics at baseline: plasma HIV-1 RNA level, CD4+ T-cell counts and 
percentages, CD8+ T-cell counts, HIV-1 subtype;

Laboratory tests at baseline;

Pre-treatment CDC Class C AIDS events;

Prior medications
8.4.2
Efficacy Analyses
The efficacy analyses will be based on the treated subjects.
8.4.2.1
Primary Efficacy Analyses
The primary efficacy endpoint is the proportion of subjects with plasma HIV-1 RNA < 40 c/mL 
at the Week 24 snapshot within each stage. This endpoint is assessed with the FDA snapshot 
algorithm. The primary analysis will be based on a modified ITT (mITT) approach. A sensitivity 
analysis will be conducted using an observed values approach. The two approaches will be 
implemented as follows:

Modified ITT: The numerator will be based on subjects with plasma HIV-1 RNA < 40 c/mL 
at Week 24. The denominator will be based on all treated subjects

Observed values: Similar to the mITT approach, the numerator will be based on subjects with 
plasma HIV-1 RNA < 40 c/mL at Week 24. However, the denominator will be based on the 
treated subjects with plasma HIV-1 RNA at Week 24
Response rates will be tabulated by treatment arm (within the stage) with exact binomial 95% 
confidence intervals.
Subgroup summaries will be provided to examine the impact of baseline viral load. Subgroup
summaries may be provided to examine the impact of other important covariates such as CD4+ 
count, sex, geographic region, etc.
At Week 24, a Time to Loss of Virologic Response (TLOVR) analysis will be conducted as a 
sensitivity analysis that compliments the snapshot analysis. The following definition for 
virologic rebound will be used:
“For subjects that have been confirmed as having reached virologic suppression, by 
having two consecutive HIV-1 RNA readings below the assay limit of detection 
(40 copies/mL), virologic rebound is defined as confirmed HIV-1 RNA levels above the 
limit of detection. For levels above the limit of detection, confirmation consists of either 
two consecutive readings, or a single reading followed by loss to follow-up.”
8.4.2.2
Secondary Efficacy Analyses
The following secondary endpoints will be summarized by treatment arm:

Proportion of subjects with HIV-1 RNA < 40 c/mL at Week 48 and Week 96 using mITT 
and observed values
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
Proportion of subjects with HIV-1 RNA < 200 c/mL at Week 24, 48 and 96 using mITT and 
observed values

Change from baseline in log10 HIV-1 RNA and in CD4+ T-cell counts, and changes in the 
percentage of CD4+ T-cells over time

Newly emergent genotypic substitutions (using all on-treatment isolates) will be tabulated by 
treatment arm

The newly emergent phenotypic resistance profile (using all on-treatment isolates) will be 
tabulated by treatment arm
8.4.3
Safety Analyses
The investigators will determine the intensity of adverse events (AEs) and the relationship of 
AEs to study therapy. The investigators’ terms will be coded and grouped by system organ class 
using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) in 
production at BMS. AEs will be presented by system organ class and preferred term. 
Presentations will include both non-serious and serious adverse events, unless specified 
otherwise. If a subject had an adverse event with different intensities over time, then only the 
greatest intensity will be reported.
Deaths will be listed for enrolled subjects without regard to onset.
In analyses of fasting lipids over time, values will be excluded after the start of serum lipid 
reducing agents.
The frequency of the following safety events will be summarized by treatment arm for treated 
subjects:

SAEs

AEs leading to discontinuation of study therapy

AEs by intensity

CDC Class C AIDS events

Laboratory abnormalities by toxicity grade
8.4.4
Pharmacokinetic Analyses
The following PK parameters will be summarized by treatment arm:

Cmax: maximum observed plasma concentration

Tmax: time of maximum observed plasma concentration

Ctau: observed plasma concentration at the end of a dosing interval (eg, concentration at 
24 hours)

C0: observed pre-dose plasma concentration

AUC(TAU) : area under the concentration-time curve in one dosing interval
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8.4.4.1
Sparse Pharmacokinetic Analyses
Sparse pharmacokinetic data will be used in population PK, PK/PD and, as available, PK/VK 
analyses.
8.4.4.2
PK/PD and PK/VK Analyses
PK data obtained from this study will be pooled with data from other studies to perform an 
integrated population PK analysis, exposure-response analyses for selected safety and efficacy 
endpoints, and, as available, viral kinetic modeling of BMS-955176 in combination with other 
ARVs to support the on-going development of BMS-955176. These analyses will facilitate 
optimal dose selection for future Phase 3 studies. 
The population PK, exposure-response, and, as available, viral kinetic analyses, will be reported 
separately.
8.4.5
Biomarker Analyses
Details about the biomarker analyses will be provided in the Statistical Analysis Plan (SAP).
8.4.6
Outcomes Research Analyses
Details about the outcomes research analyses will be provided in the SAP.
8.4.7
Other Analyses (including Virologic Futility)
An analysis of virologic futility will be performed at Week 24 when the last randomized subject 
in Stage 1 completes their Week 24 visit. This analysis will be conducted to evaluate whether the 
BMS-955176 arm shows significantly worse antiviral efficacy (HIV-1 RNA < 40 c/mL using the 
FDA snapshot algorithm) than the TDF-containing arm. The comparison of Arms 1 (containing 
BMS-955176) to Arm 2 (containing TDF) will be made with one-sided, Fisher’s exact tests, 
conducted at the 0.01 probability level.
An analysis of virologic futility will be performed at Week 24 when the last randomized subject 
in Stage 2 completes their Week 24 visit. This analysis will be conducted to evaluate whether a 
BMS-955176 arm shows significantly worse antiviral efficacy (HIV-1 RNA < 40 c/mL using the 
FDA snapshot algorithm) than the TDF-containing arm. The comparison of Arms 3-4
(containing BMS-955176) to Arm 5 (containing TDF) will be made with one-sided, Fisher’s 
exact tests, conducted at the 0.01 probability level.
8.5
Interim Analyses
There are two interim analyses scheduled before the start of Stage 2.
The first interim analysis will be conducted after approximately 50% of the randomized subjects
have completed 24 weeks of therapy in Stage 1. This analysis will use the BMS equivalent of 
SDTM (Study Data Tabulation Model) data (“level 1” data) to facilitate the development of 
models for: population pharmacokinetics; exposure-response relationships; and, as available,
viral kinetics.
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A second interim analysis will be conducted after the last subject has completed 24 weeks of 
therapy in Stage 1. This will be an analysis of the available efficacy, safety, resistance and 
pharmacokinetic data.
The schedule for additional analyses will depend upon the decision to initiate the Stage 2, as well 
as the recruiting time frame of Arms 1 & 2 relative to the time frame for Arms 3, 4, and 5. If 
Stage 2 is initiated, and recruiting follows projected timelines, then it is anticipated that analyses 
will be conducted when:

The last subject in Arms 3, 4, and 5 completes the Week 24 visit

The last subject in Arms 1 and 2 completes the Week 96 visit

The last subject in Arms 3, 4, and 5 completes the Week 96 visit
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records.
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Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the 
source documents:
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS.
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
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9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include the investigational product 
and the non-investigational product(s). Records or logs must comply with applicable regulations 
and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted)

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
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The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete Abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Female subjects must continue 
to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to 
forego complete abstinence.
If two forms of contraception is required, Complete abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as complete 
avoidance of heterosexual intercourse is an acceptable form of 
contraception for all study drugs. This also means that abstinence is the 
preferred and usual lifestyle of the patient. This does not mean periodic 
abstinence (eg, calendar, ovulation, symptothermal, profession of 
abstinence for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of contraception. Subjects 
who choose complete abstinence are not required to use a second method 
of contraception, but female subjects must continue to have pregnancy 
tests. Acceptable alternate methods of highly effective contraception must 
be discussed in the event that the subject chooses to forego complete 
abstinence
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LIST OF ABBREVIATIONS
Term
Definition
3TC
Lamivudine
AE
adverse event
AI
accumulation index
AIDS
Acquired Immunodeficiency Syndrome
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after the 
first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ARV
antiretroviral
AST
aspartate aminotransferase
ATV
atazanavir
ATV/r
atazanavir boosted with ritonavir
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of 
the last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
BID, bid
bis in die, twice daily
BCRP
Breast cancer reactive protein
BDC
Bile duct-cannulated
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BVM
bevirimat
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Term
Definition
c
copies
c/mL
copies per milliliter
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
CA
capsid
cART
Combination antiretroviral therapy
Cavg
average concentration
Cexpected-tau
expected concentration in a dosing interval
CD
Cluster designation (CD4; CD8)
CDC
Centers for Disease Control
CFC
corrected fold change
CFR
Code of Federal Regulations 
CI
confidence interval
CrCl; CCL
creatinine clearance
CLR
renal clearance
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CMV
cytomegalovirus
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Css,avg
average steady-state plasma concentration
CSR
Clinical study report
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
Trough observed plasma concentration
CT
Computed tomography
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Term
Definition
CTA
clinical trial agreement
CTX
Cross-linked C-telopeptide of Type 1 collagen
CYP
cytochrome p-450
D/C
discontinue
DDI
drug-drug interaction
DHHS
Department of Health and Human Services
dL
deciliter
DTG
dolutegravir
EC
Ethics committee
EC
effective concentration
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EFV
efavirenz
eg
exempli gratia (for example)
E-R
exposure-response
ESR
Expedited Safety Report
ET
Early termination or End of Treatment
EU
European Union
FAHI
Functional Assessment of HIV Infection
FDA
Food and Drug Administration
FDC
Fixed dose combination
FSH
follicle stimulating hormone
FTC
emtricitabine
g
gram
GFR
glomerular filtration rate
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
GSH
glutathione
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Term
Definition
h; hr
hour
HAART
Highly active antiretroviral therapy
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
hepatitis C virus
HCO3-
bicarbonate
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
HS
Human serum
HuSA
Human serum albumin
IAS
International AIDS Society
IB
Investigator brochure
IC
Inhibitory concentration
ICD
International Classification of Diseases
ICF
informed consent form
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
INI
Integrase inhibitor
IP
investigational product
IRB
Institutional Review Board
IU
International Unit
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
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Term
Definition
GALT
Gut associated lymphoid tissue
GI
gastrointestinal
kg
kilogram
L
liter
MAD
multiple ascending dose
MC
micronized crystalline
mg
milligram
MI
Maturation inhibitor
MIC
minimum inhibitory concentration
min
minute
mITT
Modified Intent to Treat
mL
milliliter
mmHg
millimeters of mercury
msec
millisecond
MOA
mechanism of action
g
microgram
M
micromolar
N
number of subjects or observations
N/A
not applicable
ng
nanogram
nM
nanomolar
NIMP
non-investigational medicinal products 
NNRTI
Non- nucleoside reverse transcriptase inhibitor
NOAEL
No observed adverse effect level
NOEL
No observed effect level
NRTI
nucleoside reverse transcriptase inhibitor
NSAID
nonsteroidal anti-inflammatory drug
pDILI
potential drug induced liver injury
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
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Term
Definition
PD
pharmacodynamics
PI
protease inhibitor
PDVF
Protocol-defined virologic criteria
PK
pharmacokinetics
PPI
proton pump inhibitor
PR
atrial depolarization to ventricular depolarization
PT
prothrombin time
PTT
partial thromboplastin time
QC
quality control
QD, qd
quaque die, once daily
QRS
interval representing the time for ventricular depolarization
QT
Duration of ventricular electrical activity
QTcF
QT corrected for heart rate using Frederica’s formula
RAL
raltegravir
RBC
red blood cell
RNA
ribonucleic acid
RTV
ritonavir
SAD
single ascending dose
SDD
spray-dried dispersion
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDTM
Study Data Tabulation Model
SOP
Standard Operating Procedures
SP1
spacer peptide 1
Subj
subject
STR
single tablet regimen
t
temperature
T
time
TDF
tenofovir
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Term
Definition
TDF/FTC
Truvada (TDF 300 mg + FTC 200 mg)
TAO
Trial Access Online, the BMS implementation of an EDC capability
TAM
Thymidine analogue mutation
T-HALF
Half life
T-HALFeff_AUC
Effective elimination half life that explains the degree of AUC 
accumulation observed
Tmax, TMAX
time of maximum observed concentration
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UGT
UDP-glucuronosyltransferase
ULN
upper limit of normal
US
United States
VF
virologic failure
VK
Viral kinetics
VLP
Virus-like particles
WBC
white blood cell
WFD
Wallingford, Connecticut, USA
WHO
World Health Organization
Wk or WK
week
WOCBP
women of childbearing potential
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12
REFERENCES
1
WHO HIV Department. Global Summary of the AIDS Epidemic 2013. Available at: 
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European AIDS Clinical Society. European Guidelines for treatment of HIV-infected adults 
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Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
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United States Department of Health and Human Services, Food and Drug Administration, 
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Stellbrink HJ., Reynes J., Lazzarin A., Dolutegravir in antiretroviral-naive adults with 
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Eron JJ., Clotet B., Durant J., Safety and efficacy of dolutegravir in treatment-experienced 
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14
Bertz RJ, Persson A, Chung E, et al. Pharmacokinetics and pharmacodynamics of atazanavir-
containing antiretroviral regimens, with or without ritonavir, in patients who are 
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15
Molto J, Santos JR, Valle M, et al. Monitoring atazanavir concentrations with boosted or 
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Goutelle S, Baudry T, Gagnieu MC, et al. Pharmacokinetic-pharmacodynamic modeling of 
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18
Malan DR, Krantz E, David N, Wirtz V, Hammond J, McGrath D. Efficacy and safety of 
atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy 
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Landman R, Diallo MB, Gueye NF, et al. Efficacy and safety of unboosted atazanavir in 
combination with lamivudine and didanosine in naive HIV type 1 patients in Senegal. AIDS 
Res Hum Retroviruses. May 2010;26(5):519-525.
20
Gianotti N, Seminari E, Guffanti M, et al. Evaluation of atazanavir Ctrough, atazanavir 
genotypic inhibitory quotient, and baseline HIV genotype as predictors of a 24-week 
virological response in highly drug-experienced, HIV-infected patients treated with 
unboosted atazanavir. New Microbiol. Apr 2005;28(2):119-125.
21
Giuntini R, Martinelli C, Ricci E, et al. Efficacy and safety of boosted and unboosted 
atazanavir-containing antiretroviral regimens in real life: results from a multicentre cohort 
study. HIV Med. Jan 2010;11(1):40-45.
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22
Two Drug Combination Studies with BMS-955176 and HIV Antiviral Agents. Version 1.0. 
June 2013. DCN 930071469
23
Song I., Borland J., Chen S. Effect of atazanavir and atazanavir/ritonavir on the 
pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572. Br. J. 
Pharm. 2011 72(1):103-108
24 BMS-955176 Investigator Brochure, Version 2.0, July 2013 DCN 930056146
25 BMS-955176 Investigator Brochure, Version 3.0, April 17, 2014 DCN 930056146
26 Partial response to FDA “May Proceed” Letter dated 27 Sep 2013 for IND 118,936. Bristol-
Myers Squibb Company; Jan 2014. Document Control No. 930076507 2.0. Insert this 
additional reference: “Evaluation of cross-resistance of HIV-1 Maturation Inhibitor 
BMS-955176 toward HIV-1 protease inhibitor resistant viruses. Bristol-Myers Squibb 
Company; 30-Sept-2014. Document Control No. 930083565.”
27 Evaluation of Cross Resistance of HIV-1 Maturation Inhibitor BMS-955176 Toward HIV-1 
Protease Inhibitor Resistant Viruses. Document Control No. 930083565
28 Gilead 
Sciences. 
Prescribing 
Information 
for 
TDF. 
Available 
at: 
http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/viread/viread_pi.pdf.
Accessed Dec 31, 2014
29
ViiV 
Healthcare. 
Prescribing 
Information 
for 
DTG. 
Available 
at: 
https://www.viivhealthcare.com/media/58599/us_tivicay.pdf. Accessed Dec 31, 2014.
30 BMS. 
Prescribing 
Information 
for 
ATV. 
Available 
at: 
http://packageinserts.bms.com/pi/pi_reyataz.pdf. Accessed Dec 31, 2014
31 AbbVie. 
Prescribing 
Information 
for 
RTV. 
Available 
at: 
http://www.rxabbvie.com/pdf/norvirtab_pi.pdf. Accessed Dec 31, 2014
32 Evaluation of Cross-Resistance of HIV-1 Maturation Inhibitor BMS-955176 Toward HIV-1 
Protease Inhibitor Resistant Viruses. DCN 930083565
33
Hasler WL Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrisons 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill
34
Hasler WL and Owyang C Approach to the Patient with Gastrointestinal Disease. Chapter 
290. Harrisons Principles of Internal Medicine 18th edition. 2012. McGraw Hill
35
Soll AH and Graham DY. Peptic Ulcer Disease. Chapter 40. Textbook of Gastroenterology. 
5th edition. 2009. Blackwell Publishing
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36
Rome Foundation. Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders. 
Available: http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed 
Dec 22 2014
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APPENDIX 1
LISTINGS OF PROHIBITED AND PRECAUTIONARY
THERAPIES
General Notes: 

Guidelines for the use of drugs with established or other potentially significant drug 
interactions listed in the Package Inserts of the marketed ARV agents used by subjects 
participating in this study (Reyataz, Norvir, Viread, Tivicay) should be followed. 

Medications listed in the Package Inserts as contra-indicated with the other marketed ARV 
agents used by subjects participating in this study are not permitted. 

Any immunizations deemed appropriate by the subject’s physician are permitted provided 
that the immunization is given > 4 weeks from any HIV-1 RNA measurement.

A subject may not be co-enrolled in a concomitant trial unless it is approved by the Medical 
Monitor prior to randomization.
Prohibited Therapies
Drugs that should not be administered throughout the duration of the study:
Anticonvulsants: Carbamazepine, 
Phenobarbital, Phenytoin
Use with ATV may result in decreased ATV concentrations. Use of 
Carbamazepine may result in decreased DTG concentrations.
Oral Antifungals: Itraconazole, 
Posaconazole, and Voriconazole
Use with ATV can result in increased ATV concentrations
Antimycobacterials: Rifampin, 
Rifapentine, Rifabutin
These antimycobacterials decrease ATV plasma concentrations and 
may decrease BMS-955176 plasma concentrations.
St. John’s wort
Use with ATV or DTG may result in loss of antiviral therapeutic effect
GI motility agent: Cisapride
Potential for serious and/or life threatening reactions such as cardiac 
arrhythmias
Pimozide
Potential for serious and/or life threatening reactions such as cardiac 
arrhythmias
Zetia (ezetimibe)
Ezetimibe is a substrate of OATP1B1 (of which BMS-955176 is an 
inhibitor in vitro).
Dofetilide
Use with DTG may result in the potential for increased Dofetilide 
plasma concentrations and the risk for serious and/or life threatening 
events
Alfuzosin
ATV increases Alfuzosin concentrations which can result in 
hypotension
Benzodiazepines: Triazolam and 
Midazolam
ATV can increase the concentration of these Benzodiazepines with the 
potential to increase sedation or respiratory depression
Ergot derivatives: 
Dihydroergotamine, ergotamine, 
ergonovine, methylergonovine
ATV can increase potential for ergot toxicity (e.g. peripheral 
vasospasm)
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HMG-CoA Reductase Inhibitors: 
Lovastatin, Simvastatin, Atorvastatin, 
Pitavastatin, Rosuvastatin, Pravastatin
Use with ATV may result in increased levels of HMG-CoA Reductase 
Inhibitors and potential for serious reactions such as myopathy
Antacids, H2 receptor angatonists, 
Proton Pump Inhibitors, Sucralfate
Use with ATV may result in decreased plasma concentrations of ATV. 
Use of Antacids containing Aluminium, Magnesium, or Calcium may 
result in decreased levels of DTG.
Macrolides: Clarithromycin
Use with ATV may result in increased Clarithromycin levels and QTc 
prolongation
Buprenorphine
Use with ATV may increase levels of Buprenorphine
Quetiapine
Use with ATV may increase levels of Quetiapine
Salmeterol
Use with ATV may result in increased levels of Salmeterol
Avanafil
Use with ATV may result in increased Avanafil levels
All drugs with antiretroviral activity 
other than those considered study 
therapy
Any drugs with antiretroviral activity not considered study therapy 
may interfere with the assessments of the study.
Precautionary Therapies
Drugs that should be administered with caution during the study:
Hormonal Contraceptives
Hormonal Contraceptives cannot be relied upon as a highly effective 
method of contraception. 
See Protocol Section 3.3.1, for more information on Highly Effective 
Methods of Contraception.
Antidepressants: Trazodone, Tricyclic 
Antidepressants (TCA)
Use with ATV/r may result in increased plasma concentrations of 
trazodone and TCA
Antimalarials: Atovaquone/Proguanil, 
Mefloquine
Use with ATV/r may result in decreased Atovaquone/Proguanil levels. 
The effect of Mefloquine on ATV/r is unknown.
Benzodiazepines: Alprazolam and 
Diazepam
ATV can increase the concentration of these Benzodiazepines 
Calcium Channel Blockers
Use with ATV may result in increased concentrations of CCB’s. 
Non-topical Corticosteroids: 
Budesonide, Fluticasone, Prednisone, 
Methylprednisolone, Prednisolone, 
Triamcinolone
Use with ATV/r may result in increased levels of glucocorticoids and 
adrenal insufficiency
Dexamethasone
Use with ATV may result in reduced levels of ATV.
Colchicine
Use with ATV may result in increased Colchicine levels
Metformin
Use with DTG may result in increased levels of metformin. 
A cation-containing (e.g. Magnesium) 
laxative
If used with DTG the laxative should be taken 2 hours before or 6 
hours after taking concomitant laxatives.
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APPENDIX 2
AIDS-DEFINING DIAGNOSES
I.
PARASITIC INFECTIONS
Pneumocystis carinii (PC)
1011
PC pneumonia histologically proven.
1012
PC pneumonia, clinical diagnosis by the following specifications and confirmed HIV 
infection:
A history of dyspnea on exertion or non-productive cough of recent onset (within the past 
3 months).
AND
Chest X-ray evidence of diffuse bilateral interstitial or gallium scan evidence of diffuse 
bilateral pulmonary disease;
AND
Arterial blood gas analysis showing an arterial pO2 of < 70 mmHg or a low respiratory 
diffusing capacity (< 80% of predicted values) or an increase in the alveolar-arterial 
oxygen tension gradient;
AND
Successful response to appropriate therapy and no evidence of pneumonias of other 
etiologies.
1013
Pneumocystis carinii, histologically proven, at a site other than lungs.
Toxoplasmosis (in patients > 1 month old)
1021
Toxoplasmosis, clinical diagnosis (of brain only) by the following specifications and 
confirmed HIV infection:
Recent onset of a neurologic disease consistent with toxoplasmosis;
AND
Brain imaging evidence of a mass lesion (on computed tomography, nuclear magnetic 
resonance of radiography enhanced by injection of contrast medium);
AND
Serum antibody to toxoplasmosis and successful response to therapy for toxoplasmosis.
1022
Toxoplasmosis, of brain or internal organs other than liver, spleen or lymph nodes. 
Proven by microscopy.
Isosporiasis
1031
Isosporiasis causing chronic diarrhea of > 1 month. Proven by microscopy.
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Cryptosporidiosis
1041
Cryptosporidiosis causing chronic diarrhea of > 1 month. Proven by microscopy.
II.
FUNGAL INFECTIONS
Candidiasis
2011
Candidiasis, Esophageal, definitive diagnosis by the following specifications:
Gross inspection by endoscopy or autopsy or by microscopy (histology or cytology) on a 
specimen obtained directly from the tissues affected (including scrapings from the 
mucosal surface), not from a culture.
2012
Candidiasis, Esophageal, presumptive diagnosis by the following specifications and 
confirmed HIV infection:
Recent onset of retrosternal pain on swallowing:
AND
Oral candidiasis diagnosed by the gross appearance of white patches or plaques on an 
erythematous base OR by the microscopic appearance of fungal mycelial filaments in an 
uncultured specimen scraped from the oral mucosa;
AND
Response to appropriate therapy.
2013
Candidiasis, Bronchial/Pulmonary, definitive diagnosis by the following specifications; 
Gross inspection by endoscopy or autopsy or by microscopy (histology or cytology) on a 
specimen obtained directly from the tissues affected (including scrapings from the 
mucosal surface), not from a culture.
Cryptococcosis
2022
Cryptococcosis, Extra-pulmonary, proven by microscopy (histology or cytology), culture 
or detection of antigen in a specimen obtained directly from the tissues affected or a fluid 
from those tissues.
Histoplasmosis
2031
Histoplasmosis, Disseminated (at a site other than or in addition to lungs or cervical or 
hilar lymph nodes), proven by microscopy (histology or cytology), culture or detection of 
antigen in a specimen obtained directly from the tissues affected or a fluid from those 
tissues.
Coccidioidomycosis
2041
Coccidioidoidomycosis, Disseminated (at a site other than or in addition to lungs or 
cervical or hilar lymph nodes), proven by microscopy (histology or cytology), culture or 
detection of antigen in a specimen obtained directly from the tissues affected or a fluid 
from those tissues.
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2042
Coccidioidomycosis, clear reactivation of prior infection, proven by microscopy 
(histology or cytology), culture or detection of antigen in a specimen obtained directly 
from the tissues affected or a fluid from those tissues.
III.
BACTERIAL INFECTIONS
Mycobacterium
3001
Mycobacterium (unidentified species). Presumptive diagnosis, by the following 
specifications and confirmed HIV infection.
Acid fast bacilli (AFB) positive stain of specimen obtained from endoscopic biopsy or 
from a normal sterile site other than lungs, skin or cervical or hilar lymph nodes. Species 
NOT identified by culture.
Mycobacterium tuberculosis
3011
Mycobacterium tuberculosis, Pulmonary, definitive diagnosis proven by culture, without 
evidence of upper respiratory infection symptoms of Mycobacterium tuberculosis that 
could account for the positive culture.
3012
Mycobacterium tuberculosis, definitive diagnosis proven by culture, of at least one extra 
pulmonary site regardless of concurrent pulmonary involvement.
3013
Mycobacterium tuberculosis, Disseminated, definitive diagnosis proven by culture.
Mycobacterium avium intracellulare
3022
MAI in Blood, proven by culture.
3023
MAI Colitis, proven by histology and culture. (This does not include MAI of the stool 
alone).
3024
MAI, Disseminated, at a site other than or in addition to lungs or cervical or hilar lymph 
nodes, proven by culture.
Mycobacterium Kansasii, Mycobacterium Scrofulaceum and Other Atypical 
Mycobacterium
3032
M. Kansasii, in Blood, proven by culture.
3033
M. Kansasii Colitis, proven by histology and culture. (NOT including positive M. 
Kansasii of stool alone).
3034
M. Kansasii, Disseminated, at a site other than or in addition to lungs, or cervical or hilar 
lymph nodes, proven by culture.
3035
M. Scrofulaceum or other Atypical Mycobacterium, proven by culture.
Salmonella
3041
Salmonella, recurrent Bacteremia (non-typhoid), proven by culture.
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IV.
VIRAL INFECTIONS
Cytomegalovirus
4011
CMV, Pneumonitis, pathologically or histologically confirmed. Serum antibody titer and 
culture alone is not sufficient for the diagnosis.
4012
CMV, Esophagitis, as diagnosed by histology, pathology or culture of an esophageal 
lesion. Serum antibody titer and culture of other than esophageal tissue is not sufficient 
for the diagnosis.
4013
CMV, Retinitis as evidenced by a characteristic appearance on serial ophthalmoscopic 
examinations (eg, discrete patches of retinal whitening with distinct borders, spreading in 
a centrifugal manner, following blood vessels, progressing over several months, 
frequently associated with retinal vasculitis, hemorrhage, and necrosis). Resolution of 
active disease leaves retinal scarring and atrophy with retinal pigment epithelial mottling.
4014
CMV, Colitis, as diagnosed by histology, pathology or culture of a colonic lesion. Serum 
antibody titer and culture of other than colonic tissue is not sufficient for the diagnosis.
4015
CMV, Encephalitis, as diagnosed by histology, pathology or culture of brain tissue or 
CSF. Serum antibody titer and culture of other than brain tissue or CSF is not sufficient 
for the diagnosis.
Herpes Simplex (in patients > 1 month old).
4021
HSV, Disseminated (but not encephalitis alone), proven by microscopy (histology or 
cytology), culture or detection of antigen in a specimen obtained directly from affected 
tissues.
4022
HSV, Esophagitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for the diagnosis.
4023
HSV, Bronchitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for the diagnosis.
4024
HSV, Pneumonitis, as diagnosed by microscopy (histology or cytology), culture or 
detection of antigen in a biopsy specimen obtained directly from affected tissue. 
Serological measurement and culture from other than the affected tissue is not sufficient 
for diagnosis.
4025
HSV, GI, other than mouth, throat, or peri-rectal, as diagnosed by microscopy (histology 
or cytology), culture or detection of antigen in a biopsy specimen obtained directly from 
affected tissue. Serological measurement and culture from other than the affected tissue is 
not sufficient for diagnosis.
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4026
HSV, Mucocutaneous, ulcers persisting for 1 month despite appropriate therapy, as 
diagnosed by microscopy (histology or cytology), culture or detection of antigen in a 
biopsy specimen obtained directly from affected tissue. Serological measurement and 
culture from other than the affected tissue is not sufficient for the diagnosis.
Progressive Multifocal Leukoencephalopathy
4041
Progressive Multifocal Leukoencephalopathy, proven by microscopy.
VI.
NEOPLASTIC DISEASES
Kaposi’s Sarcoma
6011
Kaposi’s sarcoma, Mucocutaneous, proven by microscopy.
6012
Kaposi’s sarcoma. Mucocutaneous, presumptive diagnosis with characteristic gross 
appearance and confirmed HIV infection.
6013
Kaposi’s sarcoma, Visceral.
6014
Kaposi’s sarcoma, other than above.
Lymphoma of the Brain
6021
Primary Lymphoma of the brain at any age, proven by microscopy.
Non-Hodgkins Lymphoma
6031
Small Non-cleaved lymphoma (either Burkitt or non-Burkitt type).
6032
Immunoblastic sarcoma, equivalent to any of the following, although not necessarily all 
in combination: Immunoblastic lymphoma, large-cell lymphoma, diffuse histocytic 
lymphoma.
Cervical Carcinoma
6041
Histologically proven invasive carcinoma of the cervix.
VII.
OTHER CONDITIONS
HIV Dementia/Motor Defects
7011
HIV Dementia, clinical findings of disabling cognitive and/or motor dysfunction 
interfering with occupation or activities of daily living progressing over weeks to months, 
in the absence of a concurrent illness or condition other than HIV infection that could 
explain the findings. Method to rule out such concurrent illnesses and conditions must 
include cerebrospinal fluid examination and either brain imaging (computed tomography 
or magnetic resonance) or autopsy.
Slim Disease or HIV Wasting Syndrome
7021
HIV Wasting Syndrome, findings of profound involuntary weight loss > 10% of baseline 
body weight plus either chronic diarrhea (at least two loose stools per day for 30 days) 
or chronic weakness and documented fever (for 30 days, intermittent to constant) in the 
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absence of a concurrent illness or condition other than HIV infection that could explain 
the findings (eg, cancer, tuberculosis, cryptosporidiosis, or other specific enteritis).
7061
Recurrent pneumonia, acute onset within 12 months of most recent episode.
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APPENDIX 3
DAIDS TOXICITY GRADES
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events
Version 2.0 - November 2014
http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx
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APPENDIX 4
COCKCROFT-GAULT EQUATION TO CALCULATE SERUM 
CREATINE CLEARANCE
Online calculator:
http://nephron.com/cgi-bin/CGSI.cgi
Manual calculation:
Male:
Estimated Creatinine Clearance =
(140-age in years) x Body Weight (kg)
72 x Serum Creatinine (mg/dL)
Female:
Estimated Creatinine Clearance =
(140-age in years) x Body Weight (kg) x 0.85
72 x Serum Creatinine (mg/dL)
1 pound = 0.4536 kilograms
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APPENDIX 5
LABORATORY ASSESSMENTS
HEMATOLOGY
WBC
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
RBC
Hemoglobin
Hematocrit
Platelets
Absolute Differential
CHEMISTRY
Glucose
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
Total Protein
Albumin
CK
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin
AST
ALT
Alkaline Phosphatase
LDH 
Amylase
Lipase
Electrolytes (Sodium, 
Potassium, Chloride, 
Bicarbonate)
Calcium
Phosphorous
Creatinine + eGFR
Uric Acid
BUN
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LIPIDS
Cholesterol
Screening
Day 1, Week 4, Week 12, Week 24
HDL
LDL Calculated
Triglycerides
OTHER SERUM TESTS
FSH
Screening
Optional; upon request
HCG
Optional; upon 
request
Optional; upon request
P1NP
Day 1, Week 12, Week 24, Early Term
CTX
Day 1, Week 12, Week 24, Early Term
URINE
Urine Pregnancy test (if 
positive, request serum HCG)
Screening
Every 4 weeks (either done at in-clinic 
visits, or at home)
Urine Toxicology (drugs of 
abuse)
Screening
Urine Creatinine
Day 1, Week 48, Week 96, Early Term
Urine Phosphorous
2 microglobulin
Macroscopic Urinalysis (no 
microscopic)
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
SEROLOGY
HIV-1 RNA
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
HbSAg
Screening
Week 48, Week 96, Early Term
HCV Ab (if positive, reflex to 
HCV RNA)
Screening
Week 48, Week 96, Early Term
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RESISTANCE
Specimens for HIV 
Resistance testing at 
Monogram
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
Specimens for HIV 
Exploratory Resistance 
testing at BMS
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
PHARMACOKINETICS
Intensive PK
Week 2 (optional)
Sparse PK
Week 4, Week 8, Week 12, Week 16, 
Week 24
IMMUNE PANEL
%CD3+/CD4+
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
%CD3+/CD8+
Absolute CD3/CD4
Absolute CD3/CD8
OTHER
Pharmacodiagnostic (PDx)
Screening
Plasma & Serum Back-ups 
Screening
Day 1, Week 4, Week 8, Week 12, Week 
16, Week 24, Week 32, Week 40, Week 
48, Week 60, Week 72, Week 84, Week 
96, Early Term
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