Clinical trial NCT01009814
Conditions: HIV Infections
Keywords: HIV, HIV attachment inhibitor, attachment inhibitor
Sponsor: ViiV Healthcare
Start date: 2009-11-23; Completion date: 2010-06-25
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Research Hypothesis: Administration of BMS-663068, a prodrug for HIV attachment inhibitor BMS-626529, will result in a mean decrease of at least 1 log10 in HIV RNA at Day 9 following 8 days of therapy in at least one dosing regimen that is safe and well tolerated in Clade B HIV-1 infected subjects.

Detailed description:

Arms: arm 1: All participants received BMS-663068 600 milligram (mg) and Ritonavir (RTV) 100 mg every 12 hours (Q12H) from Day 1 to Day 8. arm 2: All participants received BMS-663068 1200 mg and RTV 100 mg every night (quaque hora somni \[QHS\]) from Day 1 to Day 8. arm 3: All participants received BMS-663068 1200 mg and RTV 100 mg Q12H from Day 1 to Day 8. arm 4: All participants received BMS-663068 1200 mg Q12H and RTV 100 mg every 24 hours in the morning (quaque ante meridiem \[QAM\]) from Day 1 to Day 8. arm 5: All participants received BMS-663068 1200 mg Q12H from Day 1 to Day 8.
Interventions: intervention 1: BMS-663068 intervention 2: Ritonavir
Intervention descriptions: intervention 1: BMS-663068 will be administered as a tablet formulation intervention 2: Ritonavir will be administered as a capsule.

Protocol documents:
Prot_000.pdf: 
Page:
1 
Protocol Number:
AI438006 
IND Number:
N/A  
 
Ex-US
Non IND 
 
EUDRACT Number
2009-013657-14 
 
Date:
22-Jun-2009 
 
Revised Date:
08-Mar-2010 
Clinical Protocol AI438006 
Randomized, Open label, Multiple-Dose Study to Evaluate the Pharmacodynamics, 
Safety and Pharmacokinetics of BMS-663068 in HIV-1 Infected Subjects 
Revised Protocol Number: 03 
Incorporates Amendment 04 
Study Director/ Medical Monitor 
Clinical Scientist
 MD  
 BS 
Bristol-Myers Squibb  
Bristol-Myers Squibb 
Research and Development 
311 Pennington-Rocky Hill Road 
Pennington, NJ  08534 
Research and Development 
311 Pennington-Rocky Hill Road 
Pennington, NJ  08534 
Telephone (office): 
 
Telephone (mobile): 
 
Telephone (office):  
 
Fax: 
 
Fax:  
 
Pharmacokineticist 
Statistician
 PhD 
Bristol-Myers Squibb 
Research and Development 
311 Pennington-Rocky Hill Road 
Pennington, NJ  08534 
 
Bristol-Myers Squibb 
Research and Development 
P.O. Box 5400 
Princeton, NJ  08534 
Telephone (office):  
 
Fax: 
 
Telephone (office):  
 
Fax: 
 
24-hr Emergency Telephone Number 
USA:  
 
International:  
 
Bristol-Myers Squibb Research and Development 
311 Pennington-Rocky Hill Road 
Pennington, NJ 08534
This protocol contains information that is confidential and proprietary to 
Bristol-Myers Squibb 
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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HIV-1 Attachment Inhibitor 
AI438006 
BMS-663068 
Clinical Protocol 
Revised Protocol No.: 03 
2
Date: 08-Mar-2010 
DOCUMENT HISTORY 
Document 
Date of Issue 
Summary of Change 
Original 
Protocol 
22-Jun-2009 
Not applicable 
Amendment 02 
15-Oct-2009 
Incorporated Germany Competent Authority (BfArM) request the 
change the inclusion criteria of CD4+ counts from 100 cells/L to 
200 cells/L. 
This amendment also incorporates the Ethics Committee (EC) 
request to remove ‘legally acceptable representative’ from the 
standard protocol wordings in the Informed consent section; this 
exception to Global Standards has been granted. Also incorporated 
the EC request to include study stopping rules and clarify that 
subjects who are unwilling to practice adequate infection protection 
will be excluded from this study. 
This amendment also clarifies the following: SAE reporting 
procedure and procedures to be performed for subjects who are 
prematurely discontinued from the study.  Also, laboratory 
information regarding Troponin and creatinine clearance is updated.  
Updated statistician information. Removed requirement from 
synopsis section for WOCBP to be using acceptable method of 
contraception for at least 8 weeks before dosing. 
Revised 
Protocol 01 
15-Oct-2009 
Incorporates amendment 02 
Administrative 
Letter 01 
01-Dec-2009 
Updated international emergency number 
Amendment 03 
25-Jan-2010 
Modify inclusion/exclusion criteria and clarify operational issues.  
Incorporate a secondary objective to characterize the 
pharmacokinetics of ritonavir. 
Revised 
Protocol 02 
25-Jan-2010 
Incorporates amendment 03 and administrative letter dated 01-Dec-
2009
Amendment 04 
08-Mar-2010 
This amendment clarifies that interim analyses will be conducted. 
Revised 
Protocol 03 
08-Mar-2010 
Incorporates amendment 04 
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HIV-1 Attachment Inhibitor 
AI438006 
BMS-663068 
Clinical Protocol 
SYNOPSIS
Clinical Protocol AI438006 
Title of Study: Protocol AI438006: Randomized, Open label, Multiple-Dose Study to Evaluate the 
Pharmacodynamics, Safety and Pharmacokinetics of BMS-663068 in HIV-1 Infected Subjects 
Indication:  HIV
Estimated Number of Study Centers and Countries/Regions: Approximately 6 centers in approximately 
3 countries 
Study Phase:  IIA 
Research Hypothesis:  Administration of BMS-663068, a prodrug for BMS-626529, will result in a mean 
decrease of at least 1 log10 in HIV RNA at Day 9 following 8 days of therapy in at least one dosing 
regimen that is safe and well tolerated in Clade B HIV-1 infected subjects. 
Primary Objective:  To assess the antiviral activity of BMS-626529 following administration of selected 
regimens of BMS-663068 with and without Ritonavir (RTV) administered orally to HIV infected subjects 
for 8 days.  
Secondary Objective(s): 

To assess safety and tolerability of multiple regimens of BMS-663068 with and without RTV in 
HIV infected subjects 

To assess the effect of BMS-626529 following multiple regimens of BMS-663068 on CD4+ and 
CD8+ lymphocyte counts and percents  

To assess the PK of BMS-626529 following multiple regimens of BMS-663068 with and without 
RTV in HIV infected subjects 

To asses the diurnal variation in the PK exposures of BMS-626529 following multiple regimens of 
BMS-663068 with and without RTV in HIV infected subjects 

To assess the plasma protein binding for BMS-626529 

To assess the relationships between change from baseline in log10 HIV RNA versus Inhibitory 
Quotient (IQ) and PK exposures for BMS-626529 following multiple regimens of BMS-663068
with and without RTV 

To assess the PK of RTV when coadministered with various regimens of BMS-663068 
Exploratory Objective(s): 

To explore the effect of BMS-626529 following multiple regimens of BMS-663068 with and 
without RTV on activated (DR+) CD4+ and CD8+ subsets 

To explore the effect of BMS-626529 following multiple regimens of BMS-663068 with and 
without RTV on neutralizing antibody activity 
 
Revised Protocol No.: 03
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AI438006 
BMS-663068 
Clinical Protocol 

To explore the effect of BMS-626529 following multiple regimens of BMS-663068 with and 
without RTV on HIV co-receptor usage (CCR5 versus CXCR4) and to explore the relationship 
between HIV co-receptor usage and antiviral activity  

To explore the difference in antiviral activity of BMS-626529 following multiple regimens of 
BMS-663068 with and without RTV by prior antiretroviral (ARV) treatment history (ARV naive 
versus ARV experienced) 

To explore the change in viral susceptibility measured by envelope genotype and phenotype 
Study Design:  This is a randomized, open label, multiple-dose regimens, parallel group study.  Subjects 
will be randomized into one of 5 regimen groups:  

Group 1- BMS-663068 600 mg Q12H + RTV 100 mg Q12H;  

Group 2 - BMS-663068 1200 mg QHS + RTV 100 mg QHS;  

Group 3 - BMS-663068 1200 mg Q12H + RTV 100 mg Q12H;  

Group 4 - BMS-663068 1200 mg Q12H + RTV 100 mg QAM;  

Group 5 - BMS-663068 1200 mg Q12H.  
Each regimen group will consist of 10 subjects.  Subjects in each regimen will be randomized and stratified 
by prior antiretroviral treatment history (ARV naive versus ARV experienced). ARV naive is defined as no 
prior ARV therapy of  1 week. Each regimen group will contain approximately the same distribution of 
ARV naive and ARV experienced subjects.  No more than 70% of the total population will be ARV naive 
or ARV experienced.  All regimen groups may initiate dosing simultaneously.     
All regimens will be administered under fed conditions.  Subjects in Group 2 (QHS regimen group) will 
receive study drug every 24 hours in the evening from Day 1 to Day 8.  Subjects in Group 4 (RTV QAM 
regimen group) will receive BMS-663068 every 12 hours and RTV every 24 hours in the morning (with 
BMS-663068) from Day 1 to Day 8.  Subjects in Groups 1, 3 and 5 (Q12H regimen group) will receive 
study drug every 12 hours from Day 1 to Day 8. Plasma HIV RNA levels will be measured before study 
drug administration on the mornings of Day 1 to Day 8 in groups 1, 3, 4 and 5 and pre-PM drug 
administration in group 2. 
ECG and vital sign assessments will be done at select times during the study.  Blood and urine samples for 
clinical laboratory evaluations will be collected at specified time points throughout the study. Serial blood 
samples for pharmacokinetic determinations will be obtained on Days 1 and 8 to 11. Blood samples for 
trough concentrations will be obtained on Days 5 through 7 prior to morning study drug administrations 
(prior to evening administration for QHS regimen group) for Ctrough and steady-state assessment. In 
addition, blood samples for protein binding assay will be collected at specified timepoints throughout the 
study and selected regimen groups will be analyzed. 
Blood for CD4+ and CD8+ lymphocyte counts and percents and activated (DR+) CD4+ and CD8+ subsets, 
genotyping, phenotyping, HIV co-receptor usage (CCR5 versus CXCR4), exploratory resistance analysis, 
measurement of neutralizing antibody activity will be collected at specified timepoints throughout the 
study. Samples for genotyping, phenotyping, HIV co-receptor usage, exploratory resistance analysis, 
activation markers, exploratory apoptotic markers and neutralizing antibody activity will generally be 
stored and analyzed if deemed relevant. Screening samples for population RT/Pol genotyping to confirm 
that all subjects are infected with clade B HIV will be analyzed in all enrolled subjects. Day 1 predose 
samples for envelope phenotyping will be collected and analyzed for all randomized subjects. 
The following table summarizes the study design and study parameters. 
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HIV-1 Attachment Inhibitor 
AI438006 
BMS-663068 
Clinical Protocol 
Study Design Table 
 
Regimen 
Group 1  
(N=10)
Regimen 
Group 2  
(N=10)
Regimen 
Group 3 
 (N=10) 
Regimen 
Group 4  
(N=10)
Regimen 
Group 5 
 (N=10) 
Dose and Regimen 
600 mg 
BMS-
663068 
Q12H + 
100 mg 
RTV Q12H 
1200 mg 
BMS-
663068 
QHS + 100 
mg RTV 
QHS
1200 mg  
BMS-
663068 
Q12H + 
100 mg 
RTV Q12H 
1200 mg    
BMS-
663068 
Q12H + 
100 mg 
RTV 
QAM 
1200 mg  
BMS-
663068 
Q12H
Days subjects 
receive BMS-
663068 
Day 1-8 
In-patient Days 
Day -1 to Day 11 
Furlough from 
clinical unit  
Day 11 
Out-patient visits  
Day 15 and (Day 50 +/- 3 days) 
Discharge from 
Study 
Day 50 +/- 3 days 
Duration of Study:  Subjects will be in the study approximately 88 days.  Study participation includes a 
35-day screening period and follow-up visits.  Subjects will remain in the clinical facility from Day -1 
through Day 11. 
Number of Subjects:  50
Study Population:  HIV-1infected subjects  18 years of age and a BMI of 18 - 35kg/m2, with CD4+ 
lymphocyte count  200 cells/L and with plasma HIV RNA  5000 copies/mL who have not been on 
ARV therapy for  8 weeks and who are either ARV experienced or ARV naive (naive defined as: no prior 
ARV therapy of  1 week), and who are otherwise medically stable as determined by medical history, 
physical examination, 12-lead electrocardiogram, and clinical laboratory evaluations will be eligible to 
participate in the study.  Females must have a negative pregnancy test within 24 hours prior to start of study 
medication. Women of childbearing potential must not be nursing or pregnant and must be using an 
acceptable method of contraception.  
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with 
Investigational Product(s):  In 5 regimen groups (BMS-663068 600 mg Q12H + RTV 100 mg Q12H, 
BMS-663068 1200 mg QHS + RTV 100 mg QHS, BMS-663068 1200 mg Q12H + RTV 100 mg Q12H, 
BMS-663068 1200 mg Q12H + RTV 100 mg QAM, BMS-663068 1200 mg Q12H), each subject will be 
administered RTV capsules and/or BMS-663068 extended release tablets orally on Days 1-8. 
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HIV-1 Attachment Inhibitor 
AI438006 
BMS-663068 
Clinical Protocol 
Study Assessments and Endpoints:  

Safety Outcome Measures:  Safety assessments will be based on medical review of adverse event 
reports and the results of vital sign measurements, ECGs, physical examinations, and clinical 
laboratory tests. The incidence of observed adverse events will be tabulated and reviewed for potential 
significance and clinical importance.

Pharmacokinetic Measures: For each dosing regimen, pharmacokinetic parameters for BMS-626529 
and RTV (Cmax, Ctrough, Tmax, Css,avg, AUC(TAU), AUC(0-24), T-HALF, CLT/F, Vss/F, and AI) 
will be derived from plasma concentration versus time data. IQ for BMS-626529 will be calculated. 
Plasma protein binding (%) for BMS-626529 will be determined.  

Pharmacodynamic Measures:  Pharmacodynamic assessment will be based on change in HIV RNA.  
Additionally, CD4+ and CD8+ lymphocyte counts and percents will be assessed. 

Exploratory Measures:  Activated (DR+) CD4+ and CD8+ subsets, changes in envelope genotypes and 
phenotypes, HIV co-receptor usage (CCR5 versus CXCR4), and measurement of neutralizing antibody 
activity will be assessed, if deemed relevant.  
Statistical Methods: 
Sample Size Determination:   The sample size evaluation is based on the primary objective of the study, 
to assess the antiviral activity of BMS-626529 following administration of selected regimens of BMS-
663068 with and without RTV administered orally to HIV infected subjects for 8 days. A mean decrease 
from baseline in HIV RNA of at least 1 log10 at Day 9 within any one regimen group may suggest that that 
dose of BMS-663068 is sufficiently active against HIV to proceed with further development of the drug.  If 
the BMS-663068 containing regimen has no effect, then administration of the regimen to 10 subjects (ARV 
naive or experienced) would provide a 1% probability to observe a mean log10 drop of 1. If the true 
population mean decrease from baseline in HIV RNA is 1.5 log10, then there would be a 99% probability 
that the observed mean decline from baseline would be 1 log10. In addition, 10 subjects within each group 
can also provide >99% power to conclude the mean decreases in log10 HIV RNA from baseline > 0 if the 
true population decrease from that group is 1 log10.  Meanwhile, 10 subjects in each group can also 
provide 82% power to conclude the mean decreases in log10 HIV RNA from two groups are different if the 
true difference in population mean decreases from these two groups is 0.6 log10. 
In addition, administration of the BMS-663068 containing regimens to 10 subjects per group provides an 
80% probability of observing at least one occurrence in that regimen group of any adverse event that would 
occur with 15% incidence in the population from which the sample is drawn.   
For these calculations, it is assumed that the log10 decrease in HIV RNA from baseline to Day 9 is 
normally distributed, with a standard deviation of 0.5, as estimated from AI430003. 
Statistical Analysis:  Although the final decision on the further evaluation of BMS-663068 will be a 
broader scientific assessment of its benefit/risk profile, including consideration of safety and other 
endpoints as previously outlined, plus relevant information external to this trial, a mean decrease from 
baseline in HIV RNA of at least 1 log10 on Day 9 within any one regimen group may suggest that that dose 
of BMS-663068 is sufficiently active against HIV.  
The magnitude of the change in log10 HIV RNA levels will be assessed by summarizing changes from 
baseline, including 90% confidence intervals, by study day, regimen group, antiretroviral treatment history 
(ARV naive, ARV experienced, and combined [ARV naive + ARV experienced]). The primary assessment 
of the antiviral activity of BMS-663068 containing regimens will be based on the log10 change from 
baseline in HIV RNA to Day 9. To assess the dependency on dose, scatter plots of log10 change from 
Revised Protocol No.: 03
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HIV-1 Attachment Inhibitor 
AI438006 
BMS-663068 
Clinical Protocol 
baseline in HIV RNA at Day 9 versus dose will be provided.  Two groups t-test will be used to test the 
differences in mean log10 decrease in HIV RNA at Day 9 between two regimen groups by antiretroviral 
treatment history (ARV naive, ARV experienced, and combined [ARV naive + ARV experienced]). Each 
individual’s maximum log10 decrease from baseline in HIV RNA will be summarized by regimen group, 
antiretroviral treatment history (ARV naive, ARV experienced, and combined [ARV naive + ARV 
experienced]), and frequency distributions for maximum log10 decrease from baseline in HIV RNA will be 
provided by regimen group, antiretroviral treatment history (ARV naive, ARV experienced, and combined 
[ARV naive + ARV experienced]).    
All recorded adverse events will be listed and tabulated by system organ class, MedDRA preferred term 
and summarized by regimen group. Vital signs and results from routine laboratory tests will be listed and 
summarized by regimen group. Any significant physical exam findings and clinical laboratory results will 
be listed. ECG readings will be evaluated by the investigator and abnormalities, if present, will be listed. 
The multiple-dose pharmacokinetics of BMS-626529 and RTV will be described by summary statistics for 
the pharmacokinetic parameters by regimen group, study day, antiretroviral treatment history (ARV naive, 
ARV experienced, and combined [ARV naive + ARV experienced]). Point estimates and 90% confidence 
intervals will be constructed for accumulation indices (ratio of day 8 vs. day 1 for AUC(TAU), Cmax and 
Ctrough) by regimen group. These estimates will be generated using general linear models fitted to log-
transformed data.  Similar analysis will also be used to access the effect of RTV on PK exposure of BMS-
626529 and diurnal variation for groups 1, 3, 4 and 5. To assess the dependency of BMS-626529 on dose, 
scatter plots of Cmax, AUC(TAU), and Ctrough versus dose will be provided by day. Time to steady-state 
will be evaluated by summary statistics of Ctrough and by plotting geometric mean Ctrough versus study 
day.  
Protein binding for BMS-626529 will be evaluated by summary statistics and tabulated by regimen group. 
The effect of BMS-626529 following multiple regimens of BMS-663068 with and without RTV on PD 
measures (i.e., CD4+ and CD8+ T lymphocyte counts and percents and the corresponding changes in these 
parameters from baseline) will be assessed by summary statistics. Scatter plots will be used to assess the 
relationship between the changes from baseline in plasma HIV RNA and BMS-626529 protein biding 
adjusted EC90, a threshold of protein binding adjusted EC90 will be determined based on this scatter plot 
and summary statistics will be provided for the changes from baseline in plasma HIV RNA by regimen 
group, excluding subjects with protein binding adjusted EC90 above this threshold.    
Scatter plots will also be used to assess the relationship between the changes from baseline in plasma HIV 
RNA and BMS-626529 IQs and to assess the correlation between log10 changes from baseline in HIV 
RNA and IQs. Summary statistics for exploratory biomarkers and corresponding changes from baseline, or 
percent changes from baseline as appropriate, will be tabulated by regimen group, study day and time point.  
Possible associations between changes in exploratory biomarkers of interest and BMS-6603068 dose or 
exposure will be explored graphically and by suitable statistical models, if appropriate. Some nonlinear 
models, such as but not limited to generalized least squares, will also be explored. Ad-hoc statistical 
analysis would be considered. 
Revised Protocol No.: 03
Date: 08-Mar-2010
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TABLE OF CONTENTS
TITLE PAGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   1
DOCUMENT HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   2
SYNOPSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   3
TABLE OF CONTENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   8
1 INTRODUCTION AND STUDY RATIONALE . . . . . . . . . . .  14
1.1 Research Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . .  14
1.2 Investigational Product Development Rationale. . . . . .  14
1.3 Summary of Results of Investigational Program . . . . .  15
1.3.1 Virology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   15
1.3.1.1 BMS-663068. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   15
1.3.1.2 BMS-626529. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   15
1.3.2 Toxicology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   16
1.3.3 Preclinical Metabolism and Pharmacokinetics . . . . . . . . . .   17
1.3.3.1 Absorption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   18
1.3.3.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   18
1.3.3.3 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   18
1.3.3.4 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   19
1.3.4 Phase I Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . .   20
1.3.4.1 BMS-663068 Single Ascending Dose Study in
Healthy Subjects (AI438001) . . . . . . . . . . . . . . . . . . . . . . .   21
1.3.4.2 BMS-663068 Site of Absorption Study in Healthy
Subjects (AI438002) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   22
HIV-1 Attachment Inhibitor
AI438006
BMS-663068
Clinical Protocol
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1.3.4.3 Bioavailability Study Assessing 3 Extending Release
Formulations of BMS-663068 (AI438003) . . . . . . . . . . . . .   22
1.3.4.4 BMS-663068 Multiple Ascending Dose Study in
Healthy Subjects (AI438004) . . . . . . . . . . . . . . . . . . . . . . .   23
1.3.4.5 BMS-663068 ADME study in Healthy Subjects
(AI438005) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   23
1.3.4.6 BMS-626529 Single Ascending Dose Study in
Healthy Subjects (AI434001) . . . . . . . . . . . . . . . . . . . . . . .   24
1.3.5 Ritonavir (Norvir®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   24
1.4 Study Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  25
1.5 Overall Risk/Benefit Assessment . . . . . . . . . . . . . . . . .  27
1.5.1 BMS-663068. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   27
1.5.2 Ritonavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   29
2 STUDY OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  29
2.1 Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  29
2.2 Secondary Objectives. . . . . . . . . . . . . . . . . . . . . . . . . .  29
2.3 Exploratory Objectives . . . . . . . . . . . . . . . . . . . . . . . . .  30
3 ETHICAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . .  30
3.1 Good Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . .  30
3.2 Institutional Review Board/Independent Ethics
Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  31
3.3 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  31
4 INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . .  32
4.1 Study Design and Duration. . . . . . . . . . . . . . . . . . . . . .  32
4.2 Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  34
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BMS-663068
Clinical Protocol
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4.2.1 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   34
4.2.2 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   36
4.2.3 Discontinuation of Subjects from Treatment . . . . . . . . . . . .   39
5 TREATMENTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  40
5.1 Study Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  40
5.1.1 Investigational Product . . . . . . . . . . . . . . . . . . . . . . . . . . . .   42
5.1.2 Noninvestigational Product . . . . . . . . . . . . . . . . . . . . . . . . .   42
5.1.3 Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   43
5.1.4 Packaging and Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . .   43
5.1.5 Handling and Dispensing . . . . . . . . . . . . . . . . . . . . . . . . . .   43
5.2 Method of Assigning Subjects to a Treatment . . . . . . .  44
5.3 Selection and Timing of Dose for Each Subject . . . . . .  44
5.3.1 Dose Modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   44
5.4 Blinding/Unblinding. . . . . . . . . . . . . . . . . . . . . . . . . . . .  44
5.5 Concomitant Treatments . . . . . . . . . . . . . . . . . . . . . . .  45
5.5.1 Prohibited and/or Restricted Treatments . . . . . . . . . . . . . .   45
5.5.2 Other Restrictions and Precautions . . . . . . . . . . . . . . . . . .   45
5.6 Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . .  46
6 STUDY ASSESSMENTS AND PROCEDURES . . . . . . . . .  47
6.1 Flow Chart/Time and Events Schedule . . . . . . . . . . . .  47
6.2 Study Materials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  51
6.3 Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . .  51
6.3.1 Medical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   51
6.3.2 Vital Signs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   52
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6.3.3 Physical Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . .   52
6.3.4 Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   52
6.3.5 Electrocardiograms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   53
6.3.6 Adverse Event Monitoring. . . . . . . . . . . . . . . . . . . . . . . . . .   53
6.3.7 Laboratory Test Assessments . . . . . . . . . . . . . . . . . . . . . .   53
6.4 Efficacy Assessments. . . . . . . . . . . . . . . . . . . . . . . . . .  55
6.5 Pharmacokinetic Assessments. . . . . . . . . . . . . . . . . . .  55
6.5.1 Pharmacokinetics: Collection and Processing . . . . . . . . . .   55
6.5.2 Pharmacokinetic Sample Analyses. . . . . . . . . . . . . . . . . . .   57
6.5.3 Labeling and Shipping of Biological Samples . . . . . . . . . . .   57
6.6 Pharmacodynamics Assessments . . . . . . . . . . . . . . . .  57
6.7 Pharmacogenomic/Pharmacogenetic Assessments . .  58
6.8 Outcomes Research Assessments . . . . . . . . . . . . . . .  58
6.9 Other Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . .  58
6.9.1 Exploratory Biomarkers. . . . . . . . . . . . . . . . . . . . . . . . . . . .   58
7 ADVERSE EVENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  59
7.1 Definitions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  59
7.1.1 Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . .   59
7.1.2 Nonserious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . .   60
7.2 Assignment of Adverse Event Intensity and
Relationship to Study Drug. . . . . . . . . . . . . . . . . . . . . . .  61
7.3 Collection and Reporting . . . . . . . . . . . . . . . . . . . . . . .  61
7.3.1 Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . .   62
7.3.2 Handling of Expedited Safety Reports . . . . . . . . . . . . . . . .   63
7.3.3 Nonserious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . .   64
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7.4 Laboratory Test Abnormalities . . . . . . . . . . . . . . . . . . .  64
7.5 Overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  65
7.6 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  65
7.6.1 Requirements for Pregnancy Testing . . . . . . . . . . . . . . . . .   65
7.6.2 Reporting of Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . .   66
7.7 Other Safety Considerations . . . . . . . . . . . . . . . . . . . .  67
8 STATISTICAL CONSIDERATIONS. . . . . . . . . . . . . . . . . . .  67
8.1 Sample Size Determination . . . . . . . . . . . . . . . . . . . . .  67
8.2 Populations for Analyses . . . . . . . . . . . . . . . . . . . . . . .  68
8.3 Endpoint Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . .  68
8.3.1 Safety Endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   68
8.3.2 Pharmacokinetic Endpoint(s) . . . . . . . . . . . . . . . . . . . . . . .   68
8.3.3 Pharmacodynamic Endpoint(s). . . . . . . . . . . . . . . . . . . . . .   69
8.4 Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  69
8.4.1 Demographics and Baseline Characteristics . . . . . . . . . . .   69
8.4.2 Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   69
8.4.3 Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   69
8.4.4 Pharmacokinetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . .   70
8.4.5 Pharmacodynamic Analyses. . . . . . . . . . . . . . . . . . . . . . . .   71
8.4.5.1 Pharmacokinetics/ Pharmacodynamic Analyses . . . .   72
8.4.6 Pharmacogenomic Analyses . . . . . . . . . . . . . . . . . . . . . . .   72
8.4.7 Outcomes Research Analyses . . . . . . . . . . . . . . . . . . . . . .   72
8.4.8 Other Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   72
8.5 Interim Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  73
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9 ADMINISTRATIVE SECTION . . . . . . . . . . . . . . . . . . . . . . .  73
9.1 Compliance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  73
9.1.1 Compliance with the Protocol and Protocol Revisions . . . .   73
9.1.2 Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   74
9.1.3 Investigational Site Training . . . . . . . . . . . . . . . . . . . . . . . .   74
9.2 Records Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . .  75
9.2.1 Case Report Forms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   75
9.2.2 Study Drug Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   76
9.3 Destruction and Return of Study Drug . . . . . . . . . . . . .  77
9.3.1 Destruction of Study Drug. . . . . . . . . . . . . . . . . . . . . . . . . .   77
9.3.2 Return of Study Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   77
9.4 Publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  78
10 GLOSSARY OF TERMS . . . . . . . . . . . . . . . . . . . . . . . . . .  79
11 LIST OF ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . .  80
12 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  83
APPENDIX 1 ADDITIONAL ETHICAL CONSIDERATIONS. .  86
APPENDIX 2 DIAGNOSTIC CRITERIA FOR DRUG AND
ALCOHOL ABUSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  90
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1 
INTRODUCTION AND STUDY RATIONALE 
1.1 
Research Hypothesis  
Administration of BMS-663068, a prodrug for BMS-626529, will result in a mean 
decrease of at least 1 log10 in HIV RNA at Day 9 following 8 days of therapy in at least 
one dosing regimen that is safe and well tolerated in Clade B HIV-1 infected subjects. 
1.2 
Investigational Product Development Rationale 
Infection with HIV-1 is recognized as being of pandemic proportions, with death from 
acquired immunodeficiency syndrome (AIDS) continuing to be a leading cause of death 
in adults between the ages of 25 and 44 in developed countries, and still more devastating 
in the developing world. Despite the availability of a number of different classes of 
antiretroviral agents providing a variety of treatment options, treatment failure continues 
to occur as a result of viral heterogeneity, drug-associated toxicity, and poor adherence 
with the emergence of drug-resistant strains. Transmission of antiretroviral resistant 
viruses in newly diagnosed HIV infections has been documented1,2 and is expected to 
continue. New classes of antiretroviral drugs that are safe, tolerable and able to provide 
potent, durable antiviral activity with different mechanisms of action are needed. 
BMS-663068 is a methyl phosphate prodrug of BMS-626529,3,4 and represents one of a 
novel class of antiretroviral agents that blocks the first step of viral entry, namely the 
attachment of viral gp120 envelope to the cellular CD4 receptor. BMS-626529, the active 
moiety of BMS-663068, is efficacious against macrophage-, T-cell-, and dual tropic 
laboratory HIV-1 strains. By virtue of its novel mechanism of action, BMS-663068 is 
expected to have inhibitory activity against viral strains that exhibit resistance to other 
antiretroviral agents. Additionally, given its mechanistic and intrinsic properties, 
BMS-663068 will fill an unmet medical need and will be an important addition to the 
available antiretroviral armamentarium. 
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1.3 
Summary of Results of Investigational Program 
1.3.1 
Virology 
1.3.1.1 
BMS-663068 
In vitro data show that BMS-663068 itself has significantly less antiviral activity than 
BMS-626529, and that hydrolysis to the parent is required for potent fusion 
inhibition.  Further information is provided in the Investigator Brochure for BMS-
663068.5
1.3.1.2 
BMS-626529 
BMS-626529 is an attachment inhibitor that binds to the HIV-1 envelope glycoprotein 
gp120 and selectively inhibit the interaction between the virus and its host receptor CD4, 
thereby preventing the fusion of viral and cellular membranes. 
In cell culture assays, BMS-626529 blocked the infection of eight of nine macrophage-, 
T-, and dual tropic laboratory strains of B subtype HIV-1 with EC50 values ranging from 
0.41 to 58 nM (the ninth strain had an EC50 value of >2000 nM). It also exhibited potent 
antiviral activity against non-subtype B clinical isolates, with a median EC50 of 2.8 nM. 
BMS-626529 was inactive against HIV-2 strain 287 and other RNA viruses. It did not 
affect the major HIV-1 enzymes, reverse transcriptase, protease, or integrase, and its 
activity was minimally affected (1.5 to 2.1 fold increase in EC50) by the presence of 40% 
human serum. Cytotoxicity in cell culture was low, with EC50 values ranging from 105 to 
> 200 M in 13 cell lines examined. Finally, in a two-drug combination study in cell 
culture, BMS-626529 showed additive to synergistic interactions with 19 approved 
anti-HIV drugs. No antagonism of antiviral efficacy, or enhancement of cytotoxicity was 
seen with any of the two-drug combinations. Thus, BMS-626529 is a potent attachment 
inhibitor which merits further investigation for possible use in anti-HIV combination 
therapy. 
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1.3.2 
Toxicology 
Nonclinical toxicology studies in rats and dogs were conducted with both BMS-626529 
(active moiety) and BMS-663068 (prodrug). In vivo exposures to BMS-626529 were 
generally higher following oral administration to rats and dogs of BMS-663068. There 
was no target organ toxicity following oral administration of BMS-626529 for 2 weeks in 
either rats or dogs. In a 2-week oral toxicity study of BMS-663068 in rats, the 
no-observed-adverse-effect-level (NOAEL) was  300 mg/kg/day (mean BMS-626529 
AUC  1822 g•h/mL) with only minimal clinical pathology perturbations and organ 
weight changes that lacked correlation with other parameters. In a 1-month oral toxicity 
study in rats at doses of 0, 100, 300 and 1000 mg/kg/day, drug-related effects at 300 
and/or 1000 mg/kg/day (AUC  1860 g•h/mL) included the following: increased kidney 
weights (5 to 23%); minimal glomerulopathy, that generally (although not directly in 
individual animals) correlated with an increased urine total protein output (1.35 to 1.48x); 
increased incidence of mammary gland hyperplasia in females and a shift in estrous 
cyclicity that correlated with decreased uterine weight (~30%) and an increased incidence 
of minimal to slight degeneration of seminiferous tubular epithelium. The NOAEL for 
the 1-month study was 100 mg/kg/day (Day 30 mean AUC  1510 g•h/mL).   
In a 2-week dog study of BMS-663068, mortality and severe toxicity occurred in dogs at 
the high dose of 300/200 mg/kg/day (mean BMS-626529 AUC  851 g•hr/mL) and was 
characterized by persistent decreased physical activity, emesis, joint pain, anemia, 
increased fibrinogen, necrosis and inflammation of the adrenal gland, lymphoid 
depletion, and inflammatory lesions of the joints, heart, and meninges. BMS-663068 at 
100 mg/kg/day (mean BMS- 626529 AUC 307 - 593 g•hr/mL) was associated with 
transient decreases in physical activity, emesis and joint pain, but there were no 
microscopic correlates. BMS-663068 at 30 mg/kg/day (mean AUC  130 g•h/mL) 
produced transient decreases in physical activity only, and was considered the NOAEL. 
A 1-month oral toxicity study in dogs was conducted at doses of 0, 50, 100, 150 and 200 
mg/kg/day. Dogs that received  100 mg/kg/day (mean Day 29 AUC  477 ghr/mL) 
had prominent effects that included neurologic signs of toxicity, body-weight loss, 
increases in bilirubin, and cortical hemorrhage and coagulative necrosis of the adrenal 
gland. BMS-663068 was not tolerated at 200 mg/kg/day (mean Day 19/18 AUC  853 
gh/mL) resulting in euthanasia of 1 dog on Day 15 and early termination of this dose 
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level on Days 19/20. BMS-663068 was not genotoxic in standard genetic toxicity assays. 
Administration of either BMS-663068 or BMS-626529 prolonged (~8 to 18 msec) the 
QT interval of telemetered dogs at plasma BMS-626529 concentrations  3.6 g/mL but 
there was no drug-related effect on QT interval at plasma BMS-626529 concentrations 
 2.5 g/mL.   
BMS-663068 and BMS-626529 absorbed light in the 290 to 700 nm range.  The 
definitive in vitro phototoxicity assay in Balb/C3Tc mouse fibroblasts indicated that 
BMS-626529 had no phototoxic potential (preliminary data from study DS09011). 
BMS-663068 was administered to pregnant rats during the period of organogenesis at 
doses of 0, 100, 300, 600 and 1000 mg/kg/day. 6  BMS-663068 was well-tolerated at 100 
mg/kg/day (AUC 1430 μgh/mL). At  300 mg/kg/day, however, maternal toxicities 
were evident; and at 1000 mg/kg/day, developmental toxicities were also observed.  
Maternal toxicity included reductions in food consumption and group mean body 
weights, thinning hair or alopecia, and red perivaginal substance. Developmental 
toxicities consisted of fetal malformations (including cleft palate, microstomia and oral 
cleft) and variations as well as a reduction in mean fetal body weights. The definitive 
embryo-fetal development study in rats has not been performed and will be completed 
prior to the start of Phase 2B. 
Further information is provided in the Investigator Brochure for BMS-663068.5
1.3.3 
Preclinical Metabolism and Pharmacokinetics 
BMS-663068 is the methyl phosphate prodrug of the active HIV attachment inhibitor, 
BMS-626529. A series of exploratory and definitive (GLP) in vitro and in vivo PK and 
metabolism studies were conducted in rats, dogs, and monkeys to provide a preliminary 
assessment of the absorption, distribution, metabolism, and elimination (ADME) of 
BMS-663068.7
BMS-663068 was hydrolyzed to form the active parent BMS-626529 in the presence of 
sera, hepatocytes, and human placental alkaline phosphatase (ALP).  The conversion of 
BMS-663068 to BMS-626529 was near stoichiometric in the hepatocyte incubations, 
suggesting that non-hydrolytic metabolic pathways play minor roles for BMS-663068 in 
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the liver.  BMS-626529 was rapidly formed following IV administration of BMS-663068 
in rats, dogs and monkeys.  The absolute oral bioavailability of BMS-626529 following 
oral administration of BMS-663068 was 80% in rats and essentially 100% in dogs and 
monkeys, with very little or no BMS-663068 detected in the plasma. 
The results of two-week toxicokinetic studies in rats and dogs show that, following daily 
oral doses of BMS-663068, systemic exposure to BMS-663068 is minimal and that 
systemic exposure to BMS-626529 increases with dose in a less than dose-proportional 
manner, remains unchanged with repeated dosing, and is not substantially different for 
males and female. 
1.3.3.1 
Absorption 
BMS-663068 exhibited low permeability in Caco-2 cells (Pc = 14-18 nm/sec) whereas 
BMS-626529 showed good Caco-2 permeability (Pc = 111 nm/sec).8 No or very low 
levels of BMS-663068 were detected in rat, dog and monkey plasma after oral 
administration of BMS-663068.  The absolute bioavailability of BMS-626529 following 
oral administration of BMS-663068 was greater than 80% in rats, dogs and monkeys.  It 
is likely that following oral administration of BMS-663068, BMS-663068 was 
hydrolyzed to form BMS-626529 by ALP at the brush border membranes of the intestinal 
lumen, and BMS-626529 was readily absorbed due to its high permeability. 
1.3.3.2 
Distribution 
The steady-state volume of distribution of BMS-663068 ranged from 0.21 to 0.51 L/kg in 
rats, dogs, and monkeys, indicating limited extravascular (tissue) distribution.7  The 
percent of BMS-663068 bound to plasma protein was not determined due to instability of 
BMS-663068 in serum.7  For BMS-626529, protein binding was 95.1% and 84.0% in rat 
and human sera, respectively.8
1.3.3.3 
Metabolism 
The prodrug BMS-663068 is hydrolyzed to BMS-626529, the active compound.  The 
reaction appears to be catalyzed by hydrolytic enzymes, particularly ALP.  The in vitro
hydrolysis of BMS-663068 to BMS-626529 was evaluated in a variety of species using 
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liver microsomes and hepatocyte preparations.  In mouse, rat, dog, monkey and human 
liver microsomes, the metabolic clearance of BMS-663068 was low, suggesting relatively 
low ALP activities in these microsomal preparations and an absence of oxidative 
metabolism of BMS-663068. 
During comparative in vitro metabolism studies of BMS-626529 conducted in human, rat 
and chimpanzee liver microsomes, human, monkey and dog hepatocytes, and aroclor and 
non-aroclor-induced rat liver S9, 6 metabolites were identified as follows: a 
monooxygenated metabolite on the piperazine ring of BMS-626529 (M1), an 
O-demethylated and dehydrogenated metabolite of BMS-626529 (M2), debenzoylated 
BMS-626529 (M3), a dehydrogenated metabolite on the piperazine ring of BMS-626529 
(M4), a monooxygenated metabolite on the azaindole ring system of BMS-626529 (M6) 
and a piperazine ring-opened metabolite of BMS-626529 (M7).8 The extents of these 
pathways are unknown. 
No direct in vivo metabolism studies of BMS-663068 were conducted, but in vivo
biotransformation studies with BMS-626529 were conducted in rats, dogs, cynomolgus 
monkeys and chimpanzees.8  In a bile duct-cannulated rat study, BMS-626529 was the 
predominant drug-related component in rat plasma with only trace amounts of M1, M4 
and M7.  In rat bile, metabolites M1, M6, M7 and M5 (mono-oxygenated metabolite on 
the azaindole ring system of BMS-626529) were identified, but BMS-626529 appeared to 
be the major drug-related component.  No metabolites or BMS-626529 were identified in 
rat urine.  In plasma from monkeys and dogs, BMS-626529 appeared to be the major 
drug-related component but M7 was also identified.  In chimpanzee plasma, M1, M3, 
M4, M7 and BMS-626529 were identified.  In chimpanzee urine, M1, M3, M7 and 
BMS-626529 were all identified.  Preliminary data suggest the debenzoylated pathway 
(M3 metabolite) may be an important pathway in humans (preliminary data - subject to 
change). 
1.3.3.4 
Elimination 
In dogs, mean recoveries of administered radiolabeled BMS-663068 through 168 h 
postdose were 64.44% in feces and 21.73% in urine.9 Elimination t1/2 in rats, dogs, and 
monkeys were all less than 0.5 hours for BMS-663068 and 3.2, 4.2, and 3.2 hours for 
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BMS-626529, respectively.7  Based on the rapid appearance of BMS-626529 and lack of 
BMS-663068 in plasma following administration of BMS-663068, hydrolysis to 
BMS-626529 appears to be the major elimination pathway for BMS-663068 in vivo. 
Renal excretion is a minor pathway for BMS-626529 in chimpanzee.8  In bile duct-
cannulated (BDC) dogs, mean recoveries of the administered dose through 48 h postdose 
were 27.34% in bile, 22.71% in urine and 21.27% in feces.  Preliminary data in BDC rats 
indicate that ~35% of the administered radioactivity was recovered in bile (collected up 
to 24 h) following an oral administration of 14C-BMS-663068.
1.3.4 
Phase I Clinical Studies 
The safety, tolerability, and PK of BMS-663068 were evaluated in a single ascending 
dose (SAD) study in healthy volunteers (AI438001), a GI site of absorption study 
(AI438002), a relative bioavailabilty study of 3 ER formulations (AI438003), a multiple 
ascending dose (MAD) study in healthy volunteers (AI438004) and an absorption, 
distribution, metabolism and elimination (ADME) study (AI438005). The results of 
AI438004 and AI438005 are preliminary and not yet reported in a clinical study report. 
Additionally, a previous study (AI434001) evaluated the clinical safety, tolerability, and 
PK of BMS-626529, the active moiety of BMS-663068. The development of BMS-
626529 was suspended due to poor PK profiles.  The safety and tolerability profiles from 
the above studies are summarized below.  
PK results from the SAD study (AI438001) and preliminary results from the MAD study 
(AI438004) indicate that after oral doses the prodrug BMS-663068 was below the assay 
limit of quantitation (1 ng/mL) in the majority of subjects. In contrast, BMS-626529 was 
readily absorbed after an oral dose of BMS-663068 IR formulation and reached 
maximum concentration (Cmax) within 1 hour post dose in most subjects. When dosed 
with the slow-release ER tablet and under fed condition, Cmax can be reached within 4 
hours post dose; administration with a standard meal had no effect on Cmax and AUC 
but increased C12 by about 148%. After a single dose, the increase in exposure to BMS-
626529 was more than dose proportional over the range of 20 to 1000 mg of BMS-
663068. Following multiple doses, steady state appears to have been achieved within 24 
hours of dosing. Accumulation was modest; the average accumulation ratios based on 
AUC ranged from approximately 1.3 to 1.5 after 600 mg Q12h and 1200 mg Q12h +/- 
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RTV. Coadministration of 100 mg RTV with BMS-663068 1200 mg ER tablet Q12h 
significantly increased BMS-626529 Cmax, AUC and C12 by 64%, 2.1-fold and 4.1-fold, 
respectively; the apparent terminal half life was increased from 7 to 15 hours. Diurnal 
effect on BMS-626529 PK was observed after multiple doses. Compared to morning 
administration, evening dose of 1200 mg BMS-663068 ER resulted in approximately 
43%, 46% and 99% higher BMS-626529 Cmax, AUC and Cmin, respectively. In the 
SAD study, less than ~5% of administered dose was eliminated as BMS-626529 in the 
urine, suggesting that renal excretion is not an important elimination pathway for 
unchanged BMS-626529.  
For more information regarding clinical study results, please refer to the Investigator’s 
Brochure.5
1.3.4.1 
BMS-663068 Single Ascending Dose Study in Healthy Subjects 
(AI438001) 
Eighty-eight (88) healthy subjects were enrolled, randomized, and dosed in Protocol 
AI438001. Single, oral doses of 20 to 1000 mg BMS-663068, including 200 mg 
BMS-663068 dosed with 100 mg ritonavir (RTV) were administered. There were no 
deaths or discontinuations due to adverse events (AEs). One (1) serious adverse event 
(SAE) was reported for a subject who received BMS-663068 20 mg. The subject was 
diagnosed with viral meningitis on Day 7. Overall, a total of 33 treatment-emergent AEs 
occurred in 20 of the 66 subjects (30.3%) who received BMS-663068 at any dose. A 
similar percentage of subjects who received placebo had treatment-emergent AEs (11 
AEs, 7 of 22 subjects [31.8%]). The most frequently reported treatment-emergent AEs in 
subjects treated with BMS-663068 at any dose were nausea (7 subjects, 10.6%) and 
headache (6 subjects, 9.1%). No dose-related laboratory marked abnormalities (MA) 
trends were observed. There was no evidence that BMS-663068 had any clinically 
relevant effects on ECG parameters, systolic and diastolic blood pressures, heart rate, 
respiration, or body temperature. Although, the overall ECG data suggests no clinically 
relevant ECG effect, individual QTcF values at Tmax versus the corresponding BMS-
626529 Cmax suggests an increasing trend towards greater QTcF with higher BMS-
626529 concentration. Despite this trend, no subject had a QT interval  500 msec or had 
a QTcF  450 msec. Except for 1 subject that received 200 mg BMS-663068, no subject 
on any dose of BMS-663068 had a QTcF change from baseline > 60 msec. The finding of 
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QTcF > 60 msec was felt to be an artifact related to low T-wave amplitude after 
consultation with a BMS cardiologist. 
1.3.4.2 
BMS-663068 Site of Absorption Study in Healthy Subjects 
(AI438002) 
The site-specific GI absorption and clinical safety of BMS-663068 and the active moiety 
BMS-626529 was evaluated in Protocol AI438002, an open-label, randomized, 4-period, 
4-treatment crossover study. A total of 8 healthy males received 100 mg BMS-663068 in 
a clinical capsule or in an InteliSite capsule for release of 100 mg BMS-663068 to the 
designated region of the GI tract (proximal small intestine, distal small intestine, and 
ileocecal/ascending colon) under fasted conditions. There were no deaths, no dose-
limiting toxicities and no discontinuations due to AEs. Nine (9) AEs were reported in a 
total of 3 of 8 (38%) subjects. The most common AE was sore throat for which there 
were 3 events experienced by 2 subjects (25%, 2 of 8). All events of sore throat were 
considered unrelated to study drug. All other AEs were reported by 1 subject each (13%, 
1 of 8). The data suggest that single doses of BMS-663068 had no clinically relevant 
effects on laboratory assessments, ECG, vital sign measurements or physical 
examinations. 
1.3.4.3 
Bioavailability Study Assessing 3 Extending Release 
Formulations of BMS-663068 (AI438003) 
Protocol AI438003 was a 2-part study. Part I was an open-label, 4- or 3-way crossover 
study designed to assess the PK of BMS-663068 when administered in each of 3 ER 
formulations, relative to the immediate release (IR) formulation all under fasted 
conditions or each of the 3 ER formulations under fed conditions. Twenty-eight (28) 
subjects were enrolled, randomized, and received at least 1 dose of study drug in Part I. 
In addition, there was a second part to the study where subjects received either the slow 
or intermediate ER formulations at single doses of 1200 mg, 1800 mg, and 600 mg plus 
RTV with a standard meal. Twenty-eight (28) subjects were enrolled in Part 2 and 
received at least 1 dose of the study drug. There were no deaths or dose-limiting toxicities. 
There was 1 SAE reported (Mobitz type I second degree atrioventricular (AV) block) 
following administration of Slow ER 1800 mg BMS-663068 fed considered by the 
Investigator to be possibly related to study treatment. A total of 55 treatment-emergent 
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AEs occurred in 29 of the 56 subjects (51.8%) who received BMS-663068 at any dose. 
The most frequently reported treatment-emergent AEs in subjects treated with BMS 
663068 were headache (18 events in 16 subjects, 28.6%) and nausea (5 events in 5 
subjects, 8.9%). There were no clinically relevant trends in changes in laboratory 
parameters or vital signs and no trends in physical examination findings. Though the 
study was not designed to assess time matched changes in ECG parameters, the overall 
ECG data suggests no clinically relevant effect including no trend in individual QTcF 
values at Tmax versus the corresponding BMS-626529 Cmax. Overall, BMS-663068 ER 
formulations were generally safe and well tolerated when given as single oral doses to 
healthy subjects. 
1.3.4.4 
BMS-663068 Multiple Ascending Dose Study in Healthy Subjects 
(AI438004) 
Forty (40) healthy subjects were enrolled in Protocol AI438004. Ten days of oral doses 
of 100 and 200 mg IR Q8H and 600 mg + RTV, 1200 mg, and 1200 mg +RTV Q12H 
were to be administered to 30 subjects and 10 subjects received placebo. The results of 
this study are preliminary and have not been reported in a CSR. There were no deaths.  
One subject discontinued dosing due to an AE of rash.  Rash and pruritis were  common 
AEs when coadministered with RTV, generally occurring in a similar percentage of 
BMS-663068 + RTV versus placebo + RTV-recipients.  A complete list of AEs is 
provided in the IB5. All laboratory abnormalities were considered not clinically relevant. 
The data suggest that multiple doses of BMS-663068 had no clinically relevant effects on 
laboratory assessments, ECG, vital sign measurements or physical examinations. Overall, 
10 days of dosing with BMS-663068 IR and ER formulations with and without RTV 
were generally safe and well tolerated when given to healthy subjects. 
1.3.4.5 
BMS-663068 ADME study in Healthy Subjects (AI438005)  
This is a non-randomized, open-label, single dose study in healthy male subjects to assess 
the pharmacokinetic and metabolism of [14C]-labeled BMS-663068 administered with 
and without RTV. A total of 18 healthy male subjects were enrolled into the study.  
Subjects received a single oral dose of 300 mg of [14C] BMS-663068 containing 100 μCi 
of total radioactivity administered without or with a RTV lead-in period. The results of 
this study are preliminary and have not been reported in a CSR. Adverse events reported 
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in greater than 10% of subjects were flatulence (7 of 18 subjects, 39%) and headache (2 
of 18, 11%).  No other AE occurred in more than 1 subject. The data suggest that single 
doses of [14C]-labeled BMS-663068 had no clinically relevant effects on laboratory 
assessments, ECG, vital sign measurements or physical examinations. Overall, single 
doses of [14C]-labeled BMS-663068 administered with and without RTV were generally 
safe and well tolerated when given to healthy subjects. 
1.3.4.6 
BMS-626529 Single Ascending Dose Study in Healthy Subjects 
(AI434001) 
The active moiety, BMS-626529, was also evaluated in a Phase 1 SAD study in healthy 
subjects.  Eighty-eight (88) healthy subjects were enrolled in Protocol AI434001.  Single, 
oral doses of 25 to 1800 mg of BMS-626529 were administered to 66 subjects and 22 
subjects received placebo. There were no SAEs, deaths, or discontinuations due to AEs. 
Overall, 16 AEs were reported for 11 of 88 (13%) subjects: 7 (11%) BMS-626529 and 
4 (18%) placebo. The most frequent AEs were CK elevation and myalgia (2 subjects 
each). The CK elevations were severe and very severe and were reported by 1 subject 
who received placebo (unresolved at study closure) and 1 who received BMS-626529 
50-mg capsule (resolved 8 days later). Similarly, the AEs of myalgia (both mild) were 
reported by 1 placebo recipient and 1 subject who received BMS-626529 50-mg capsule; 
neither had CK elevations. All other AEs were reported by 1 (1%) subject each. The 
incidence of AEs did not appear dose related. Data suggest that BMS-626529 had no 
clinically relevant effect on laboratory measures, vital sign measurements, physical 
examinations, or ECGs. Overall, BMS-626529 appeared to be safe and well tolerated 
when given as single oral doses to healthy subjects.  
1.3.5 
Ritonavir (Norvir)
Ritonavir (RTV) is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases.  
Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol 
polyprotein precursor which leads to production of non-infectious immature HIV 
particles. The PK of RTV have been studied in healthy subjects and HIV-infected 
patients. After a 600 mg dose of oral solution, peak concentrations of RTV were achieved 
approximately 2 hours and 4 hours after dosing under fasting and non-fasting conditions, 
respectively. In vitro studies utilizing human liver microsomes have demonstrated that 
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CYP3A is the major isoform involved in RTV metabolism, although CYP2D6 also 
contributes. Ritonavir inhibits CYP3A in vitro and in vivo.  Agents that are extensively 
metabolized by CYP3A and have high first pass metabolism appear to be the most 
susceptible to large increases in AUC (>3-fold) when co-administered with RTV.  RTV 
also inhibits CYP2D6 to a lesser extent.  Co-administration of substrates of CYP2D6 
with RTV could result in increases (up to 2-fold) in the AUC of the other agent, possibly 
requiring a proportional dosage reduction. RTV also appears to induce CYP3A as well as 
other enzymes, including glucuronosyl transferase, CYP1A2, and possibly CYP2C9. 
RTV is rarely used at the original therapeutic dose of 600 mg administered b.i.d. because 
of the high incidence of a variety of side effects. The fact that RTV is a potent inhibitor 
of cytochrome P450-based metabolism has been employed to increase the exposure of 
other co-administered HIV protease inhibitors which are better tolerated.10,11 Ritonavir 
achieves its metabolic inhibition at doses, which are much lower than therapeutic, for 
example 100 mg QD when combined with atazanavir will boost the AUCs of 
atazanavir.12 The most frequent clinical and laboratory AEs reported in subjects receiving 
RTV as monotherapy or in combination with nucleoside analogues include asthenia, 
nausea, vomiting, abdominal pain, diarrhea, anorexia, taste perversion, circumoral 
paresthesia, peripheral neuropathy, dizziness and insomnia. Laboratory abnormalities 
reported with the use of RTV are elevations in hepatic transaminase levels, nonfasting 
triglyceride, cholesterol, creatine phosphokinase, and uric acid. It has been reported, in 
rare cases, post marketing, hepatic dysfunction including some fatalities generally 
occurred in subjects taking RTV 600 mg BID and multiple concomitant medication in 
patients suffering from advanced HIV disease. The frequency of adverse events following 
administration of low-dose RTV is not well known, as it would not be administered 
alone, in such low doses. However, it is expected that the incidence of AEs would be 
reduced at low doses. Additional information on Norvir can be found in the package 
insert.13
1.4 
Study Rationale 
This study is being conducted to assess the antiviral activity, safety, tolerability and PK 
of selected regimens of BMS-663068 with and without RTV in HIV-1 infected subjects. 
BMS-663068 is a methyl phosphate prodrug of BMS-626529,3,4 and represents one of a 
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novel class of antiretroviral agents that blocks the first step of viral entry, namely the 
attachment of viral gp120 envelope to the cellular CD4 receptor.  Proof of concept was 
achieved with a prior HIV attachment inhibitor, BMS-488043, in Protocol AI430003.14
BMS-488043 at doses of 800 and 1800 mg produced viral load decline of greater than 0.7 
log10 copies/mL from baseline on Day 8, thereby providing confidence that the 
compound has antiviral activity in HIV infected subjects. BMS-488043 was safe and well 
tolerated; however, a high fat meal were required to achieve adequate exposure. 
Therefore, development of BMS-488043 was halted. The current formulation of BMS-
663068 has improved PK properties and BMS-626529 has an ~ 16 fold slower off rate; 
thus, BMS-663068 should produce antiviral effects at least as good as BMS-448043 
without the undesirable dosing requirements. 
BMS-626529, the active moiety of BMS-663068, is efficacious against macrophage-, T-
cell-, and dual tropic laboratory HIV-1 strains. Given the in vitro sensitivity of BMS-
626529, it is anticipated that BMS-663068 will be most effective at inhibiting entry of 
clade B HIV-1; therefore, this study will restrict enrollment to subjects infected by HIV-1 
clade B. Clade B HIV is a frequent encountered clade in many parts of the world, 
including North /Central/South America and Europe.  
In study AI430003, antiviral effect of BMS-488043 was greater in treatment naive 
patients compared to treatment experienced patients. Viral susceptibility and exposure to 
the study drug, especially Cmin values, were lower in treatment experienced patients 
compared to treatment naive patients. This was an unexpected finding without a clear 
explanation; therefore, the current study will be stratified to assess the antiviral activity of 
BMS-626529 in antiretroviral naive versus experienced subjects to reassess the prior 
finding. 
The current study will employ an 8 day dosing duration which is fairly standard for novel 
HIV therapeutics, is the same dosing duration used in the AI430003 study and generally 
allows adequate assessment of antiviral activity without an unreasonable amount of risk 
that viral resistance to BMS-663068 will occur. The 8 day dosing duration is also 
supported by a completed 10 day study in healthy volunteers, AI438004.   
The twice daily doses of BMS-663068 in the current study were selected because they are 
anticipated to provide Cmin BMS-626529 concentrations above the majority of HIV 
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protein binding adjusted EC90.  Most groups will coadminister RTV, which has been 
shown to improve BMS-626529 exposures in humans.  A once daily regimen group has 
been selected to better define the PK parameter (Cmin versus AUC) most important to 
antiviral effect.  
Pharmacodynamic parameters and endpoints (HIV RNA, CD4+ and CD8+ lymphocyte 
counts and percents, viral susceptibility measured by phenotype) have been selected to 
optimize the doses of BMS-663068 which will move into later phase development. 
Exploratory biomarkers (activated (DR+) CD4+ and CD8+ subsets, neutralizing antibody 
activity and HIV co-receptor) usage have been included to fully characterize the potential 
for BMS-663068 as a therapeutic. 
1.5 
Overall Risk/Benefit Assessment 
Since this is not a treatment study, there is no direct benefit to the subjects participating 
in this study other than contributing to the research of a product. The antiviral effect 
anticipated to be observed in this study are likely to be transient and of no clinical benefit.  
Resistance may develop to HIV attachment inhibitors or HIV protease inhibitors, and this 
resistance may result in lifelong loss in ability to use these classes of medication for 
treatment benefit. Subjects should not delay or defer use of HAART regimens 
specifically to allow participation in this trial. 
1.5.1 
BMS-663068 
The preclinical and clinical safety profile of BMS-663068 and BMS-626529 are 
described in this protocol in section 1.3.3 and 1.3.4 and in the BMS-663068 IB. In 
general, BMS-663068 and BMS-626529 have been well tolerated with no clinically 
relevant impact on laboratory assessments, ECGs, vital signs or physical examinations. 
High exposures associated with the immediate formulation were associated with nausea. 
In most studies, the most frequent AE was headache, which generally occurred in a 
similar percentage of BMS-663068- versus placebo-recipients.  Rash and pruritis were a 
common AE when coadministered with RTV, generally occurring in a similar percentage 
of BMS-663068 + RTV- versus placebo + RTV-recipients. Details on exposure margin 
relative to NOAEL from toxicology studies are also outlined in the BMS-663068 IB.5
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There is a risk of increased Cmax and possible drug toxicity (nausea or vomiting) 
associated with chewing or breaking the tablets.  
BMS-663068 was administered to pregnant rats during the period of organogenesis at 
doses of 0, 100, 300, 600 and 1000 mg/kg/day. 15  BMS-663068 was well-tolerated at 100 
mg/kg/day. At  300 mg/kg/day, however, maternal toxicities were evident; and at 1000 
mg/kg/day, developmental toxicities were also observed.  Maternal toxicity included 
reductions in food consumption and group mean body weights, thinning hair or alopecia, 
and red perivaginal substance.  Developmental toxicities consisted of fetal malformations 
(including cleft palate, microstomia and oral cleft) and variations as well as a reduction in 
mean fetal body weights. The definitive embryo-fetal development study in rats has not 
been performed and will be completed prior to the start of Phase 2B. 
Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy for 8 weeks prior to dosing, throughout the study, and 
for 12 weeks after the study in such a manner that the risk of pregnancy is minimized. 
Women will undergo frequent pregnancy tests and will remain as inpatients during 
dosing. Women who are pregnant or breastfeeding are excluded. Sexually active fertile 
men not using effective birth control if their partners are WOCBP will also be excluded.  
BMS-663068 is hydrolyzed to the active form (BMS-626529) through the action of 
intestinal alkaline phosphatase with the concomitant liberation of an equimolar amount of 
formaldehyde. The amount of formaldehyde estimated to be released at the highest 
dosage of BMS-663068 is still about 7-fold below the established NOAEL dosage of 
formaldehyde of 15 mg/kg/day in a 2-year bioassay.16,17 Therefore based on the data, 
there is little potential for formaldehyde-related toxicities from exposure to BMS-663068, 
and if there were any potential toxicity due to formaldehyde exposure, it would be 
irritation to the gastrointestinal tract directly exposed to the tablets. Due to the potential 
for toxicities associated with formaldehyde exposure the following safeguards are being 
implemented in this protocol: subjects will be informed in the consent of the possible risk 
of gastrointestinal tract irritation, individuals with recent gastrointestinal conditions that 
would increase the likelihood of clinically relevant gastrointestinal irritation or bleeding 
will be excluded, concomitant use if medications associated with gastrointestinal tract 
irritation will be excluded, and stopping rules related to new onset of signs or symptoms 
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associated with severe gastrointestinal irritation or gastrointestinal tract bleeding will be 
defined.
1.5.2 
Ritonavir 
The most frequent clinical and laboratory adverse events reported in subjects who 
received RTV as monotherapy or in combination with nucleoside analogues include 
asthenia, nausea, vomiting, abdominal pain, and diarrhea.13  Laboratory abnormalities 
reported with the use of RTV include elevations in hepatic transaminase levels, 
nonfasting triglyceride, cholesterol, creatine phosphokinase, and uric acid. The frequency 
of adverse events following administration of low dose RTV (100 mg QD) is not well 
known. However, it is expected that the incidence of adverse events with this low dose 
would be reduced. Subjects in the current study will be monitored for all adverse events 
and clinical laboratory abnormalities. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to assess the antiviral activity of BMS-626529 
following administration of selected regimens of BMS-663068 with and without RTV 
administered orally to HIV infected subjects for 8 days.   
2.2 
Secondary Objectives 
Secondary objective(s): 

To assess safety and tolerability of multiple regimens of BMS-663068 with and 
without RTV in HIV infected subjects 

To assess the effect of BMS-626529 following multiple regimens of BMS-663068 on 
CD4+ and CD8+ lymphocyte counts and percents 

To assess the PK of BMS-626529 following multiple regimens of BMS-663068 with 
and without RTV in HIV infected subjects 

To assess the diurnal variation in the PK exposures of BMS-626529 following 
multiple regimens of BMS-663068 with and without RTV in HIV infected subjects 

To assess the plasma protein binding for BMS-626529 
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
To assess the relationships between change from baseline in log10 HIV RNA versus 
Inhibitory Quotient (IQ) and PK exposures for BMS-626529 following multiple 
regimens of BMS-663068 with and without RTV 

To assess the PK of RTV when coadministered with various regimens of 
BMS-663068 
2.3 
Exploratory Objectives 

To explore the effect of BMS-626529 following multiple regimens of BMS-663068 
with and without RTV on activated (DR+) CD4+ and CD8+ subsets 

To explore the effect of BMS-626529 following multiple regimens of BMS-663068 
with and without RTV on neutralizing antibody activity 

To explore the effect of BMS-626529 following multiple regimens of BMS-663068 
with and without RTV on HIV co-receptor usage (CCR5 versus CXCR4) and to 
explore the relationship between HIV co-receptor usage and antiviral activity 

To explore the difference in antiviral activity of BMS-626529 following multiple 
regimens of BMS-663068 with and without RTV by prior antiretroviral (ARV) 
treatment history (ARV naive versus ARV experienced) 

To explore the change in viral susceptibility measured by envelope genotype and 
phenotype 
3 
ETHICAL CONSIDERATIONS 
3.1 
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. 
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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. 
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective task(s). 
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). 
Systems with procedures that assure the quality of every aspect of the study will be 
implemented. 
3.2 
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/process (eg, advertisements), and any other written information to be provided 
to subjects. The investigator or sponsor 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 sponsor 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. 
3.3 
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. Freely given written informed consent must be obtained from every subject 
prior to clinical study participation, including informed consent for any screening 
procedures conducted to establish subject eligibility for the study. 
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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. 
Appendix 1 contains BMS procedures on obtaining informed consent from all subjects, 
prior to participating in a clinical study. The relevant procedures must be used whenever 
they are applicable (see subject selection criteria in Sections 4.2.1 and 4.2.2). 
Informed consent given by legally acceptable representatives or witnesses is not
permitted in this study. 
4 
INVESTIGATIONAL PLAN 
4.1 
Study Design and Duration 
This is a randomized, open label, multiple-dose parallel study.  Subjects will undergo 
screening evaluations to determine eligibility within 35 days prior to study enrollment.  
Subjects will be admitted to the clinical facility the evening prior to dosing (Day -1).  
Subjects will be randomized into one of 5 regimen groups: Group 1 - BMS-663068 600 
mg Q12H + RTV 100 mg Q12H; Group 2 - BMS-663068 1200 mg QHS + RTV 100 mg 
QHS;  Group 3 - BMS-663068 1200 mg Q12H + RTV 100 mg Q12H;  Group 4 - BMS-
663068 1200 mg Q12H + RTV 100 mg QAM;  Group 5 - BMS-663068 1200 mg Q12H.  
Each regimen group will consist of 10 subjects.    Subjects in each regimen will be 
randomized and stratified by prior antiretroviral treatment history (ARV naive versus 
ARV experienced).  ARV naive is defined as; no prior ARV therapy of  1 week.  Each 
regimen group will contain approximately the same distribution of ARV naive and ARV 
experienced subjects.  No more than 70% of the total population (or within each regimen 
group) will be ARV naive or ARV experienced. All regimen groups may initiate dosing 
simultaneously. Subjects will be confined to the clinical facility until Day 11.  Subjects 
will return to the unit on Day 15 for a follow-up visit and on Day 50 for discharge 
procedures.  Subjects may have a  3 day window around the discharge visit day (Day 
50). Safety assessments consisting of ECGs, vital signs, physical exams and clinical 
laboratory tests will be conducted at screening and at selected time points throughout the 
study.  
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All doses will be administered under fed conditions. Subjects in Group 2 (QHS regimen 
group) will receive study drug every 24 hours in the evening (PM) from Day 1 to Day 8. 
Subjects in Group 4 (RTV QAM regimen group) will receive BMS-663068 every 12 
hours and RTV every 24 hours in the morning (with BMS-663068) from Day 1 to Day 8. 
Subjects in Groups 1, 3 and 5 (Q12H regimen group) will receive study drug every 12 
hours from Day 1 to Day 8.  
Plasma HIV RNA levels will be measured pre-AM drug administration on the mornings 
of Day 1 to Day 8 in groups 1, 3, 4 and 5 and Pre-PM drug administration in group 2.  On 
days when dose is not administered, sample collection time should be maintained.  Serial 
blood samples for pharmacokinetic determinations will be obtained on Days 1 and 8-11. 
Blood samples for trough concentrations will be obtained on Days 5 through 7 prior to 
morning study drug administrations (prior to evening administration for Group 2, QHS 
regimen group) for Ctrough and steady-state assessment.  In addition, blood samples for 
protein binding assay will be collected at specified timepoints throughout the study and 
selected regimen groups will be analyzed. 
Blood for CD4+ and CD8+ lymphocyte counts and percents and activated (DR+) CD4+ 
and CD8+ subsets, genotyping, phenotyping, HIV co-receptor usage (CCR5 versus 
CXCR4), exploratory resistance analysis, measurement of neutralizing antibody activity 
will be collected at specified timepoints throughout the study. These samples may be 
analyzed if deemed relevant.  Screening samples for population RT/Pol genotyping to 
confirm that all subjects are infected with clade B HIV will be analyzed in all enrolled 
subjects. Day 1 predose samples for envelope phenotyping will be collected and analyzed 
for all randomized subjects.   
Approximately 800 mL of blood will be drawn from each subject during the study. 
The approximate duration of the study is 88 days.  Study participation includes a 35-day 
screening period, 8-day treatment and 2 follow-up visits. 
End of the study will be the date of the last visit of the last subject undergoing the study.  
Last visit will be the last follow-up visit of a subject. 
At the end of the study, the sponsor will not continue to supply study drug to 
subjects/investigators unless the sponsor chooses to extend the study. The investigator 
should ensure that the subject receives appropriate standard of care to treat the condition 
under study. 
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Table 4.1 summarizes the study design and study parameters. 
Table 4.1: 
AI438006 Study Design 
Regimen 
Group 1 
(N=10)
Regimen 
Group 2 
(N=10)
Regimen 
Group 3 
(N=10)
Regimen 
Group 4 
(N=10)
Regimen 
Group 5 
(N=10)
Dose and Regimen 
600 mg 
BMS-
663068 
Q12H + 100 
mg RTV 
Q12H
1200 mg 
BMS-
663068 
QHS + 100 
mg RTV 
QHS
1200 mg  
BMS-
663068 
Q12H + 
100 mg 
RTV Q12H 
1200 mg    
BMS-
663068 
Q12H + 
100 mg 
RTV QAM 
1200 mg  
BMS-
663068 
Q12H
Days subjects receive 
BMS-663068 
Day 1-8 
In-patient Days 
Day -1 to Day 11 
Furlough from clinical 
unit  
Day 11 
Out-patient visits  
Day 15 and (Day 50 +/- 3 days) 
Discharge from Study 
Day 50 +/- 3 days 
4.2 
Study Population 
For entry into the study, the following criteria MUST be met prior to dosing on Day 1. 
No exceptions will be granted. 
4.2.1 
Inclusion Criteria 
1) Signed Written Informed Consent 
a) The signed informed consent form 
2) Target Population 
a) Clade B HIV-1 infected subjects meeting the following criteria at the screening 
visit (within 35 days of enrollment): 
i)
Plasma HIV RNA level  5,000 copies/mL (may be repeated for 
confirmation)
ii) Antiretroviral naive or experienced (ARV naive is defined by: No prior 
antiretroviral therapy of  1 week)
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iii) CD4+ lymphocyte measurement  200 cells/L (may be repeated for 
confirmation)
iv) Off all antiretroviral therapy with HIV activity for > 8 weeks 
v) Have not previously received an HIV attachment inhibitor 
b) Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive. BMI = weight (kg)/ [height 
(m)]2
c) Not currently co-infected with HCV or HBV 
3) Age and Sex 
a) Men and women,  18 years of age  
Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception (generally defined as two separate forms of contraception, one of 
which must be an effective barrier method (eg, condom with spermicide), to avoid 
pregnancy throughout the study and for up to 12 weeks after the last dose of 
investigational product in such a manner that the risk of pregnancy is minimized. 
WOCBP include any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy) or is not postmenopausal.  Post menopause is defined 
as:  

Amenorrhea  12 consecutive months without another cause or  

For women with irregular menstrual periods and on hormone replacement 
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level 
> 35 mIU/mL 
Women who are using oral contraceptives, other hormonal contraceptives (vaginal 
products, skin patches, or implanted or injectable products), or mechanical 
products such as an intrauterine device or barrier methods (diaphragm, condoms, 
spermicides) to prevent pregnancy, or are practicing abstinence or where their 
partner is sterile (eg, vasectomy) should be considered to be 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 investigational product. 
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4.2.2 
Exclusion Criteria 
1) Sex and Reproductive Status 
a) WOCBP who are unwilling or unable to use an acceptable method to avoid 
pregnancy (generally defined as two effective forms of contraception) for the 
entire study period and for up to 12 weeks after the last dose of investigational 
product.
b) WOCBP using a prohibited contraceptive method including oral, injectable, or 
implantable hormonal contraceptive agent within 12 weeks of enrollment. 
c) Women who are pregnant or breastfeeding. 
d) Women with a positive pregnancy test on enrollment or prior to investigational 
product administration. 
e) Sexually active fertile men not using effective birth control (generally defined as 
two effective forms of contraception) during study participation and for at least 12 
weeks after the last dose of investigational product if their partners are WOCBP.  
2) Medical History and Concurrent Diseases 
a) Any significant acute or chronic medical illness which is not stable or is not 
controlled with medication or not consistent with HIV infection. 
b) Current or recent (within 3 months) gastrointestinal disease that, in the opinion of 
the Investigator or Medical Monitor, may impact on drug absorption and/or put 
the subject at risk for GI tract irritation and/or bleeding. Exclusionary diseases 
include, but are not limited to gastrointestinal ulcers, esophageal or gastric 
varicies, or hematochezia. 
c) Acute diarrhea lasting  1 day, within 3 weeks prior to randomization. Diarrhea 
will be defined as the passage of liquid feces and/or a stool frequency greater than 
three times per day. 
d) Any major surgery within 4 weeks of study drug administration. 
e) Any gastrointestinal surgery that could impact upon the absorption of study drug. 
f)
Donation of blood or plasma to a blood bank or in a clinical study (except a 
Screening visit or follow up visit of less than 50 mL) within 4 weeks of study 
drug administration. 
g) Blood transfusion within 4 weeks of study drug administration. 
h) Inability to tolerate oral medication. 
i)
Inability to be venipunctured and/or tolerate venous access. 
j)
A personal history of clinically relevant cardiac disease, symptomatic or 
asymptomatic arrhythmias, syncopal episodes, or additional risk factors for 
torsades de pointes. 
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k) A personal or family history of long QT syndrome. 
l)
Subjects who are unwilling to practice adequate infection protection during and 
after study participation to minimize potential for spread of HIV infection, 
including HIV which may have developed resistance to HIV attachment 
inhibitors.  Such protections could include, but are not limited to behaviors to 
minimize potential for exposure to the subjects’ bodily fluids or initiation of 
HAART therapy if indicated and recommended by a physician. 
m) Recent (within 6 months) drug or alcohol abuse as defined in DSM IV, Diagnostic 
Criteria for Drug and Alcohol Abuse (Appendix 2). 
n) Any other medical, psychiatric and/or social reason which, in the opinion of the 
Investigator, would make the candidate inappropriate for participation in this 
study. 
3) Physical and Laboratory Test Findings 
a) Evidence of organ dysfunction or any clinically significant deviation from normal 
in physical examination, vital signs, ECG or clinical laboratory determinations or 
not consistent with the subject’s degree of HIV infection. 
b) Confirmed QT value > 500 msec at screening or Day -1. 
c) Confirmed QTc value > 470 msec for women and > 450 msec for men at 
screening or Day -1. 
d) Evidence of second or third degree heart block at screening or Day -1, confirmed 
by repeat ECG. 
e) Positive urine screen for drugs of abuse at either Screening or Day -1 without a 
valid prescription (subjects positive for cannabinoids and/or amphetamines will 
be included, unless excluded by exclusion criteria 2m in Section 4.2.2). 
f)
Positive blood screen for hepatitis B surface antigen. 
g) Positive blood screen for hepatitis C antibody and hepatitis C RNA. 
h) Any of the following screening or Day -1 laboratory results outside of the ranges 
specified below as defined by the central laboratory, confirmed by repeat analysis.   
i)
Absolute Neutrophil Count (ANC) 0.7 x lower limit of normal (LLN) 
ii) Hemoglobin 0.8 x LLN 
iii) ALT > 3 x upper limit of normal (ULN) 
iv) Creatinine clearance (as estimated by method of Cockcroft and Gault18) less 
than 60 mL/min. 
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4) Allergies and Adverse Drug Reactions 
a) History of allergy to an HIV attachment inhibitor. 
b) History of allergy to HIV protease inhibitor (e.g. RTV). 
c) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity). 
5) Prohibited Treatments and/or Therapies  
a) Prior exposure to an HIV attachment inhibitor (including BMS-488043 or BMS-
663068).
b) Exposure to any investigational drug or placebo within 4 weeks of study drug 
administration.
c) Use of any prescription drugs within 4 weeks prior to study drug administration. 
However, certain drugs may be allowed if approved by the BMS medical monitor. 
d) Use of any other drugs, including over-the-counter medications, vitamins and/or 
herbal preparations (eg. St. John’s wort), within 1 week prior to study drug 
administration. However, certain drugs may be allowed if approved by the BMS 
medical monitor. 
e) Use of an oral, injectable or implantable hormonal contraceptive agent within 12 
weeks of study drug administration. 
f)
Use of any prescription drugs or OTC drugs that may cause GI tract irritation or 
bleeding (ie, NSAIDs, aspirin) within 2 weeks of study drug administration, 
unless approved by the BMS medical monitor. 
g) Use of alcohol-containing beverages within 3 days prior to study drug 
administration.
h) Use of grapefruit or grapefruit-containing products or Seville orange-containing 
products within 7 days prior to study drug administration. 
6) 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 to ensure that the results of the study can be used. It is imperative that 
subjects fully meet all eligibility criteria.  
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4.2.3 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue investigational product (and noninvestigational product at 
the discretion of the investigator) (investigational or noninvestigational treatment) for any 
of the following reasons: 

Withdrawal of informed consent (subject’s decision to withdraw for any reason) 

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 

Pregnancy (see Section 7.6.2) 

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 

Inability to comply with protocol 

Discretion of the investigator 

Clinically relevant ventricular arrhythmia including torsades de pointes 

Confirmed QTcB or QTcF value > 500 msec 

Type 2 (Mobitz II) second or third-degree heart block (confirmed by repeat ECG)

New onset of clinically relevant gastrointestinal bleeding

New onset of signs and symptoms of severe persistent gastrointestinal irritation (such 
as abdominal pain) deemed unrelated to another etiology
All subjects who discontinue should comply with protocol specified follow-up 
procedures as outlined in Section 6. The only exception to this requirement is when a 
subject withdraws consent for all study procedures or loses the ability to consent freely 
(ie, is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or 
physical illness). 
If a subject was withdrawn before completing the study, the reason for withdrawal must 
be entered on the appropriate case report form (CRF) page. 
Dosing within a regimen group will be stopped and the study halted until safety 
information can be reviewed in the event of the following situations: 
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
Two or more subjects within a regimen group experience new onset of QTcF values 
>500 msec following dosing (confirmed by repeat ECG) 

Two or more subjects within a regimen group experience second-degree Mobitz II or 
third-degree heart block (confirmed by a repeat ECG) 

Clinically relevant ventricular arrhythmia including torsades de pointes in any subject 
in a given dose panel 

Two or more subjects within a regimen group experience new onset of clinically 
relevant gastrointestinal bleeding

Two or more subjects within a regimen group experience new onset of signs and 
symptoms of severe persistent gastrointestinal irritation (such as abdominal pain) 
deemed unrelated to another etiology

Two or more subjects within a regimen group experience the same drug-related 
severe clinical or laboratory adverse event 
The study may be terminated prematurely if:

The Sponsor, in consultation with the Principal Investigators, feels that the number 
and/or severity of AEs justifies discontinuation of the study. 

The Sponsor considers the applied doses of the study drug to be no longer relevant. 

The Sponsor decides to discontinue the study. 

Data not known before become available and raise concern about the safety of the 
study drug so that continuation would pose potential risks to the subjects. 
Premature termination of the study must be documented and clinical study results will be 
reported according to the requirements outlined in this protocol as far as applicable. 
5 
TREATMENTS 
5.1 
Study Treatment 
All protocol-specified investigational and noninvestigational products are considered 
study drug. BMS-663068 will be administered as a tablet formulation.  Ritonavir will be 
administered as a capsule.  Table 5.1A outlines the total dose and number of tablets or 
capsules per daily dose for each group. 
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Table 5.1A: 
Treatment Administration 
Group 
Study Drug 
Tablet/Capsule Strength 
Number of Tablets or 
Capsules per time of day 
Total Daily Dose 
BMS-663068 600 mg tablet 
1 in AM; 1 in PM 
1200 mg 
1
RTV 100 mg capsule 
1 in AM; 1 in PM 
200 mg 
BMS-663068 600 mg tablet 
2 in PM 
1200 mg 
2
RTV 100 mg capsule 
1 in PM 
100 mg 
BMS-663068 600 mg tablet 
2 in AM; 2 in PM 
2400 mg 
3
RTV 100 mg capsule 
1 in AM; 1 in PM 
200 mg 
BMS-663068 600 mg tablet 
2 in AM; 2 in PM 
2400 mg 
4
RTV 100 mg capsule 
1 AM 
100 mg 
5 
BMS-663068 600 mg tablet 
2 in AM; 2 in PM 
2400 mg 
All doses will be administered under fed conditions.  In the morning of Days 1 through 8 
a standard breakfast meal will be administered as breakfast to subjects in Groups 1, 3, 4, 
and 5 prior to dosing of study drug.  On Days 1 through 8 for all groups, an evening 
snack (approximately 300 - 350 kcal) will be administered prior to the evening dose of 
study drug.  The meal and snack will be ingested within ~30 minutes and will be 
completed within ~5 minutes prior to dosing of study drug.  At the time of dosing, ~240 
mL of water will be administered to the subjects along with the study medication.  The 
BMS-663068 tablet(s) must be swallowed intact and are not to be chewed.  The water 
will be consumed within approximately 5 minutes of dosing.  The time of the first dose 
administration will be called “0” hour (AM for groups 1, 3, 4 and 5; PM for group 2).  
Table 5.1B provides a description of a representative standard breakfast. 
Restrictions related to food and fluid intake are described in Section 5.5.2. 
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Table 5.1B: 
Representative Standard Breakfast 
Food Item 
Calories 
(kcal) 
Fat
(g)
Carbohydrates 
(g)
Protein 
(g)
1 egg fried 
90
7.0
0.4
6.3
2 slices of white bread toasted 
129 
1.8 
24.0
4.0
1 tablespoon jelly 
56 
Trace 
13.8 
Trace 
8 fluid ounces (237 mL) of whole milk 
146 
7.9 
11.0
7.9
Total Grams (g) 
- 
16.7 
49.3 
18.2 
Total Calories (kcal) 
421 
153 
197 
73 
% of Total Calories 
100 
36 
47 
17 
Source: US Department of Agriculture, Agricultural Research Service. 2007 USDA National Nutrient 
Database for Standard Reference, Release 21.19
5.1.1 
Investigational Product 
An investigational product, also known as investigational medicinal product in some 
regions, is defined as follows: 
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) in a way different from the authorized 
form, or used for an unauthorized indication, or when used to gain further information 
about the authorized form. 
In this protocol, investigational product(s) are: BMS-663068 tablets and Ritonavir 
capsules
5.1.2 
Noninvestigational Product 
Other medications used in the study as support or escape medication for preventative, 
diagnostic, or therapeutic reasons, as components of the standard of care for a given 
diagnosis, are considered noninvestigational products.  
In this protocol, noninvestigational product(s) is/are: Not applicable for this study. 
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5.1.3 
Identification 
For all study sites, Bristol-Myers Squibb R&D will supply the following investigational 
product:
Table 5.1.3: 
Investigational Product Identification 
Unit 
Route 
Appearance
BMS-663068-03 Tablet, 600 mg 
Oral 
Plain, white biconvex, capsule-
shaped film-coated tablet 
Ritonavir Capsule, 100 mg 
Oral 
White, soft capsule 
5.1.4 
Packaging and Labeling 
BMS-663068-03 tablets and ritonavir capsules will be packaged in bottles.  Each bottle 
will be labeled as open-label with a 1-panel label which will contain at least the following 
information: protocol number (either as a prefix or full number), container number, batch 
number, product name and potency, number of tablets/capsules, dosing instructions, and 
storage conditions. 
Bottles of BMS-663068-03 600 mg tablets will contain 35 tablets each and bottles of 
ritonavir 100 mg capsules will contain 84 capsules each. 
5.1.5 
Handling and Dispensing 
Study drug supplied by the sponsor or sourced by the investigator should be stored in a 
secure area according to local regulations. It is the responsibility of the investigator to 
ensure that study drug is only dispensed to study subjects. The study drug must be 
dispensed only from official study sites by authorized personnel according to local 
regulations.  
The investigator should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the 
sponsor.  If concerns regarding the quality or appearance of the study drug arise, do not 
dispense the study drug and contact the sponsor immediately. 
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BMS-663068-03 tablets should be stored at 15-25ºC (59-77ºF).  Ritonavir 100 mg 
capsules should be stored in a refrigerator, at 2-8ºC (36-46ºF) until dispensed, protected 
from freezing and excessive heat, and the bottles should be kept tightly closed. 
Please refer to Section 9.2.2 for information on study drug record retention and 9.3 for 
destruction and return instructions.
5.2 
Method of Assigning Subjects to a Treatment 
Subjects in each group will be randomized and stratified by prior antiretroviral (ARV) 
treatment history (ARV naive versus ARV experienced).  No more than 70% of the total 
population will be ARV naive or ARV experienced. All regimen groups may initiate 
dosing simultaneously.     
Subjects will be randomized to a group according to a computer-generated randomization 
scheme.  The Randomization schedule will be prepared by a Randomization Coordinator 
within the Drug Supply Management Department of the Bristol-Myers Squibb Research 
and Development or the designated CRO.  
All enrolled subjects will be assigned a sequential subject number starting with 
 at 
the time the study specific ICF is signed. Screen failures will keep their subject number 
assigned at enrollment. Enrolled subjects meeting inclusion and exclusion criteria will be 
randomized. Randomization numbers will be assigned prior to dosing for each group. 
Subjects will not be replaced. 
5.3 
Selection and Timing of Dose for Each Subject 
5.3.1 
Dose Modifications 
Modification of the dosage schedule may not be made without a written amendment to 
the protocol. 
5.4 
Blinding/Unblinding 
Not applicable. 
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5.5 
Concomitant Treatments  
5.5.1 
Prohibited and/or Restricted Treatments 
Restrictions on medications taken prior to enrollment in the study are described in 
Section 4.2.2.  Medications taken within 4 weeks prior to administration of study 
medication must be recorded on the CRF. 
No concomitant medications (prescription, over-the-counter or herbal) are to be 
administered during study unless they are prescribed by the investigator for treatment of 
specific clinical events.  Any concomitant therapies must be recorded on the CRF. 
5.5.2 
Other Restrictions and Precautions 
1) Subjects are not permitted to use any other drugs, including prescription medications, 
over-the-counter medications, and herbal preparations, for the duration of the study, 
including any that prolong the QT/QTc interval, alter GI motility or may cause GI 
bleeding and/or irritation. 
2) Subjects are to refrain from strenuous exercise, contact sports, and sunbathing from 
Day -1 to Day 15. 
3) Subjects are not permitted to consume alcohol-containing beverages from 3 days 
prior to the first dose until Day 15. 
4) Subjects are not permitted to consume grapefruit-containing products or Seville 
orange-containing products from 7 days prior to the first dose until Day 15. 
5) Subjects are permitted to smoke during the study.  However, during the inpatient 
phase, subjects must abide by the policies of the clinical facility.   
6) Subjects are required to remain in the clinical facility from Day -1 to Day 11, or until 
furloughed.  
7) On study Days 1 to 8, subjects are required to fast (nothing to eat or drink except 
water) for at least 7 hours prior to breakfast. Subjects may not drink water one hour 
after study drug administration except with dosing. Water may be consumed ad
libitum at other times. 
8) On study Days 1 to 8, a standard breakfast will be served prior to the first AM dose of 
study drug; a standard lunch will be served approximately 4 hours post the AM dose; 
a standard dinner will be served approximately 8 hours post the AM dose and a 
standard light snack will be served in conjunction with the PM dose (approximately 
12 hours post the AM dose).  No other food should be consumed.  Refer to Section 
5.1 for details regarding study drug administration.  
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9) On study Days 1 to 8, subjects should maintain an upright (seated or standing) 
position for at least 2 hours postdose, with the exception of being supine in 
preparation for ECG recordings. 
10) Male subjects are not permitted to donate sperm or father a child throughout the study 
and for 12 weeks after the last dose of investigational product. 
11) Subjects are not permitted to consume food containing poppy seeds from the time of 
screening until Day 15. 
5.6 
Treatment Compliance 
Study drug will be administered in the clinical facility. After administration of BMS-
663068 and/or RTV, a mouth check will be performed to verify that the subject has 
swallowed the dose.  When multiple tablets or capsules are administered as part of a 
single dose, the mouth check should be performed after the final pill has been taken.  The 
volunteer should drink the entire aliquot of water given to swallow the pills.   
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6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Flow Chart/Time and Events Schedule  
Table 6.1: 
Flow Chart for Protocol AI438006 
Screening
Study Day 
Follow 
up
Study 
Dischargej
Protocol 
Sections 
Event 
Within 35 
Days of 
Study Day 1 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
15 
50  3 days 
Signed Protocol Specific 
Consent Form / 
Enrollment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3, 4.2.1 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2, 6.3 
Vital Signs 
x 
x 
xa 
 
 
xa
 
 
 
xa
 
 
x 
x 
x 
6.3 
Physical Measurements 
x 
xb
 
 
 
 
 
 
 
xb 
 
 
xb
xb
xb
6.3
Physical Examination 
x 
 
xi 
 
 
 
 
 
 
x 
 
 
x 
x 
x 
6.3 
12-lead ECG 
x 
x 
xa
 
 
xa
 
 
 
xa
 
 
x 
 
x 
6.3 
Clinical Laboratory 
Tests 
x 
x 
 
 
 
x
 
 
 
x
 
 
x
 
x 
6.3 
Serology  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
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Clinical Protocol 
Table 6.1: 
Flow Chart for Protocol AI438006 
Screening
Study Day 
Follow 
up
Study 
Dischargej
Protocol 
Sections 
Event 
Within 35 
Days of 
Study Day 1 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
15 
50  3 days 
Urine Drug Screen 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Pregnancy Test 
x 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
x 
4.2.1, 6.3, 
7.6
Report to Study Site 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
4.1 
Study Drug 
Administration 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
5
Blood Pharmacokinetic 
Sampling 
 
 
x 
xc
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
6.5, Tables 
6.5.1A and 
6.5.1B 
Blood Sampling for 
HIV-1 RNA Analysis 
x 
 
xd 
xd
xd
xd
xd
xd
xd
xd
xd
xd
xd
x 
x 
6.3
Blood Sampling for 
Protein Binding  
 
 
 
 
 
 
 
 
 
xe 
 
 
 
 
 
6.5
Blood Sampling for 
CD4+ and CD8+ Counts 
x 
 
xd 
 
 
 
 
 
 
xd 
 
 
 
x 
x 
6.3
Plasma Collection 
RT/Pol genotype 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3
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Table 6.1: 
Flow Chart for Protocol AI438006 
Screening
Study Day 
Follow 
up
Study 
Dischargej
Protocol 
Sections 
Event 
Within 35 
Days of 
Study Day 1 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
15 
50  3 days 
Plasma Collection HIV 
Env genotyping & 
phenotypingf
x 
 
xd 
 
 
xd 
 
 
 
xd 
 
 
 
x 
x 
6.9.1
Plasma Collectiong 
x 
 
xd 
 
 
 
 
 
 
xd 
 
 
 
x 
x 
6.9.1 
Blood (PBMC) 
Collectionh
x 
 
x
 
 
x 
 
 
 
x 
 
 
 
x 
x 
6.9.1
Monitor for Serious  
Adverse Events 
All SAEs must be collected from the date of subject’s written consent until 30 days post discontinuation of dosing 
or subject’s participation in the study if the last scheduled visit occurs at a later time. 
7
Monitor for Non-
Serious Adverse Events 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
7
a 4 hours post-AM dose in groups 1, 3, 4 and 5; 4 hours post-PM dose in group 2.  Vital signs will include heart rate and blood pressure measurements. 
b Weight only 
c Group 2 only 
d Pre-AM dose in groups 1, 3, 4 and 5; Pre-PM dose in group 2.  On days when dose is not administered, sample collection time should be maintained. 
e Pre-PM dose and 4 hours post-PM dose 
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f Env Genotyping and phenotyping analysis: Env. phenotyping to be analyzed on Day 1 in all dosed subjects; all other samples to be stored and analyzed if 
deemed relevant.   
g Neutralizing antibody activity, HIV co-receptor usage and samples for exploratory resistance analysis; to be stored and analyzed if deemed relevant 
h Activation markers and exploratory apoptotic markers; to be stored and analyzed if deemed relevant  
i If the screening physical exam is performed within 24 hours of dosing on Day 1, then a single examination may count as both the screening and predose 
evaluation 
j Evaluations performed prior to study discharge or for subjects who are prematurely discontinued from the study. 
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In the event multiple procedures are required at a single timepoint, the following is a list 
of procedures from highest priority to low: 
1) Pharmacokinetic Sampling 
2) Safety (ECG) 
3) Safety (vital signs) 
4) Safety (clinical labs) 
6.2 
Study Materials 
The site will provide all required materials for the tests performed locally (ie, relevant 
clinical laboratory tests and urine drug screens). The site will have available a well-
calibrated scale for recording body weight, a 12-lead ECG machine, and a calibrated 
sphygmomanometer and thermometer for vital signs assessments. A current and fully-
stocked advanced cardiac life support (ACLS) cart will be immediately available on the 
premises. The site will have a refrigerated centrifuge, a monitored and alarmed 
refrigerator, and freezer (-20°C or below), as well as containers and dry ice for shipment 
and storage of blood samples. The site will provide all materials required for accurate 
source documentation of study activities and for housing the subjects during the study.    
BMS will provide a BMS-approved protocol and any amendments or administrative 
letters (if required), investigator brochure and study drug (BMS-663068 and ritonavir). 
Case report forms (electronic or hard copy) will be provided by BMS. The Central 
Laboratory will provide labels and tubes for the collection of blood samples for PK/PD, 
for genotyping analysis, and for clinical lab samples being analyzed centrally. 
6.3 
Safety Assessments 
6.3.1 
Medical History 
A detailed medical history will be obtained at screening.  Include the history of any 
toxicities or allergy related to previous treatments. 
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6.3.2 
Vital Signs 
Vital signs (body temperature, respiratory rate, seated blood pressure and heart rate) will 
be recorded during the screening visit, Day -1, Day 11, Day 15 and at study discharge.  
Additionally, on Days 1, 4 and 8, seated blood pressure and heart rate will be measured 4 
hours post AM dose in groups 1, 3, 4 and 5 and 4 hours post PM dose in group 2. 
Blood pressure and/or heart rate values that meet exclusion criteria may be confirmed by 
repeat analysis at the screening visit and/or Day -1. In the event that the repeat blood 
pressure and/or heart rate value(s) do not exclude the subject, a third assessment should 
be taken approximately 5 minutes later. The subject may be enrolled if the third 
assessment does not meet exclusion criteria for blood pressure and/or heart rate. 
Blood pressure and heart rate should be measure after the subject has been seated or 
supine quietly for at least 5 minutes. 
Note: For any time point when vital signs and ECG are both required, the heart rate 
measurement from the ECG machine is to be entered in the CRF. At these time points it 
will not be necessary to measure heart rate by other means. However, for time points 
when an ECG will not be recorded but vital signs are to be measured, the heart rate is to 
be measured by other means (ie, Dynamap or manual count over 60 seconds) and that 
result entered in the CRF. 
6.3.3 
Physical Measurements 
Height and weight will be measured and body mass index (BMI) calculated at screening 
as part of the physical exam.  Weight will also be measure on Days -1, 8, 11, 15, and at 
study discharge. 
6.3.4 
Physical Examination 
A physical examination will be performed at the screening visit, Days 1 (predose), 8, 11, 
15 and at study discharge.  If the screening physical examination is performed within 24 
hours of dosing on Day 1, then a single examination may count as both the screening and 
predose evaluation. 
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6.3.5 
Electrocardiograms 
A 12-lead ECG will be recorded at screening, Day -1, Day 11 and at study discharge.  
Additionally, on Days 1, 4 and 8, a 12-lead ECG will be recorded 4 hours post AM dose 
in groups 1, 3, 4 and 5 and 4 hours post PM dose in group 2. 
6.3.6 
Adverse Event Monitoring 
Subjects will be closely monitored throughout the study for adverse events and will not 
be discharged from the study until the investigator has determined that adverse events 
have either completely resolved or are not of clinical significance (refer to Section 7). 
6.3.7 
Laboratory Test Assessments 
Blood and urine samples will be obtained at selected times (refer to Table 6.1) for clinical 
laboratory evaluations.  Subjects are required to fast for at least 7 hours prior to the 
collection of specimens for clinical laboratory tests.  A central laboratory will perform the 
analyses, unless results are needed immediately, then a local lab can be used.  Reference 
ranges from these tests will be provided by the laboratory.  Sample collection time 
(relative to dosing) should be maintained throughout the inpatient portion of the study.  
Samples should be collected prior to dosing.  Samples for clinical laboratory tests for 
subjects assigned to group 2 can be collected in the AM, prior to the PM dosing. 
Results of clinical laboratory test performed on Day -1 must be available prior to dosing. 
The following clinical laboratory tests will be performed. 
Hematology 
Hemoglobin 
Hematocrit 
Total leukocyte count, including differential 
Platelet count 
Serum Chemistry 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Total bilirubin (if abnormal, direct 
Fasting glucose 
Total Protein 
Albumin
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bilirubin should be performed, except at 
screening) 
Alkaline phosphatase 
Lactate dehydrogenase (LDH) 
Creatinine  
Creatinine Clearance (Screening only) 
Blood Urea Nitrogen (BUN) 
Uric acid 
C-Reactive Protein (CRP) 
Amylase (if abnormal, lipase should be 
performed, except at screening) 
Sodium
Potassium
Chloride 
Calcium 
Phosphorus
Creatine kinase (CK), CK not to be drawn 
after day 11. If CK is 2 times the upper 
limit of normal, Troponin T should be 
performed (except at screening) 
Urinalysis
Protein
Glucose
Blood 
Leukocyte esterase 
Microscopic examination of the sediment if blood, protein or leukocytes esterase are 
positive on the dipstick 
Serology
Serum for hepatitis C (reflex to HCV RNA if hepatitis C antibody positive) antibody, 
hepatitis B surface antigen, HIV-1, -2 antibody (screening only)
Other Analyses  
Urine for drugs of abuse (screening and on Day -1) 
Pregnancy test (WOCBP only:  screening*, Days -1*, 4, 11 and at discharge). 
RT/Pol genotype and HIV clade (screening) 
*Lab result MUST be available prior to dosing 
Results of all laboratory tests required by this protocol must be provided to BMS, either 
recorded on the laboratory pages of the CRF or by another mechanism as agreed upon 
between the investigator and BMS (eg, provided electronically). If the units of a test 
result differ from those printed on the CRF, the recorded laboratory values must specify 
the correct units. Any abnormal laboratory test result considered clinically significant by 
the investigator must be recorded on the appropriate AE page of the CRF (see Section 7.4 
Laboratory Test Abnormalities). 
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6.4 
Efficacy Assessments 
Not applicable. 
6.5 
Pharmacokinetic Assessments 
6.5.1 
Pharmacokinetics: Collection and Processing 
Tables 6.5.1A and 6.5.1B lists the sampling schedule to be followed for the assessment of 
pharmacokinetics.  Further details of blood sample collection and processing will be 
provided to the site in the procedure manual. 
Table 6.5.1A: 
PK Sample Schedule (Groups 1, 3, 4 and 5 Only) 
Study Day 
Time (Event)  
Hour 
Time 
(Relative To Last 
Dose)
Hour:Min 
BMS-626529 and 
RTVa
1 and 8 
0 (pre-AM dose) 
00:00 
x 
1 and 8 
1
01:00 
x 
1 and 8 
2
02:00 
x 
1 and 8 
3
03:00 
x 
1 and 8 
4
04:00 
x 
1 and 8 
5
05:00 
x 
1 and 8 
6
06:00 
x 
1 and 8 
8
08:00 
x 
1 and 8 
12* 
12:00 
xb
8 
13 
01:00 
x 
8 
14 
02:00 
x 
8 
15 
03:00 
x 
8 
16 
04:00 
xb
8 
17 
05:00 
x 
8 
18 
06:00 
x 
8 
20 
08:00 
x 
9 
0 
12:00 
x 
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Table 6.5.1A: 
PK Sample Schedule (Groups 1, 3, 4 and 5 Only) 
Study Day 
Time (Event)  
Hour 
Time 
(Relative To Last 
Dose)
Hour:Min 
BMS-626529 and 
RTVa
9 
4 
16:00 
x 
9 
12 
24:00 
x 
10 
0 
36:00 
x 
10 
12 
48:00 
x 
11 
0 
60:00 
x 
5, 6, 7 
0 (pre-AM dose) 
00:00 
x 
*: Samples to be taken before evening dosing 
a RTV will be measured in Group 1, 3 and 4 only 
b Additional blood samples will be drawn on Day 8 for protein binding analysis 
Table 6.5.1B: 
PK Sample Schedule (Group 2 Only) 
Study Day 
Time (Event)  
Hour 
Time 
(Relative To Last 
Dose)
Hour:Min 
BMS-626529 and RTV 
1 and 8 
0 (pre-PM dose)* 
00:00 
xa
1 and 8 
1
01:00 
x 
1 and 8 
2
02:00 
x 
1 and 8 
3
03:00 
x 
1 and 8 
4
04:00 
xa
1 and 8 
5
05:00 
x 
1 and 8 
6
06:00 
x 
1 and 8 
8
08:00 
x 
2 and 9 
12
12:00 
x 
2 and 9 
16
16:00 
x 
2 and 9 
0 (pre-PM dose Day 2) 
24:00 
x 
10 
0 
36:00 
x 
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Table 6.5.1B: 
PK Sample Schedule (Group 2 Only) 
Study Day 
Time (Event)  
Hour 
Time 
(Relative To Last 
Dose)
Hour:Min 
BMS-626529 and RTV 
10 
12 
48:00 
x 
11 
0 
60:00 
x 
5, 6, 7 
0 (pre-PM dose)* 
00:00 
x 
*: Subject will receive study drug in the evening. 
a: Additional blood samples will be drawn on Day 8 for protein binding analysis. 
6.5.2 
Pharmacokinetic Sample Analyses 
The serial plasma PK samples will be analyzed for BMS-626529 and RTV by a validated 
LC/MS/MS assay. If warranted by further clinical investigation, BMS-626529 
metabolites may also be analyzed.  Plasma samples collected for BMS-626529 protein 
binding assay will be initially analyzed for Groups 3 and 5 only, and remaining samples 
will be stored for future analysis, if deemed appropriate. 
6.5.3 
Labeling and Shipping of Biological Samples 
Detailed instructions for the pharmacokinetic blood collection, labeling, processing, 
storage, and shipping will be provided to the site in the procedure manual. 
6.6 
Pharmacodynamics Assessments 
Viral activity will be assessed by the magnitude and rate of change in plasma HIV RNA 
levels from baseline (predose Day 1).  Blood samples from all subjects will be obtained 
for analyses of HIV RNA level at Screening, on Days 1 through 11, 15 and discharge.  
Samples should be collected prior to dosing (pre AM dose in groups 1, 3, 4, and 5; pre 
PM dose in group 2).  The plasma collection time (relative to dosing) should be 
maintained throughout the inpatient portion of the study (Days 1 through 11). 
CD4+ and CD8+ lymphocyte counts and percents will be assessed.  Blood samples from 
all subjects will be obtained for CD4+ and CD8+ cell counts at Screening, Days 1, 8, 15 
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and discharge.  Samples should be collected prior to dosing (pre AM dose in groups 1, 3, 
4, and 5; pre PM dose in group 2).  Collection time (relative to dosing) should be 
maintained throughout the inpatient portion of the study (Days 1 through 11). 
RT/Pol genotyping to determine HIV clade will be performed.  A plasma sample will be 
obtained at screening for RT/Pol genotype and HIV clade determination. 
6.7 
Pharmacogenomic/Pharmacogenetic Assessments 
See Amendment 01 for pharmacogenomics blood sampling. 
6.8 
Outcomes Research Assessments 
Not applicable. 
6.9 
Other Assessments  
6.9.1 
Exploratory Biomarkers 
Plasma samples for HIV envelope genotyping and phenotyping will be collected at 
Screening, Days 1, 4, 8, 15 and discharge. Collection time (relative to dosing) should be 
maintained throughout the inpatient portion of the study (Days 1 through 11).  Envelope 
phenotype will be determined on samples from Day 1.  All other samples may be 
analyzed if deemed relevant. 
Plasma samples for HIV co-receptor usage and neutralizing antibody activity will be 
collected at Screening, Days 1, 8, 15 and discharge.  Collection time (relative to dosing) 
should be maintained throughout the inpatient portion of the study (Days 1 through 11).  
These samples may be analyzed if deemed relevant.  
Plasma samples will also be collected for exploratory resistance analysis at Screening, 
Days 1, 8, 15 and discharge. These samples could be used for performing clonal analysis 
to detect or quantitate minor resistant variants or for viral culture, genotyping, or 
phenotyping of the HIV genome to determine sensitivity to additional therapeutic agents.  
These samples may be analyzed if deemed relevant. 
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Blood samples for activation marker and exploratory apoptotic markers analysis using 
PBMCs will be collected at Screening, Days 1, 4, 8, 15 and discharge in special tubes 
with special handling and shipping instructions.  These samples may be analyzed if 
deemed relevant.  Collection time (relative to dosing) should be maintained throughout 
the inpatient portion of the study (Days 1 through 11). 
Further details of sample collection, processing and shipping will be provided to the site 
in the procedure manual. 
7 
ADVERSE EVENTS 
7.1 
Definitions 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a patient or clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product. 
7.1.1 
Serious Adverse Events 
A serious AE (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 for exceptions) 

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 
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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.) 
Suspected transmission of an infectious agent (eg, any organism, virus or infectious 
particle, pathogenic or non-pathogenic) via the study drug is an SAE and must be 
reported accordingly. 
Although overdose and cancer are not always serious by regulatory definition, these 
events should be reported on an SAE form and sent to BMS in an expedited manner.  
All pregnancies, regardless of outcome, must be reported to the sponsor on a Pregnancy 
Surveillance Form, not an SAE form (see Section 7.6). 
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 "important medical event" or event life 
threatening) 
	
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 for purpose other than remedying ill health state and 
was 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, care-giver respite, family circumstances, administrative) 
7.1.2 
Nonserious Adverse Events 
All AEs that are not classified as serious. 
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7.2 
Assignment of Adverse Event Intensity and 
Relationship to Study Drug 
The following categories and definitions of intensity as determined by a physician should 
be used for all BMS clinical study AEs:  

Mild (Grade 1) - Awareness of event but easily tolerated 

Moderate (Grade 2) - Discomfort enough to cause some interference with usual 
activity 

Severe (Grade 3) - Inability to carry out usual activity 

Very Severe (Grade 4) - Debilitating, significantly incapacitates subject despite 
symptomatic therapy 
The following categories and definitions of causal relationship to study drug as 
determined by a physician should be used for all BMS clinical study AEs: 

Related: There is a reasonable causal relationship to study drug administration and the 
AE

Not related: There is not a reasonable causal relationship to study drug administration 
and the AE 
The expression "reasonable causal relationship" is meant to convey in general that there 
are facts (eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a 
positive causal relationship.  
7.3 
Collection and Reporting 
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.) 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather 
than its individual symptoms. The following information should be captured for all AEs: 
onset, duration, intensity, seriousness, relationship to study drug, action taken, and 
treatment required. If treatment for the AE was administered, it should be recorded on the 
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appropriate CRF page. The investigator shall supply the sponsor and Ethics Committee 
with any additional requested information, notably for reported deaths of subjects. 
Completion of supplemental CRFs may be requested for AEs and/or laboratory 
abnormalities that are reported/identified during the course of the study.  
7.3.1 
Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs must be 
collected, including those thought to be associated with protocol-specified procedures. 
All SAEs must be collected that occur within 30 days of discontinuation of dosing or 
within 30 days of the last visit for screen failures. If applicable, SAEs must be collected 
that relate to any later protocol-specified procedure (eg, a follow-up skin biopsy).  
The investigator should notify BMS (or designee) of any SAE occurring after these time 
periods that is believed to be related to study drug or protocol-specified procedure.  
Serious adverse events, whether related or unrelated to study drug, must be recorded on 
the SAE page of the CRF and reported within 24 hours to BMS (or designee) to comply 
with regulatory requirements. An SAE report should be completed for any event where 
doubt exists regarding its status of seriousness.
All SAEs must be reported within 24 hours by confirmed facsimile transmission (fax). 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.) In 
selected circumstances, the protocol may specify conditions that require additional 
telephone reporting. The SAE electronic CRF in the electronic data capture tool should 
not be used. 
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 page of the CRF. 
If an ongoing SAE changes in its intensity or relationship to study drug, a follow-up SAE 
report should be sent within 24 hours to the sponsor (or designee). As follow-up 
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information becomes available it should be sent within 24 hours using the same 
procedure used for transmitting the initial SAE report. All SAEs should be followed to 
resolution or stabilization. 
SGS Contact Information:
SAE Facsimile Number: 
 
SAE Telephone Contact (24h emergency phone number): 
7.3.2 
Handling of Expedited Safety Reports 
In accordance with local regulations, BMS will notify investigators of all SAEs that are 
suspected (related to the investigational product) and unexpected (ie, not previously 
described in the Investigator Brochure). In the European Union (EU), an event meeting 
these criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Investigator notification of these events will be in the form of an expedited safety report 
(ESR).  
Other important findings which may be reported by the sponsor as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack of 
efficacy that poses significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (eg, animal) study, important safety recommendations from a 
study data monitoring committee, or sponsor decision to end or temporarily halt a clinical 
study for safety reasons. 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the Investigator Brochure. Where required by local regulations or when there is a central 
IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. When 
BMS has a written agreement with a local IRB/IEC, BMS will directly submit ESR(s).  
The investigator should also comply with the IRB/IEC procedures for reporting any other 
safety information.  
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In addition, suspected serious adverse reactions (whether expected or unexpected) shall 
be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate reports). 
7.3.3 
Nonserious Adverse Events 
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.
If an ongoing nonserious AE worsens in its intensity or its relationship to the study drug 
changes, a new nonserious AE entry for the event should be completed. Nonserious AEs 
should be followed to resolution or stabilization, or reported as SAEs if they become 
serious (see Section 7.3.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug, or those that are present at the end of study 
treatment as appropriate. 
All identified nonserious AEs must be recorded and described on the appropriate 
nonserious AE page of the CRF (paper or electronic). 
7.4 
Laboratory Test Abnormalities 
All laboratory test values captured as part of the study should be recorded on the 
appropriate laboratory test results pages of the CRF, or be submitted electronically from a 
central laboratory. In addition, the following laboratory abnormalities should also be 
captured on the nonserious AE CRF page (paper or electronic) or SAE paper CRF page 
as appropriate: 

Any laboratory test result that is clinically significant or meets the definition of an 
SAE  

Any laboratory abnormality that required the subject to have study drug discontinued 
or interrupted 

Any laboratory abnormality that required the subject to receive specific corrective 
therapy 
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It is expected that wherever possible, the clinical, rather than the laboratory term would 
be used by the reporting investigator (eg, anemia versus low hemoglobin value). 
7.5 
Overdose 
An overdose is defined as the accidental or intentional ingestion or infusion 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 7.3.1 for reporting details.) 
7.6 
Pregnancy 
Sexually active WOCBP must use an effective method of birth control during the course 
of the study, in a manner such that risk of failure is minimized (See Section 4.2.1 for the 
definition of WOCBP). 
Before enrolling WOCBP in this clinical study, investigators must review the sponsor-
provided information about study participation for WOCBP. The topics include the 
following: 

General Information 

Informed Consent Form 

Pregnancy Prevention Information Sheet 

Drug Interactions with Hormonal Contraceptives 

Contraceptives in Current Use 

Guidelines for the Follow-up of a Reported Pregnancy  
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form documenting this discussion.  
7.6.1 
Requirements for Pregnancy Testing 
All WOCBP MUST have a negative pregnancy test within 24 hours as specified in 
Section 6.1 prior to receiving the investigational product. The minimum sensitivity of the 
pregnancy test must be 25 IU/L or equivalent units of HCG. If the pregnancy test is 
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positive, the subject must not receive the investigational product and must not continue in 
the study. 
Pregnancy testing must also be performed throughout the study as specified in 
Section 6.1 (see flow chart/time and events schedule) and the results of all pregnancy 
tests (positive or negative) recorded on the CRF or transferred electronically. 
In addition, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (eg, missed or late menstrual period) at any time 
during study participation. 
7.6.2 
Reporting of Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety). The investigator must immediately notify 
the SGS medical monitor of this event, record the pregnancy on the Pregnancy 
Surveillance Form (not an SAE form). Initial information on a pregnancy must be 
reported immediately to SGS and the outcome information provided once the outcome is 
known. Completed Pregnancy Surveillance Forms must be forwarded to SGS according 
to SAE reporting procedures described in Section 7.3.1.  
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 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 the sponsor. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
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7.7 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded on the appropriate 
nonserious AE page of the CRF (paper or electronic) or SAE paper CRF page.  
8 
STATISTICAL CONSIDERATIONS 
8.1 
Sample Size Determination 
The sample size evaluation is based on the primary objective of the study, to assess the 
antiviral activity of BMS-626529 following administration of selected regimens of BMS-
663068 with and without RTV administered orally to HIV infected subjects for 8 days. A 
mean decrease from baseline in HIV RNA of at least 1 log10 at Day 9 within any one 
regimen group may suggest that the dose of BMS-663068 is sufficiently active against 
HIV to proceed with further development of the drug.  If the BMS-663068 containing 
regimen has no effect, then administration of the regimen to 10 subjects (ARV naive or 
experienced) would provide a 1% probability to observe a mean log10 drop of 1. If the 
true population mean decrease from baseline in HIV RNA is 1.5 log10, then there 
would be a 99% probability that the observed mean decline from baseline would be 1
log10. In addition, 10 subjects within each group can also provide >99% power to 
conclude the mean decreases in log10 HIV RNA from baseline > 0 if the true population 
decrease from that group is 1 log10.  Meanwhile, 10 subjects in each group can also 
provide 82% power to conclude the mean decreases in log10 HIV RNA from two groups 
are different if the true difference in population mean decreases from these two groups is 
0.6 log10.
In addition, administration of the BMS-663068 containing regimen to 10 subjects per 
group provides an 80% probability of observing at least one occurrence in that regimen 
group of any adverse event that would occur with 15% incidence in the population from 
which the sample is drawn.   
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For these calculations, it is assumed that the log10 decrease in HIV RNA from baseline to 
Day 9 is normally distributed, with a standard deviation of 0.5, as estimated from 
AI430003. 
8.2 
Populations for Analyses 
All subjects who receive study medication will be included in the safety data set.  
All available data from subjects who receive BMS-663068 will be included in the 
pharmacokinetic data set. 
All available data from subjects for whom pharmacodynamic measurements are available 
at baseline and at least one other time will be included in the pharmacodynamic data set. 
8.3 
Endpoint Definitions 
8.3.1 
Safety Endpoint 
Safety assessments will be based on adverse event reports and the results of vital sign 
measurements, ECGs, physical examinations, and clinical laboratory tests. The incidence 
of adverse events will be tabulated and reviewed for potential significance and clinical 
importance. 
8.3.2 
Pharmacokinetic Endpoint(s) 
Pharmacokinetics of BMS-626529 and RTV will be derived from plasma concentration 
versus time data. The pharmacokinetic parameters to be assessed include: 
Cmax 
Maximum observed plasma concentration 
Ctrough 
Trough observed plasma concentration 
Tmax 
Time of maximum observed plasma concentration 
AUC(TAU) 
Area under the concentration-time curve in one dosing interval 
AUC(0-24h) 
Area under the concentration-time curve over a 24-hour period 
following the AM dose (PM for Group 2) on Day 8 
Css,avg 
Average steady-state plasma concentration, calculated as AUC(0-
24h)/24
T-HALF 
Terminal half-life (after last dose only) 
CLT/F 
Apparent total body clearance 
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Vss/F 
Apparent volume of distribution at steady-state 
AI 
Accumulation index; ratio of AUC(TAU) at steady-state to AUC(TAU) 
after the first dose 
Protein
binding (%) 
Percent of BMS-626529 that are bound to total plasma proteins 
IQ 
Inhibitory quotient, calculated as the ratio of BMS-626529 in vivo 
exposure to in vitro measured protein binding adjusted EC90. The 
following in vivo exposure measures will be used in evaluating IQ: 
Cmax, Ctrough and Css,avg. 
Individual subject pharmacokinetic parameter values will be derived by non 
compartmental methods by a validated pharmacokinetic analysis program. 
8.3.3 
Pharmacodynamic Endpoint(s) 
Pharmacodynamic assessment will be based on change in HIV RNA.  Additionally, 
CD4+ and CD8+ lymphocyte counts and percents will be assessed.  
8.4 
Analyses 
8.4.1 
Demographics and Baseline Characteristics 
Frequency distributions of gender and race will be tabulated. Summary statistics for age, 
body weight, height, and Body Mass Index (BMI) will be tabulated. 
8.4.2 
Safety Analyses 
All recorded adverse events will be listed and tabulated by system organ class, preferred 
term and treatment. Vital signs and clinical laboratory test results will be listed and 
summarized by treatment. Any significant physical examination findings, and clinical 
laboratory results will be listed. ECG readings will be evaluated by the investigator and 
abnormalities, if present, will be listed. 
8.4.3 
Efficacy Analyses 
Not Applicable. 
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8.4.4 
Pharmacokinetic Analyses 
The multiple-dose pharmacokinetics of BMS-626529 following administration of BMS-
663068 with or without RTV will be described by summary statistics for the 
pharmacokinetic parameters by regimen group, study day, dose time (AM or PM, Groups 
1, 3, 4 and 5 only), antiretroviral treatment history (ARV naive, ARV experienced, and 
combined [ARV naive + ARV experienced]). Medians and ranges will be presented for 
Tmax. Means and standard deviations will be provided for T-HALF. Geometric means 
and coefficients of variation will be presented for Cmax, Ctrough, Css,avg, AUC(TAU), 
AUC(0-24), CLT/F, Vss/F and AI. 
To assess the dependency on regimen, scatter plots of Cmax, AUC(TAU), and Ctrough 
versus regimen group will be provided by day and dose time (Groups 1, 3, 4 and 5 only). 
Time to steady-state will be evaluated by summary statistics of Ctrough (following AM 
doses except Group 2) by study day and by plot of geometric mean Ctrough versus study 
day.  
Protein binding (%) for BMS-626529 will be evaluated by summary statistics and 
tabulated by regimen group. Inhibitory Quotient (IQ) of Cmax, Ctrough (both on Day 8 
following AM regimens except Group 2) and Css-avg of BMS-626529 (defined in 
section 8.3.2) will be summarized and tabulated by regimen group. 
Point estimates and 90% confidence intervals will be constructed for accumulation 
indices (ratio of Day 8 [AM doses except Group 2] vs. Day 1 for AUC(TAU), Cmax and 
Ctrough) by regimen group. These estimates will be generated using general linear 
models fitted to log-transformed data with study day as a fixed effect, and measurements 
within each subject as repeated measurements. Point estimates and 90% confidence 
intervals for differences at the log-scale will be exponentiated to obtain estimates and 
confidence intervals for ratios of geometric means in the original scale. No adjustments 
will be made for multiplicity. 
Similar analysis will be used to access the effect of RTV on PK exposure of BMS-
626529, by comparing the exposure of BMS-626529 in group 3 vs. group 5 and group 4 
vs. group 5 with regimen groups as a fixed effect in the general linear models. The effects 
of diurnal PK variation (PM vs. AM) will also be assessed by the similar model for 
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Groups 1, 3, 4 and 5 only with time point (PM or AM) as a fixed effect and 
measurements within each subject as repeated measurements in the general linear models. 
The multiple-dose pharmacokinetics of RTV when coadministered with various regimens 
of BMS-663068 will be described by summary statistics for the pharmacokinetic 
parameters by regimen group, study day, dose time (AM or PM, Groups 1 and 3), 
antiretroviral treatment history (ARV naive, ARV experienced, and combined [ARV 
naive + ARV experienced]).  Medians and ranges will be presented for Tmax. Means and 
standard deviations will be provided for T-HALF.  Geometric means and coefficients of 
variation will be presented for Cmax, Ctrough, Css, avg, AUC(TAU), AUC(0-24), 
CLT/F, Vss/F and AI. 
8.4.5 
Pharmacodynamic Analyses 
Although the final decision on the further evaluation of BMS-663068 will be a broader 
scientific assessment of its benefit/risk profile, including consideration of safety and other 
endpoints as previously outlined, plus relevant information external to this trial, a mean 
decrease from baseline in HIV RNA of at least 1 log10 on Day 9 within any one regimen 
group may suggest that that dose of BMS-663068 is sufficiently active against HIV.  
The magnitude of the change in log10 HIV RNA levels will be assessed by summarizing 
changes from baseline, including 90% confidence intervals, at study day 2 through day 
11 and at day 15, by regimen group and antiretroviral treatment history (ARV naive, 
ARV experienced, and combined [ARV naive + ARV experienced]). The primary 
assessment of the antiviral activity of BMS-663068 will be based on the log10 change 
from baseline in HIV RNA to Day 9. To assess the dependency on dose, scatter plots of 
log10 change from baseline in HIV RNA at Day 9 versus dose will be provided.  Two 
groups t-test will be used to test the differences in mean log10 decrease in HIV RNA at 
Day 9 between two regimen groups by antiretroviral treatment history (ARV naive, ARV 
experienced, and combined [ARV naive + ARV experienced]). Each individual’s 
maximum log10 decrease from baseline in HIV RNA will be summarized by regimen 
group, antiretroviral treatment history (ARV naive, ARV experienced, and combined 
[ARV naive + ARV experienced]), and frequency distributions for maximum log10
decrease from baseline in HIV RNA will be provided by regimen group, antiretroviral 
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treatment history (ARV naive, ARV experienced, and combined [ARV naive + ARV 
experienced])..    
8.4.5.1 
Pharmacokinetics/ Pharmacodynamic Analyses 
The effect of BMS-626529 on PD measures (i.e., CD4+ and CD8+ T lymphocyte counts 
and percents and the corresponding changes in these parameters from baseline) will be 
assessed by summary statistics. Scatter plots will be used to assess the relationship 
between the changes from baseline in plasma HIV RNA and BMS-626529 EC90
(determined from Day 1 sample), a threshold of protein binding adjusted EC90 will be 
determined based on this scatter plot and summary statistics will be provided for the 
changes from baseline in plasma HIV RNA by group, excluding subjects with protein 
binding adjusted EC90 above this threshold.
Scatter plots will also be used to assess the relationship between the changes from 
baseline in plasma HIV RNA and BMS-626529 IQs, and to assess the correlation 
between log10 changes from baseline in HIV RNA and IQs   
8.4.6 
Pharmacogenomic Analyses 
See Amendment 01 for pharmacogenomics blood sampling assessments. 
8.4.7 
Outcomes Research Analyses 
Not applicable. 
8.4.8 
Other Analyses  
Summary statistics for exploratory biomarkers, such as but not limited to those stated in 
sections 6.6 and 6.9, and corresponding changes from baseline, or percent changes from 
baseline as appropriate, will be tabulated by regimen group, study day and time point.  
Possible associations between changes in exploratory biomarkers of interest and BMS-
663068 dose or exposure will be explored graphically and by suitable statistical models, 
if appropriate.  Some nonlinear models, such as but not limited to generalized least 
squares, will also be explored.  Ad-hoc statistical analysis would be considered. 
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8.5 
Interim Analyses 
The primary analyses will be conducted after all subjects have completed the study and 
after the formal study database lock.  
Interim analyses will be conducted for internal decision making. Data that may be 
included in the interim analysis are measures of antiviral activity, PK, and safety. 
Analyses will only consist of listings, summaries, and graphs, and no formal inferences 
requiring any adjustment to statistical significance levels will be performed.  
In addition, a structural population PK and PK/PD model will be developed based on 
approximately 50% and repeated when 100% of PK data are available.  This data will be 
combined with data from previous clinical studies with BMS-663068 to assist in internal 
decision making that could include, but is not limited to selecting possible phase IIb 
doses.
9 
ADMINISTRATIVE SECTION 
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. Any significant deviation must be 
documented in the CRF. 
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 

Bristol-Myers Squibb 

Regulatory Authority(ies), if required by local regulations 
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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 an administrative letter, investigators must inform their IRB(s)/IEC(s).  
9.1.2 
Monitoring 
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.             
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. 
9.1.3 
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, study documentation, informed consent, and enrollment of 
WOCBP. 
For sites using the BMS electronic data capture tool, each individual making entries 
and/or corrections on electronic CRFs must meet BMS training requirements and must 
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only access the BMS electronic data capture tool using the unique user account provided 
by the sponsor. User accounts are not to be shared or reassigned to other individuals. 
For electronic CRFs, corrections are made through the BMS electronic data capture tool 
that generates an automated audit trail including date and timestamp, full name of the 
person making the correction and original entry. The system also prompts the user to 
document reason for change that is also maintained in the audit trail. 
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 the sponsor. User accounts are not to be shared or reassigned to 
other individuals. 
9.2 
Records Retention 
The investigator must retain study drug (those supplied by the sponsor or sourced by the 
investigator) disposition records, copies of CRFs (or electronic files), and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by the sponsor, 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.  
9.2.1 
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 reported on the CRF 
that are derived from source documents must be consistent with the source documents or 
the discrepancies must be explained.  
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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 Pregnancy Surveillance Form. Spaces may be left blank only in those 
circumstances permitted by study-specific CRF completion guidelines provided by the 
sponsor.
Paper CRFs must be completed legibly in ink. Subjects are to be identified by birth date 
and subject number, if applicable. All requested information must be entered on the CRF 
in the spaces provided. If an item is not available or is not applicable, it must be 
documented as such; do not leave a space blank.
Electronic data transfer is acceptable. 
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.  
For paper CRFs, a correction must be made by striking through the incorrect entry with a 
single line and entering the correct information adjacent to the incorrect entry. The 
correction must be dated, initialed and explained (if necessary) by the person making the 
correction and must not obscure the original entry. 
The completed CRF, including any paper SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by a qualified physician who is an investigator or 
subinvestigator. 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. 
9.2.2 
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by the sponsor) is maintained at each study site 
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where study drug is inventoried and disposed. 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 ID number or batch number and use date 

dates and initials of person responsible for the inventory /entry/ movement of each 
study drug  

amount dispensed to and returned by each subject, including unique subject 
identifiers 

amount transferred to another area/site for dispensing or storage 

non-study disposition (eg, lost, wasted, broken) 

amount returned to the sponsor 

amount destroyed at study site, if applicable 

retain samples sent to third party for bioavailability/bioequivalence, if applicable 
The sponsor will provide forms to facilitate inventory control if the staff at the 
investigational site does not have an established system that meets these requirements. 
9.3 
Destruction and Return of Study Drug 
9.3.1 
Destruction of Study Drug 
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be 
destroyed on site, it is the investigator’s responsibility to ensure that arrangements have 
been made for the disposal, procedures for proper disposal have been established 
according to applicable regulations, guidelines and institutional procedures, and 
appropriate records of the disposal have been documented. The unused study drugs can 
only be destroyed after being inspected and reconciled by the responsible Study Monitor. 
9.3.2 
Return of Study Drug 
Upon completion or termination of the study, all unused and/or partially used study drug 
that was supplied by the sponsor must be returned to BMS. 
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All study drug returned to BMS must be accompanied by the appropriate documentation 
and be clearly identified by protocol number and study site number on the outermost 
shipping container. Returned supplies should be in the original containers (eg, patient kits 
that have clinical labels attached). Empty containers should not be returned to BMS. 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. The return of unused study drug, those that were supplied by 
the sponsor, should be arranged by the responsible Study Monitor.  
9.4 
Publications 
The data collected during this study are confidential and proprietary to the sponsor. Any 
publications or abstracts arising from this study require approval by the sponsor prior to 
publication or presentation and must adhere to the sponsor’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 the 
sponsor 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. Sponsor 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 
Adverse Reaction 
An adverse event that is considered by either the 
investigator or the sponsor as related to the 
investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures.  
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction as 
termed by the European Clinical Trial Directive 
(2001/20/EC).
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved 
investigational product) 
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11 
LIST OF ABBREVIATIONS 
Term
Definition
AE 
adverse event 
ACLS 
advanced cardiac life support 
ADME 
absorption, distribution, metabolism and elimination 
AI 
accumulation index 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase 
ANC
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AV
atrioventricular 
-HCG 
beta-human chorionic gonadotrophin 
BDC 
bile duct-cannulated 
BMI 
body mass index 
BMS 
Bristol-Myers Squibb
BP 
blood pressure
BUN 
blood urea nitrogen 
C 
Celsius 
C12
concentration at 12 hours 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CLR 
renal clearance 
Cmax 
maximum concentration 
CRF 
Case Report Form, paper or electronic 
CTA
clinical trial agreement 
D/C 
discontinue 
DSM IV 
Diagnostic and Statistical Manual of Mental Disorders 
EC50
50% effective concentration 
EC90
90% effective concentration 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
eg 
exempli gratia (for example) 
ER 
extended release 
ESR 
Expedited Safety Report 
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Term
Definition
et al 
and others 
FSH 
follicle stimulation hormone 
g 
gram 
GCP
good clinical practice 
GI 
gastrointestinal 
GLP 
good laboratory practice 
HBV 
hepatitis B virus 
HCV
hepatitis C virus 
HIV 
human immunodeficiency virus
HR 
heart rate 
HRT
hormone replacement therapy 
IB 
investigator brochure 
ie 
id est (that is) 
IEC 
Independent Ethics Committee 
IR 
immediate release 
IRB 
Institutional Review Board 
IQ 
Inhibitory Quotient
IU 
International Unit
kg 
kilogram 
LLN 
lower limit of normal 
LOQ 
limit of quantitation 
m 
meter 
mg 
milligram 
MA 
marked abnormalities 
MAD
multiple ascending dose 
mL 
milliliter 
N/A 
not applicable
NOAEL 
no-observed-adverse-effect-level 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PBMC 
peripheral blood mononuclear cell 
Q12H
every 12 hours 
QAM
Quaque die Ante Meridiem, every day before noon 
QD
quaque die, once a day, once-daily 
QHS
Quaque hora somni (every night) 
QTcB
QT interval corrected for Bazett’s 
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Term
Definition
RNA 
ribonucleic acid 
RTV 
ritonavir 
SAD
single ascending dose 
SAE 
serious adverse event 
SD 
standard deviation
T-Half 
half life 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
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12 
REFERENCES 
1  Little SJ, Routy JP, et al. Antiretroviral-drug resistance among 
patients recently infected with HIV. New England Journal of 
Medicine 2002;347:385-94. 
2  Yerly S, Vora S, Rizzardip, et al. Acute HIV infection: impact 
on the spread of HIV and transmission of drug resistance. AIDS 
2001; 15:2287-92. 
3  Anti-HIV activity of the HIV-1 attachment inhibitor BMS-
626529. Bristol-Myers Squibb Pharmaceutical Research 
Institute, 2004. BMS Document Control No. 930007751. 
4  Mechanism of inhibition by the HIV-1 attachment inhibitor 
BMS-626529. Bristol-Myers Squibb Pharmaceutical Research 
Institute, 2004. BMS Document Control No. 930007753. 
5  BMS-663068 Investigators Brochure (version 06).  Bristol 
Myers Squibb Co. Pharmaceutical Research Institute, 2009. 
BMS Document Control No. 930012869. 
6  BMS-663068: Ten day oral range-finding study in pregnant 
rats (Study No DN09011). Bristol-Myers Squibb Research and 
Development, Preliminary Data 
7  
 Preclinical evaluation of the PK and metabolism of 
BMS-663068. Bristol-Myers Squibb Pharmaceutical Research 
Institute, 2005. BMS Document Control No. 930010576. 
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8  
 Preclinical evaluation of the PK 
and metabolism of BMS-626529. Bristol-Myers Squibb 
Pharmaceutical Research Institute, 2004. BMS Document 
Control No. 930007496. 
9  
  Biliary Excretion and Mass Balance of 
Radioactivity following Oral Administration of [14C]BMS-
663068 to Intact and Bile Duct-Cannulated Beagle Dogs. 
Charles River Laboratories, 2008.  BMS Document Control 
No. 930031847. 
10  Aarnoutse, R, Brinkman, K, Benetucci J, et al. Pharmacokinetics 
of indinavir and low-dose ritonavir (800/100 mg twice daily) 
combined with efavirenz in HIV-infected patients in the 
EASIER study. 4th International Workshop on Clinical 
Pharmacology of HIV Therapy, Cannes, France, March 27-29, 
2003.
11 Piliero, PJ, Preston, SL, Japour A, et al. Pharmacokinetics (PK) 
of the combination of ritonavir (RTV) plus saquinavir (SQV), 
with and without efavirenz (EFV), in healthy volunteers. 41st 
Interscience 
Conference 
on 
Antimicrobial 
Agents 
and 
Chemotherapy 2001; Sep 22-25: p.15. 
12 Reyataz® (Atazanavir Sulfate) Capsules Package Insert, 
Bristol-Myers Squibb Company, Princeton, NJ, 2004. 
13 Norvir 
(Ritonavir) 
Capsules 
Package 
Insert, 
Abbott 
Laboratories, North Chicago, IL, 2005. 
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14  Clinical Study Report.  Placebo controlled, ascending multiple 
dose study to evaluate the Antiviral Activity, safety, tolerability 
and pharmacokinetics of BMS-488043 in HIV-1 infected 
subjects. Bristol-Myers Squibb Research and Development, 
2005.  BMS Document Control No. 930012530. 
15  BMS-663068: Ten day oral range-finding study in pregnant 
rats (Study No DN09011). Bristol-Myers Squibb Research and 
Development, Preliminary Data 
16  Hileman, B. 1984. Formaldehyde:  Assessing the risk.  
Environmental Science Technology; 18:218A-221A. 
17  Til, HP, Woutersen, RA, Feron VJ, Hollanders VHM, and 
Falke HE.  Two-year drinking water study of formaldehyde in 
rats.  1999. Fd. Chem Toxic; 27: 77-87. 
18  Cockroft DW, Gault MH.  Prediction of creatinine clearance 
from serum creatinine.  Nephron, 1976;16:31-44. 
19  U.S. Department of Agriculture, Agricultural Research Service. 
2007 USDA National Nutrient Database for Standard 
Reference, Release 21. Nutrient Data Laboratory Home Page 
(http://www.nal.usda.gov/fnic/foodcomp/search/). 
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APPENDIX 1 
ADDITIONAL ETHICAL CONSIDERATIONS 
1 
INFORMED CONSENT PROCEDURES 
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.  
The consent form must also include a statement that BMS and regulatory authorities have 
direct access to subject records. Prior to the beginning of the study, the investigator must 
have the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects. 
The investigator must provide the subject, or, in those situations where consent cannot be 
given by subjects, their legally acceptable representative with a copy of the consent form 
and written information about the study in the language in which the subject is most 
proficient. The language must be non-technical and easily understood. The investigator 
should allow time necessary for subject or subject's legally acceptable representative to 
inquire about the details of the study, then informed consent must be signed and 
personally dated by the subject or the subject's legally acceptable representative and by 
the person who conducted the informed consent discussion. The subject or legally 
acceptable representative should receive a copy of the signed informed consent and any 
other written information provided to study subjects prior to subject's participation in the 
study. 
1.1 
Subjects Unable to Give Written Informed Consent 
1.1.1 
Minors 
For minors, according to local legislation, one or both parents or a legally acceptable 
representative must be informed of the study procedures and must sign the informed 
consent form approved for the study prior to clinical study participation. (In the event that 
the parents or legal guardians are unable to read, then an impartial witness should be 
present during the entire informed consent discussion). Whenever feasible, minors who 
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are judged to be of an age of reason must also give their written assent by signing and 
dating the completed informed consent. All local laws, rules and regulations regarding 
informed consent of minors must be followed. 
1.1.2 
Subjects Experiencing Acute Events or Emergencies 
A legally acceptable representative or legal guardian must provide informed consent 
when consent of the subject is not possible prior to clinical study participation, eg, for 
subjects experiencing an acute medical event such as myocardial infarction or stroke. 
Informed consent of the subject must additionally be obtained if they become capable of 
making and communicating their informed consent during the clinical study. All local 
laws, rules and regulations regarding informed consent of adult subjects incapable of 
giving informed consent must be followed. 
1.1.3 
Mentally Impaired or Incapacitated Subjects 
Investigators (or whoever required by local regulations) should determine whether or not 
a mentally impaired or incapacitated subject is capable of giving informed consent and 
should sign a statement to that effect. If the subject is deemed mentally competent to give 
informed consent, the investigator should follow standard procedures. If the subject is 
deemed not to be mentally competent to give informed consent, a fully informed legal 
guardian or legally acceptable representative can be asked to give consent for, or on 
behalf of, the subject. All local laws, rules and regulations regarding informed consent of 
mentally impaired or incapacitated subjects must be followed. 
Patients who are involuntarily hospitalized because of mental illness must not be enrolled 
in clinical studies 
1.1.4 
Other Circumstances 
Subjects who are imprisoned or involuntarily detained for treatment of either a 
psychiatric or physical (eg, infectious disease) illness must not be enrolled in clinical 
studies.
In circumstances where a subject’s only access to treatment is through enrollment in a 
clinical study, eg, for subjects in developing countries with limited resources or for 
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subjects with no marketed treatment options, the investigator must take special care to 
explain the potential risks and benefits associated with the study and ensure that the 
subject is giving informed consent. 
When a subject may be in a dependent relationship with the investigator, a well-informed 
physician who is not engaged in the clinical study and is completely independent of the 
relationship between the subject and investigator should obtain the subject’s informed 
consent.
1.1.5 
Illiterate Subjects 
If the subject, or, in those situations where consent cannot be given by the subject, their 
legally acceptable representative is unable to read, a reliable and independent witness 
should be present during the entire informed consent discussion. The choice of the 
witness must not breach the subject’s rights to confidentiality. A reliable independent 
witness is defined as one not affiliated with the institution or engaged in the investigation. 
A family member or acquaintance is an appropriate independent witness. After the 
subject or legally acceptable representative orally consents and has signed, if capable, the 
witness should sign and personally date the consent form attesting that the information is 
accurate and that the subject, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative has fully understood the content of the 
informed consent agreement and is giving true informed consent.   
1.2 
Update of Informed Consent 
The informed consent and any other information provided to subjects, or, in those 
situations where consent cannot be given by subjects, the subject's legally acceptable 
representative, should be revised whenever important new information becomes available 
that is relevant to the subject's consent, and should receive IRB/IEC approval/favorable 
opinion prior to use. The investigator, or a person designated by the investigator should 
fully inform the subject or the subject's legally acceptable representative 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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During a subject's participation in the study, any updates to the consent form and any 
updates to the written information will be provided to the subject. 
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APPENDIX 2 
DIAGNOSTIC CRITERIA FOR DRUG AND 
ALCOHOL ABUSE 
The following is taken from DSM-IV: 
Diagnostic Criteria for Psychoactive Substance Dependence
A maladaptive pattern of substance use, leading to clinically significant impairment or 
distress as manifested by three (or more) of the following, occurring at any time in the 
same 12-month period: 
1) Tolerance, as defined by either of the following: 
a) A need for markedly increased amounts of the substance to achieve intoxication 
or desired effect, 
b) Markedly diminished effect with continued use of the same amount of the 
substance.
2) Withdrawal, as manifested by either of the following: 
a) The characteristic withdrawal syndrome for the substance, 
b) The same (or closely related) substance is taken to relieve or avoid withdrawal 
symptoms. 
3) The substance is often taken in larger amounts or over a longer period than was 
intended.
4) There is a persistent desire or unsuccessful efforts to cut down or control substance 
use.
5) A great deal of time is spent in activities necessary to obtain the substance 
(e.g., visiting multiple doctors or driving long distances), use the substance 
(e.g., chain-smoking) or recover from its effects. 
6) Important social, occupational or recreational activities are given up or reduced 
because of substance use. 
7) The substance use is continued despite knowledge of having a persistent or recurring 
physical or psychological problem that is likely to have been caused or exacerbated 
by the substance (e.g., current cocaine use despite recognition of cocaine-induce 
depression, or continued drinking despite recognition that an ulcer was made worse 
by alcohol consumption. 
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Criteria for Severity of Psychoactive Substance Dependence: 
Mild:  Few, if any, symptoms in excess of those required to make the diagnosis, and the 
symptoms result in no more than mild impairment in occupational functioning or in usual 
social activities or relationships with others. 
Moderate:  Symptoms or functional impairment between “mild” and “severe”. 
Severe:  Many symptoms in excess of those required to make the diagnosis, and the 
symptoms markedly interfere with occupational functioning or with usual social activities 
or relationships with others. 
In Partial Remission:  During the past six months, some use of the substance and some 
symptoms of dependence. 
In Full Remission: During the past six months, either no use of the substance, or use of 
the substance and no symptoms of dependence. 
Diagnostic Criteria for Psychoactive Substance Abuse
A. A maladaptive pattern of psychoactive substance use, leading to clinically significant 
impairment or distress as manifested by one (or more) of the following, occurring at 
any time in the same 12-month period: 
1) Recurrent substance use resulting in a failure to fulfill major role obligations at 
work, school, or home (e.g., repeated absences or poor work performance related 
to substance use; substance-related absences, suspensions, or expulsions from 
school, neglect of children or household). 
2) Recurrent substance use in situations in which it is physically hazardous 
(e.g., driving an automobile or operating a machine when impaired by substance 
use).
3) Recurrent substance-related legal problems (e.g., arrests for substance-related 
disorderly conduct). 
4) Continued substance use despite having persistent or recurrent social or 
interpersonal problems caused or exacerbated by the effects of the substance 
(e.g., arguments with spouse about consequences of intoxication, physical fights). 
B. The symptoms have never met the criteria for substance dependence for this class of 
substance.
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Trial identification: 
AI438006
1090387
Title:
Randomized, Open label, Multiple-Dose Study to Evaluate the 
Pharmacodynamics, Safety and Pharmacokinetics of BMS-663068 
in HIV-1 Infected Subjects
Trial phase: 
II A 
Design:
Randomized, open label, multiple-dose regimens, parallel group 
study. Subjects will be randomized into one of 5 regimens. 
Expected sample size: 
50
Trial objectives: 
Primary: to assess the antiviral activity of BMS-626529 following 
administration of selected regimens of BMS-663068 with and 
without Ritonavir (RTV) administered orally to HIV infected subjects 
for 8 days. 
Secondary: to assess: 
- 
the safety and tolerability of multiple regimens of BMS-663068 
with and without RTV in HIV infected subjects 
- 
the effect of BMS-626529 following multiple regimens of BMS-
663068 on CD4+ and CD8+ lymphocyte counts and percents 
- 
the PK of BMS-626529 following multiple regimens of BMS-
663068 with and without RTV in HIV infected subjects 
- 
the diurnal variation in the PK exposures of BMS-626529 
following multiple regimens of BMS-663068 with and without 
RTV in HIV infected subjects 
- 
the plasma protein binding for BMS-626529 
- 
the relationships between change from baseline in log10 HIV 
RNA versus Inhibitory Quotient and PK exposures for BMS-
626529 following multiple regimens of BMS-663068 with and 
without RTV. 
- 
To assess the PK of RTV when coadministered with various 
regimens of BMS-663068 
SGS-LSS statisticians: 
 biostatistician 
 biostatistics manager 
SGS-LSS pharmacokineticist: 
 pharmacokineticist 
Sponsor:
Bristol-Myers Squibb Research and Development 
Sponsor contact persons: 
 Outsourcing Manager, Discovery Medicine/Clinical 
Pharmacology
 Group Medical Director, Discovery Medicine 
(virology)
 Biostatistician, Global Biometric Sciences 
Version number: 
Final
Version date: 
07SEP2010 
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0
TABLE OF CONTENTS 
0.1 Table of contents (analysis plan) 
0
TABLE OF CONTENTS .............................................................................................3
0.1
Table of contents (analysis plan) .......................................................................3
0.2
Table of contents (analysis figures) ...................................................................5
0.3
Table of contents (analysis tables) ....................................................................7
0.4
Table of contents (analysis listings) ................................................................10
1
INTRODUCTION .....................................................................................................12
1.1
Trial objectives ................................................................................................12
1.2
Design ............................................................................................................. 13
1.3
Expected sample size .....................................................................................13
1.4
Randomization and blinding ............................................................................14
1.5
Protocol amendments .....................................................................................15
1.6
Flow chart (V2.0 protocol) ...............................................................................17
2
GENERAL SPECIFICATIONS .................................................................................19
2.1
Analysis populations ........................................................................................19
2.2
Variables and derived parameters ..................................................................19
2.3
Analysis timepoints ..........................................................................................20
2.3.1
Allocation into analysis phases....................................................................20
2.3.2
Treatment-emergent allocation of adverse events ...................................... 20
2.3.3
Non-treatment-emergent allocation of concomitant therapies ..................... 21
2.3.4
Allocation into visit windows ........................................................................ 21
2.4
Handling of missing data .................................................................................22
2.4.1
Missing values when computing percentages ............................................. 22
2.4.2
Handling of values below (or above) a threshold ........................................22
2.4.3
Handling of unscheduled assessments or retests ....................................... 22
2.4.4
HIV RNA viral load testing ........................................................................... 22
2.4.5
Baseline ....................................................................................................... 23
2.5
Validation model ..............................................................................................23
3
STATISTICAL METHODS .......................................................................................24
3.1
Planned analysis (protocol amendments included) .........................................24
3.2
Changes to the planned analysis ....................................................................27
3.3
Further specifications ......................................................................................27
4
ANALYSIS DETAILS ...............................................................................................28
4.1
General characteristics ....................................................................................28
4.1.1
Allocation ..................................................................................................... 28
4.1.2
Investigator information ............................................................................... 28
4.1.3
Subject disposition.......................................................................................28
4.1.4
Trial termination ........................................................................................... 29
4.1.5
Protocol deviations ...................................................................................... 29
4.1.6
In- and exclusion criteria..............................................................................29
4.1.7
Demographic data and baseline disease characteristics ............................29
4.1.8
Baseline physical examination ....................................................................31
4.1.9
Concomitant therapy ...................................................................................31
4.1.10
Diagnostic and medical treatment procedures ........................................31
4.1.11
Medical/Surgical history and concomitant diseases ................................ 31
4.1.12
Exposure .................................................................................................31
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4.2
Pharmacokinetics ............................................................................................ 33
4.3
Pharmacodynamics ......................................................................................... 35
4.3.1
Primary parameter: Log10 HIV RNA ............................................................. 35
4.3.2
CD4+ and CD8+ counts and percentages...................................................39
4.4
Pharmacokinetics/pharmacodynamics relation ...............................................41
4.5
Safety ..............................................................................................................43
4.5.1
Adverse events ............................................................................................ 43
4.5.2
Laboratory safety: hematology and biochemistry ........................................ 45
4.5.3
Urinalysis ..................................................................................................... 47
4.5.4
ECG ............................................................................................................. 47
4.5.5
Vital signs .................................................................................................... 50
4.5.6
Physical examinations ................................................................................. 52
5
REFERENCES ........................................................................................................53
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0.2 Table of contents (analysis figures) 
General descriptive part: 
NAP. 
Pharmacokinetics part: 
Figure PK 1: Average BMS-626529 plasma concentration vs. time profiles................... 33
Figure PK 2: Individual BMS-626529 plasma concentration vs. time profiles, by regimen 
group ......................................................................................................................... 33
Figure PK 3: Individual BMS-626529 plasma concentration vs. time profiles, by subject
................................................................................................................................... 33
Figure PK 4: Average ritonavir plasma concentration vs. time profiles ........................... 33
Figure PK 5: Individual ritonavir plasma concentration vs. time profiles, by regimen 
group ......................................................................................................................... 33
Figure PK 6: Individual ritonavir plasma concentration vs. time profiles, by subject ..... 34
Figure PK 7: Dependency on regimen of BMS-626529 pharmacokinetic parameters .... 34
Figure PK 8: Dependency on regimen of ritonavir pharmacokinetic parameters ............ 34
Figure PK 9: Steady-state assessment for BMS-626529 plasma concentration ............... 34
Figure PK 10: Steady-state assessment for ritonavir plasma concentration ..................... 34
Pharmacodynamics part: 
Figure PD 1: HIV log10 RNA: Subject profile plots of the actual values (+IA)............... 35
Figure PD 2: HIV log10 RNA: Subject profile plots of the changes from baseline (+IA) 35
Figure PD 3: HIV log10 RNA: Mean plot of the changes from baseline (+IA) ................ 35
Figure PD 4: HIV log10 RNA: Median plot of the changes from baseline (+IA) ............. 36
Figure PD 5: HIV log10 RNA: Scatter plots ...................................................................... 36
Figure PD 6: HIV log10 RNA: Scatter plot of the maximum change from baseline in HIV 
RNA .......................................................................................................................... 37
Figure PD 7: HIV log10 RNA: Scatter plot of change from baseline in HIV log10 RNA on 
Day 9 vs. Envelope Phenotype (Protein Binding Adjusted EC90) on Day 1 separated 
by ARV experience ................................................................................................... 37
Figure PD 8: HIV log10 RNA: Mean plot of the changes from baseline by ARV treatment 
history (+IA) ............................................................................................................. 37
Figure PD 9: HIV log10 RNA: Median plot of the changes from baseline by ARV 
treatment history (+IA) ............................................................................................. 37
Figure PD 10: HIV log10 RNA: Scatter plot of the maximum change from baseline in HIV 
RNA by ARV treatment history ............................................................................... 38
Figure PD 11: HIV log10 RNA: Scatter plot of maximum HIV log10 RNA decrease from 
baseline vs. Envelope Phenotype (Protein Binding Adjusted EC90) on Day 1 
separated by ARV experience ................................................................................... 38
Figure PD 12: CD4+ and CD8+: Subject profile plots of the actual values (+IA) ........... 39
Figure PD 13: CD4+ and CD8+: Subject profile plots of the changes from baseline (+IA)
................................................................................................................................... 39
Figure PD 14: CD4+ and CD8+: Mean plot of the changes from baseline (+IA) ............ 39
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Figure PD 15: CD4+ and CD8+: Median plot of the changes from baseline (+IA) ......... 39
Figure PD 16: CD4+ and CD8+: Mean plot of the changes from baseline by ARV 
treatment history (+IA) ............................................................................................. 40
Figure PD 17: CD4+ and CD8+: Median plot of the changes from baseline by ARV 
treatment history (+IA) ............................................................................................. 40
PK/PD part: 
Figure PK/PD 1: PK/PD: scatter plot of changes from baseline in plasma HIV RNA and 
RNA nadir versus Protein Binding Adjusted BMS-626529 EC90 ............................ 41
Figure PK/PD 2: PK/PD: scatter plot of changes from baseline in CD4+ and CD8+ cell 
counts versus Protein Binding Adjusted BMS-626529EC90 and versus PK 
parameters ................................................................................................................. 41
Figure PK/PD 3: PK/PD: scatter plot of changes from baseline in plasma HIV RNA and 
RNA nadir versus BMS-626529 Iqs and versus PK parameters .............................. 41
Safety part: 
Figure SAF 1: ECG: Mean plot of the changes from baseline ......................................... 49
Figure SAF 2: ECG: Scatter plot of the actual QT(c) interval versus the plasma 
concentration ............................................................................................................. 49
Figure SAF 3: ECG: Scatter plot of the changes from baseline in QT(c) interval versus 
the plasma concentration........................................................................................... 49
Figure SAF 4: ECG: Plots of mean QT and QTc and mean BMS-626529 concentration 
versus time since dosing ........................................................................................... 49
Figure SAF 5: Vital signs: Mean plot of the changes from baseline ................................ 51
Figure SAF 6: Vital signs: Plots of mean vital signs and mean BMS-626529 
concentration versus time since dosing ..................................................................... 52
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0.3 Table of contents (analysis tables) 
General descriptive part: 
Table GEN 1: Countries and sites: Tabulation ................................................................. 28
Table GEN 2: Subject disposition: Descriptive statistics of the number of days in trial .. 28
Table GEN 3: Subject disposition: Tabulation ................................................................. 28
Table GEN 4: Trial termination: tabulation ...................................................................... 29
Table GEN 5: Demographic data: descriptive statistics ................................................... 30
Table GEN 6: Baseline disease characteristics: descriptive statistics .............................. 30
Table GEN 7: Physical examinations: tabulation ............................................................. 31
Table GEN 8: Concomitant therapies: tabulation ............................................................. 31
Table GEN 9: Diagnostic and medical treatment procedures: tabulation ......................... 31
Table GEN 10: Exposure: tabulation ................................................................................ 32
Pharmacokinetics part: 
Table PK 1: Actual PK blood sampling times .................................................................. 33
Table PK 2: BMS-626529 plasma concentrations ............................................................ 33
Table PK 3: Ritonavir plasma concentrations .................................................................. 33
Table PK 4: BMS-626529 pharmacokinetic parameters .................................................. 34
Table PK 5: Ritonavir pharmacokinetic parameters ......................................................... 34
Table PK 6: Statistical assessment of the accumulation of plasma BMS-626529 ........... 34
Table PK 7: Statistical assessment of the effect of RTV on BMS-626529 pharmacokinetic 
parameters ................................................................................................................. 34
Table PK 8: Statistical assessment of the diurnal variation of BMS-626529 
pharmacokinetic parameters ..................................................................................... 34
Pharmacodynamics part: 
Table PD 1: HIV RNA and HIV log10 RNA: Descriptive statistics of the actual values 
(+IA) ......................................................................................................................... 35
Table PD 2: HIV log10 RNA: Descriptive statistics of the changes from baseline (+IA)36
Table PD 3: HIV log10 RNA: Inferential statistics of the changes from baseline (+IA) . 36
Table PD 4: HIV log10 RNA: Categorized changes from baseline (+IA) ....................... 36
Table PD 5: HIV log10 RNA: Descriptive statistics on maximum log10 decrease from 
baseline in HIV RNA (+IA) ...................................................................................... 36
Table PD 6: HIV log10 RNA: Inferential statistics on maximum log10 decrease from 
baseline in HIV RNA (+IA) ...................................................................................... 36
Table PD 7: HIV log10 RNA: Categorized maximum change from baseline (+IA) ........ 37
Table PD 8: HIV log10 RNA: Day of maximum log10 decrease from baseline in HIV RNA
................................................................................................................................... 37
Table PD 9: HIV RNA and HIV log10 RNA: Descriptive statistics of the actual values by 
ARV treatment history (+IA) .................................................................................... 37
Table PD 10: HIV log10 RNA: Descriptive statistics of the changes from baseline by 
ARV treatment history (+IA) .................................................................................... 38
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Table PD 11: HIV log10 RNA: Inferential statistics of the changes from baseline by ARV 
treatment history (+IA) ............................................................................................. 38
Table PD 12: HIV log10 RNA: Categorized changes from baseline by ARV treatment 
history (+IA) ............................................................................................................. 38
Table PD 13: HIV log10 RNA: Descriptive statistics on maximum log10 decrease from 
baseline in HIV RNA by ARV treatment history (+IA) ........................................... 38
Table PD 14: HIV log10 RNA: Inferential statistics on maximum log10 decrease from 
baseline in HIV RNA by ARV treatment history (+IA) ........................................... 38
Table PD 15: HIV log10 RNA: Categorized maximum change from baseline by ARV 
treatment history (+IA) ............................................................................................. 38
Table PD 16: HIV log10 RNA: Day of maximum log10 decrease from baseline in HIV 
RNA by ARV treatment history ............................................................................... 38
Table PD 17: CD4+ and CD8+: Descriptive statistics of the actual values ..................... 39
Table PD 18: CD4+ and CD8+: Descriptive statistics of changes from baseline (+IA) .. 39
Table PD 19: CD4+ and CD8+: Cross-tabulation of time points versus baseline ............ 40
Table PD 20: CD4+ and CD8+: Descriptive statistics of the actual values by ARV 
treatment history ....................................................................................................... 40
Table PD 21: CD4+ and CD8+: Descriptive statistics of changes from baseline by ARV 
treatment history (+IA) ............................................................................................. 40
Table PD 22: CD4+ and CD8+: Cross-tabulation of time points versus baseline by ARV 
treatment history ....................................................................................................... 40
PK/PD part: 
Table PK/PD 1: PK/PD: Descriptive statistics of changes from baseline of plasma HIV 
RNA .......................................................................................................................... 41
Safety part: 
Table SAF 1: Adverse events: Summary table ................................................................. 43
Table SAF 2: Adverse events: Tabulation of all events ................................................... 44
Table SAF 3: Adverse events: Tabulation per intensity ................................................... 44
Table SAF 4: Adverse events: Tabulation per action taken against study treatment ....... 44
Table SAF 5: Adverse events: Tabulation of all treatment-related adverse events .......... 44
Table SAF 6: Adverse events: Tabulation of the intensity of all treatment-related adverse
events ........................................................................................................................ 44
Table SAF 7: Adverse events: Tabulation of the intensity of all not treatment-related 
adverse events ........................................................................................................... 44
Table SAF 8: Laboratory safety: Descriptive statistics of the actual values .................... 46
Table SAF 9: Laboratory safety: Descriptive statistics of the changes from baseline ..... 46
Table SAF 10: Laboratory safety: Shift table of the abnormalities at each time point 
versus baseline .......................................................................................................... 46
Table SAF 11: Laboratory safety: Shift table of the worst-case abnormalities versus 
baseline ..................................................................................................................... 46
Table SAF 12: Laboratory safety: Cross-tabulation of the urinalysis results against 
baseline ..................................................................................................................... 47
Table SAF 13: ECG: Descriptive statistics of actual values ............................................. 49
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Table SAF 14: ECG: Descriptive statistics of changes from baseline .............................. 49
Table SAF 15: ECG: Shift-table per time point of QRS and PR intervals ....................... 49
Table SAF 16: ECG: Shift-table of the worst-case QRS and PR intervals ...................... 49
Table SAF 17: ECG: Shift-table per time point of QT and QTc intervals ....................... 50
Table SAF 18: ECG: Shift-table of the worst-case QT and QTc intervals ....................... 50
Table SAF 19: ECG: Tabulation per time point of changes in QT and QTc intervals ..... 50
Table SAF 20: ECG: Tabulation of the worst-case change in QT and QTc intervals ...... 50
Table SAF 21: Vital signs: Descriptive statistics of actual values ................................... 51
Table SAF 22: Vital signs: Descriptive statistics of changes from baseline .................... 52
Table SAF 23: Vital signs: Tabulation per time point of the abnormalities ..................... 52
Table SAF 24: Vital signs: Tabulation of the worst-case abnormalities .......................... 52
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0.4 Table of contents (analysis listings) 
General descriptive part: 
Listing GEN 1: Allocation: Randomization list ................................................................ 28
Listing GEN 2: Subject disposition: number of days in trial ............................................ 28
Listing GEN 3: Subject disposition: trial phases .............................................................. 28
Listing GEN 4: Subject disposition: first and last contact in the trial .............................. 29
Listing GEN 5: Trial termination ...................................................................................... 29
Listing GEN 6: No-treatment subjects .............................................................................. 29
Listing GEN 7: In- and exclusion criteria (violations) ..................................................... 29
Listing GEN 8: Demographic data ................................................................................... 30
Listing GEN 9: Baseline disease characteristics ............................................................... 30
Listing GEN 10: RT/Pol genotype .................................................................................... 30
Listing GEN 11: Envelope phenotype .............................................................................. 30
Listing GEN 12: Physical examinations: abnormalities ................................................... 31
Listing GEN 13: Concomitant therapies ........................................................................... 31
Listing GEN 14: Diagnostic and medical treatment procedures ...................................... 31
Listing GEN 15: Medical history ...................................................................................... 31
Listing GEN 16: Concomitant diseases ............................................................................ 31
Listing GEN 17: Exposure ................................................................................................ 32
Listing GEN 18: Exposure: breakfast ............................................................................... 32
Listing GEN 19: Exposure: snacks ................................................................................... 32
Pharmacodynamics part: 
Listing PD 1: HIV RNA viral load data (+IA) ................................................................. 38
Listing PD 2: CD4+ and CD8+ data ................................................................................. 40
PK/PD part: 
Listing PK/PD 1: HIV RNA and PK parameters .............................................................. 42
Safety part: 
Listing SAF 1: Adverse events: Summary listing of all events (+IA) .............................. 45
Listing SAF 2: Adverse events: All events ....................................................................... 45
Listing SAF 3: Adverse events: Death (+IA) ................................................................... 45
Listing SAF 4: Adverse events: Serious events (+IA) ...................................................... 45
Listing SAF 5: Adverse events: Events for which the study or the study treatment were 
permanently discontinued (+IA) ............................................................................... 45
Listing SAF 6: Laboratory safety: All test results ............................................................ 46
Listing SAF 7: Laboratory safety: Abnormal test results ................................................. 46
Listing SAF 8: Laboratory safety: pregnancy tests ........................................................... 46
Listing SAF 9: Laboratory safety: Comments .................................................................. 46
Listing SAF 10: Laboratory safety: Urinalysis results ..................................................... 47
Listing SAF 11: ECG: Actually measured intervals ......................................................... 50
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Listing SAF 12: ECG: Morphology results ...................................................................... 50
Listing SAF 13: ECG: abnormalities ................................................................................ 50
Listing SAF 14: Vital signs: Actually measurements ....................................................... 52
Listing SAF 15: Vital signs: Abnormalities...................................................................... 52
Listing SAF 16: Physical examination: Abnormalities .................................................... 52
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1
INTRODUCTION
1.1 Trial objectives 
Primary Objective
The primary objective of the trial is: 
 
To assess the antiviral activity of BMS-626529 following administration of 
selected regimens of BMS-663068 with and without Ritonavir (RTV) administered 
orally to HIV infected subjects for 8 days. 
Secondary Objectives 
The secondary objectives are: 
 
To assess safety and tolerability of multiple regimens of BMS-663068 with and 
without RTV in HIV infected subjects 
 
To assess the effect of BMS-626529 following multiple regimens of BMS-663068 
on CD4+ and CD8+ lymphocyte counts and percents 
 
To assess the PK of BMS-626529 following multiple regimens of BMS-663068 
with and without RTV in HIV infected subjects 
 
To asses the diurnal variation in the PK exposures of BMS-626529 following 
multiple regimens of BMS-663068 with and without RTV in HIV infected subjects 
 
To assess the plasma protein binding for BMS-626529 
 
To assess the relationships between change from baseline in log10 HIV RNA 
versus Inhibitory Quotient (IQ) and PK exposures for BMS-626529 following 
multiple regimens of BMS-663068 with and without RTV 
 
To assess the PK of RTV when coadministered with various regimens of BMS-
663068
Exploratory Objectives 
The exploratory objectives are: 
 
To explore the effect of BMS-626529 following multiple regimens of BMS-663068 
with and without RTV on activated (DR+) CD4+ and CD8+ subsets 
 
To explore the effect of BMS-626529 following multiple regimens of BMS-663068 
with and without RTV on neutralizing antibody activity 
 
To explore the effect of BMS-626529 following multiple regimens of BMS-663068 
with and without RTV on HIV co-receptor usage (CCR5 versus CXCR4) and to 
explore the relationship between HIV co-receptor usage and antiviral activity 
 
To explore the difference in antiviral activity of BMS-626529 following multiple 
regimens of BMS-663068 with and without RTV by prior antiretroviral (ARV) 
treatment history (ARV naive versus ARV experienced) 
 
To explore the change in viral susceptibility measured by envelope genotype and 
phenotype
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1.2 Design
This is a randomized, open label, multiple-dose parallel study. Subjects will undergo 
screening evaluations to determine eligibility within 28 days prior to study enrollment. 
Subjects will be admitted to the clinical facility the evening prior to dosing (Day -1). 
Subjects will be randomized into one of 5 regimen groups:  
- 
Group 1 - BMS-663068 600 mg Q12H + RTV 100 mg Q12H;  
- 
Group 2 - BMS-663068 1200 mg QHS + RTV 100 mg QHS;  
- 
Group 3 - BMS-663068 1200 mg Q12H + RTV 100 mg Q12H;  
- 
Group 4 - BMS- 663068 1200 mg Q12H + RTV 100 mg QAM;  
- 
Group 5 - BMS-663068 1200 mg Q12H.  
Each regimen group will consist of 10 subjects. Subjects in each regimen will be 
randomized and stratified by prior antiretroviral treatment history (ARV naive versus ARV 
experienced). ARV naive is defined as; no prior ARV therapy of  1 week. Each regimen 
group will contain approximately the same distribution of ARV naive and ARV 
experienced subjects. No more than 70% of the total population (or within each regimen 
group) will be ARV naive or ARV experienced. All regimen groups may initiate dosing 
simultaneously. Subjects will be confined to the clinical facility until Day 11. Subjects will 
return to the unit on Day 15 for a follow-up visit and on Day 50 for discharge procedures. 
Subjects may have a ± 3 day window around the discharge visit day (Day 50). Safety 
assessments consisting of ECGs, vital signs, physical exams and clinical laboratory 
tests will be conducted at screening and at selected time points throughout the study. 
All doses will be administered under fed conditions. Subjects in Group 2 (QHS regimen 
group) will receive study drug every 24 hours in the evening (PM) from Day 1 to Day 8. 
Subjects in Group 4 (RTV QAM regimen group) will receive BMS-663068 every 12 hours 
and RTV every 24 hours in the morning (with BMS-663068) from Day 1 to Day 8. 
Subjects in Groups 1, 3 and 5 (Q12H regimen group) will receive study drug every 12 
hours from Day 1 to Day 8. 
The approximate duration of the study is 81 days. Study participation includes a 28-day 
screening period, 8-day treatment and 2 follow-up visits. 
End of the study will be the date of the last visit of the last subject undergoing the study. 
Last visit will be the last follow-up visit of a subject. 
At the end of the study, the sponsor will not continue to supply study drug to 
subjects/investigators unless the sponsor chooses to extend the study. The investigator 
should ensure that the subject receives appropriate standard of care to treat the 
condition under study. 
1.3 Expected sample size 
A total of 50 patients will be enrolled in the study, namely HIV-1infected subjects  18 
years of age and a BMI of 18 - 35kg/m2, with CD4+ lymphocyte count  200 cells/L and 
with plasma HIV RNA  5000 copies/mL who have not been on ARV therapy for  8 
weeks and who are either ARV experienced or ARV naive (naive defined as: no prior 
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ARV therapy of  1 week), and who are otherwise medically stable as determined by 
medical history, physical examination, 12-lead electrocardiogram, and clinical laboratory 
evaluations will be eligible to participate in the study. Females must have a negative 
pregnancy test within 24 hours prior to start of study medication. Women of childbearing 
potential must not be nursing or pregnant and must be using an acceptable method of 
contraception. 
The sample size evaluation is based on the primary objective of the study, to assess the 
antiviral activity of BMS-626529 following administration of selected regimens of BMS- 
663068 with and without RTV administered orally to HIV infected subjects for 8 days. A 
mean decrease from baseline in HIV RNA of at least 1 log10 at Day 9 within any one 
regimen group may suggest that that dose of BMS-663068 is sufficiently active against 
HIV to proceed with further development of the drug. If the BMS-663068 containing 
regimen has no effect, then administration of the regimen to 10 subjects (ARV naive or 
experienced) would provide a  1% probability to observe a mean log10 drop of  1. If 
the true population mean decrease from baseline in HIV RNA is  1.5 log10, then there 
would be a 99% probability that the observed mean decline from baseline would be 1
log10. In addition, 10 subjects within each group can also provide > 99% power to 
conclude the mean decreases in log10 HIV RNA from baseline > 0 if the true population 
decrease from that group is 1 log10. Meanwhile, 10 subjects in each group can also 
provide 82% power to conclude the mean decreases in log10 HIV RNA from two groups 
are different if the true difference in population mean decreases from these two groups is 
0.6 log10. In addition, administration of the BMS-663068 containing regimens to 10 
subjects per group provides an 80% probability of observing at least one occurrence in 
that regimen group of any adverse event that would occur with 15% incidence in the 
population from which the sample is drawn. 
For these calculations, it is assumed that the log10 decrease in HIV RNA from baseline 
to Day 9 is normally distributed, with a standard deviation of 0.5, as estimated from 
AI430003.
1.4 Randomization and blinding 
Subjects in each group will be randomized and stratified by prior antiretroviral (ARV) 
treatment history (ARV naive versus ARV experienced). No more than 70% of the total 
population will be ARV naive or ARV experienced. All regimen groups may initiate 
dosing simultaneously. Subjects will be randomized to a group according to a computer-
generated randomization scheme. The Randomization schedule is prepared by SGS 
Biostat. 
All enrolled subjects will be assigned a sequential subject number starting with 
 at 
the time the study specific ICF is signed. Screen failures will keep their subject number 
assigned at enrollment. Enrolled subjects meeting inclusion and exclusion criteria will be 
randomized. Randomization numbers will be assigned prior to dosing for each group. 
Subjects will not be replaced. 
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1.5 Protocol amendments 
Amendment 1 includes changes to permit the collection and storage of blood samples 
for use in future exploratory pharmacogenetic research. Bristol-Myers Squibb will use 
DNA obtained from the blood sample and health information collected from the main 
clinical trial, AI438006 to study the association between genetic variation and drug 
response. Bristol-Myers Squibb may also use the DNA to study the causes and further 
progression of HIV. Samples from this study may also be used in conjunction with 
pharmacogenetic research results from other clinical studies to accomplish this 
objective. 
In amendment 2 following changes were made: 
- 
Updated the statistician personnel and contact information. 
- 
Incorporated Germany Competent Authority (BfArM) request to change the 
inclusion criteria of CD4+ counts  100 cells/L to  200 cells/L.
- 
Removed the statement that women of childbearing potential must be using an 
acceptable method of contraception for at least 8 weeks before dosing to be 
consistent with the inclusion criteria. 
- 
In response to the comments received from the Ethics Committee of the Land 
Berlin, a clarification of the intent to exclude informed consent given by legally 
acceptable representatives (or witnesses) in the protocol is deemed necessary. 
- 
In response to the comments received from the Ethics Committee of the Land 
Berlin, clarified that subjects who are unwilling to practice adequate infection 
protection will be excluded from this study. 
- 
In response to the comments received from the Ethics Committee of the Land 
Berlin, added study stopping rules.  
- 
Provided clarification that study evaluations need to be performed prior to study 
discharge or for subjects who are prematurely discontinued from the study. 
- 
To assess Troponin T rather than Troponin I. 
- 
Clarify that creatinine clearance needs to be calculated at screening. 
- 
Serious Adverse Event (SAE) submission process per new standard operating 
procedure. 
In amendment 3 following changes were made: 
- 
Add secondary objective to characterize the PK of RTV. 
- 
Changed the duration of study from 81 days to 88 days to accommodate an 
increase in the screening period for reporting of RT/Pol genotype.  
- 
Changed the duration of the screening period from 28 days to 35 days to allow 
enough time for confirmation of Clade B infection in all subjects. 
- 
Clarified EC90 as protein binding adjusted EC90. 
- 
Added criteria that subjects who test positive for amphetamines (which, like 
cannabinoids, may be used for life style enhancement without meeting criteria for 
addiction) can be included in the study, unless they are excluded due to 
Exclusion criteria 2m in Section 4.2.2 (recent drug abuse). 
- 
Changed exclusion criteria for absolute neutrophil count (ANC) 0.9 x lower limit 
of normal (LLN) to 0.7 x LLN.  BMS-663068 and BMS-626529 do not appear to 
impact white blood cells (WBC) or ANC counts and this slight change to the 
exclusion criteria will avoid having to disqualify subjects based on clinically 
irrelevant variations in ANC between screening at Day -1. 
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- 
Removed footnote from clinical laboratory tests and blood (PBMC) collection that 
specified the collection should occur Pre-PM in group 2. 
- 
Clarified that samples for clinical laboratory tests for subjects assigned to group 2 
can be collected in the AM.  Removed HIV-1 RNA analysis and CD4+ and CD8+ 
counts from this section since these samples need to be collected prior to dosing 
(ie. in the PM for group 2). 
- 
Corrected spelling error. 
- 
Add information for PK analyses of RTV. 
Amendment 4 clarifies that interim analyses will be conducted for internal Bristol-Myers 
Squibb decision making that could include, but is not limited to selecting possible phase 
IIb doses.
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1.6 Flow chart (V2.0 protocol) 
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Footnotes:
a)
4 hours post-AM dose in groups 1, 3, 4 and 5; 4 hours post-PM dose in group 2. Vital signs will 
include heart rate and blood pressure measurements. 
b)
Weight only 
c)
Group 2 only 
d)
Pre-AM dose in groups 1, 3, 4 and 5; Pre-PM dose in group 2. On days when dose is not administered, 
sample collection time should be maintained. 
e)
Pre-PM dose and 4 hours post-PM dose 
f)
Env Genotyping and phenotyping analysis: Env. phenotyping to be analyzed on Day 1 in all dosed 
subjects; all other samples to be stored and analyzed if 
1.
deemed relevant. 
g)
Neutralizing antibody activity, HIV co-receptor usage and samples for exploratory resistance analysis; 
to be stored and analyzed if deemed relevant 
h)
Activation markers and exploratory apoptotic markers; to be stored and analyzed if deemed relevant 
i)
If the screening physical exam is performed within 24 hours of dosing on Day 1, then a single 
examination may count as both the screening and predose evaluation 
j)
Evaluations performed prior to study discharge or for subjects who are prematurely discontinued from 
the study.
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2
GENERAL SPECIFICATIONS
2.1 Analysis populations 
Definition: 
-
All randomized population: all randomized subjects. 
- 
Safety population: all randomized subjects who used the trial medication at least 
once. 
- 
Pharmacokinetic population: all subjects who receive BMS-663068 and provided 
pharmacokinetic samples. 
- 
Pharmacodynamic population: all subjects for whom pharmacodynamic 
measurements are available at baseline and at least one other time. Only Clade B 
subjects will be included in the population. Whether a subject is clade B or not will 
be derived from the protocol deviations. 
- 
Pharmacokinetic/Pharmacodynamic: a combination of both populations. 
The safety population will be used for the general descriptive part and for the safety part. 
The Pharmacokinetic population will be used for the Pharmacokinetic analysis. 
The Pharmacodynamic population will be used for the Pharmacodynamic analysis. 
The Pharmacokinetic/Pharmacodynamic population will be used for the Pharmacokinetic   
 /Pharmacodynamic relation analysis. 
2.2 Variables and derived parameters 
Pharmacokinetic variables: 
- Cmax
Maximum observed plasma concentration 
- Ctrough 
Trough observed plasma concentration 
A composite Ctrough will be calculated as the geometric mean of all 
trough concentrations except the 12 h sample on Day 1 (24 h for group 2) 
- Tmax  
Time of maximum observed plasma concentration 
- AUC(TAU) 
Area under the concentration-time curve in one dosing interval 
- AUC(0-24h) Area under the concentration-time curve over a 24-hour period following 
the AM dose (PM for Group 2) on Day 8 
- Css,avg  
Average steady-state plasma concentration, calculated as AUC(0-24h)/24 
- T-HALF  
Terminal half-life (after last dose only) 
- CLT/F  
Apparent total body clearance (after last dose only) 
- Vz/F  
Apparent volume of distribution based on the terminal phase (after last 
dose only) 
- AI  
Accumulation index; ratio of AUC(TAU) at steady-state to AUC(TAU) after 
the first dose 
- Protein 
Percent of BMS-626529 that are bound to total plasma proteins 
binding (%) 
- IQ  
Inhibitory quotient, calculated as the ratio of BMS-626529 in vivo 
exposure to in vitro measured protein biding adjusted EC90. The 
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following in vivo exposure measures will be used in evaluating IQ: 
Cmax, composite Ctrough and Css,avg. 
Pharmacodynamic assessment will be based on change in HIV RNA. Additionally, CD4+ 
and CD8+ lymphocyte counts and percents will be assessed. 
Safety assessments: 
- 
adverse events 
- 
laboratory safety 
- 
vital signs 
- 
ECG 
2.3 Analysis timepoints 
2.3.1
Allocation into analysis phases 
Adverse events and concomitant therapies will be allocated into the following phases. 
For concomitant therapies a non-treatment-emergent analysis will be done. For adverse 
events, a treatment-emergent analysis will be done. 
Phase 
Start phase 
End phase 
Screening 
Date of signing ICF 
Date/time first intake of study 
medication – 1 minute 
Treatment 
Date/time first intake of study 
medication
Date/time last intake of study 
medication  + 3 days(*) 
Follow-up 
Date/time last intake of study 
medication  + 3 days + 1 minute 
Trial termination date (*) 
(*) Note that the last phase (in case of early termination) will always be closed by the trial 
termination date. 
2.3.2
Treatment-emergent allocation of adverse events 
A treatment-emergent way of allocation means that an event is allocated to an analysis 
phase according to its start date. If the event continues to be present during a 
subsequent analysis phase, it is not reported there again. So each event is reported 
exactly once. The main allocation rule is as follows: select the analysis phase for which 
“start phase  event start  end phase”. In order to be able to do this, the start date of 
the event should be known. If this is not true, so if the start date(time) is only partially 
known or completely missing, then a worst-case allocation is performed as follows: 
- 
The event start date(time) is completely unknown: the event will be allocated to the 
first treatment analysis phase in the trial; 
- 
The date(time) is only partially known: then the event will be allocated to the first 
analysis phase for which the known part of the event start date makes sense: 
o Select all analysis phases for which the known parts satisfy the main 
allocation rule mentioned above. 
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o Pick the first treatment analysis phase from this selection. If there is no 
treatment analysis phase in the selection, then pick the first analysis phase of 
the selection. 
Notes:
- 
Missing date(time) parts will not be imputed. The matching datetime field will remain 
missing. 
- 
If variables would be derived from such incomplete dates, they would be set to 
“missing”. 
- 
If any of the event properties change in case of adverse events, it is recorded as a 
new event in the CRF and in the database. So if during a subsequent analysis phase 
the AE properties change, the event is reported as a new event. 
- 
The assumption is that all analysis phase start and end dates are known, and also 
the dates of planned visit are known. 
2.3.3
Non-treatment-emergent allocation of concomitant therapies 
An event (e.g., a concomitant therapy) is allocated to EACH analysis phase during which 
the event is present. So each individual event can be reported more than once. 
This way of allocation means that an event is allocated to each analysis phase during 
which the event was present, so not only to the analysis phase during which it started. 
An additional possibility is that the event may be still ongoing at the end of the trial, or 
that the event might even have started prior to trial start.  Because there is no flag in the 
database to indicate whether the event started pre-trial or is still ongoing at the end of 
the trial, the following assumptions will be made: 
- 
In case the start date is missing, it will be assumed that the event started prior to the 
trial.   
- 
In case the end date is missing, it will be assumed that the event is still ongoing at 
the end of the trial. 
The main allocation rule is as follows: select all analysis phases for which at least one 
of the following is true: 
- 
“started prior to trial start” AND “still ongoing at trial end” 
- 
“started prior to trial start” AND “start phase  event stop (nonmissing)” 
- 
“start phase  start event  phase end” 
- 
 “start event (nonmissing) < start phase” AND “event stop  start phase”  
- 
“start event (nonmissing) < start phase” AND “still ongoing at trial end”  
If the start date(time) and/or stop date(time) is only partially known, then a worst-case 
allocation is performed as follows: 
- 
If the event start date(time) is only partially known, then select all analysis phases 
that satisfy the above-mentioned general rules for the known date(time) parts. 
- 
If the event stop date(time) is only partially known, then select all analysis phases 
that satisfy the above-mentioned general rules for the known date(time) parts. 
Notes:
- 
Missing date(time) parts will not be imputed. The matching datetime field will remain 
missing. 
- 
If variables would be derived from such incomplete dates, they would be set to 
“missing”. 
- 
The assumption is that all analysis phase start and end dates are known, and also 
the dates of planned visit are known. 
2.3.4
Allocation into visit windows 
The number of days in trial (relday) will be defined as:  
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relday = 
visit date – reference date + 1 if the visit is on or after the reference visit; 
visit date – reference date  if the visit is before the reference visit, 
and where the reference day equals the first day of trial medication use. 
Visits will be tabulated according to the planned visit number. No visit windows or time 
intervals will be used since visits are scheduled very quickly after one another. One 
exception to this rule is that baseline data may be imputed with earlier results (screening 
or unscheduled) if not available at the baseline visit. If this occurs, a footnote will be 
added.
 The primary discussion of HIV RNA change from baseline will focus on day 9. 
2.4 Handling of missing data 
2.4.1
Missing values when computing percentages 
Missing values will not be included in the denominator count when computing 
percentages.
Similarly, empty classes will not be shown in frequency tabulations. 
2.4.2
Handling of values below (or above) a threshold 
If the database contains values like e.g. “<0.04”, then for the descriptive statistics the 
value of the detection limit shall be used. In the above example, the value 0.04 will be 
used to replace the character value of “<0.04”. 
Note that this rule only applies to safety data and to the HIV RNA (see also section 
4.3.1).
For the purpose of calculating PK parameters, predose concentrations that are below 
the lower limit of quantification (BLQ), and concentrations prior to the first quantifiable 
concentration that are BLQ, will be set to zero. 
2.4.3
Handling of unscheduled assessments or retests 
Predose retests: use the LATEST one for the analysis. 
Postdose retests: use the ORIGINAL/PLANNED one for the analysis. Retests or 
unscheduled samples will not be used in the descriptive statistics, but all be shown in 
listings. They will be used if there is a worst-case determination over a period of time. 
2.4.4
HIV RNA viral load testing 
For HIV RNA, multiple tests can be available: standard assay, ultra-sensitive assay and 
diluted sample assay.  
If for a single sample multiple test results are available the following priority rules apply: 
1: use left-censored result (<50) 
2: use uncensored result: standard test has first priority; ultrasensitive second priority 
and diluted has third priority 
3: use right censored result (> 100000) 
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2.4.5
Baseline 
Baseline will be defined as the last non-missing measurement prior to the first study 
medication intake. 
2.5 Validation model 
SAS version 9.1 will be used for the analysis. The following statistical analysis validation 
models can be applied: 
- 
Model A: 
Minimal validation. Review of the output, source code and program log by the person 
who designed/created the programs. 
- 
Model B: 
Review of the output, source code and program log by an independent person (i.e., 
somebody else than the person who designed/created the programs). 
- 
Model C: 
Review of the output, source code and program log by an independent person (i.e., 
somebody else than the person who designed/created the programs). This person 
will also reprogram the primary parameter(s) independently, and these results should 
match with the original analysis. 
- 
Model D: 
Sponsor-specific. 
The following validation model will be applied to this particular analysis: 
  A 
  B 
  C: specifications of independent programming (e.g., for which parameters) are 
below:
- 
xxxxx 
- 
xxxxx 
  D 
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3
STATISTICAL METHODS 
3.1 Planned analysis (protocol amendments included) 
Populations for Analyses
All subjects who receive study medication will be included in the safety data set. 
All available data from subjects who receive BMS-663068 and provided pharmacokinetic 
samples will be included in the pharmacokinetic data set. 
All available data from subjects for whom pharmacodynamic measurements are 
available at baseline and at least one other time will be included in the 
pharmacodynamic data set. 
Endpoint Definitions 
Safety Endpoint 
Safety assessments will be based on adverse event reports and the results of vital sign 
measurements, ECGs, physical examinations, and clinical laboratory tests. The 
incidence of adverse events will be tabulated and reviewed for potential significance and 
clinical importance. 
Pharmacokinetic Endpoint(s) 
Pharmacokinetics of BMS-626529 and RTV will be derived from plasma concentration 
versus time data. The pharmacokinetic parameters to be assessed include: 
- Cmax 
Maximum observed plasma concentration 
- Ctrough 
Trough observed plasma concentration 
A composite Ctrough will be calculated as the geometric mean of all 
trough concentrations except the 12 h sample on Day 1 (24 h for group 2) 
- Tmax  
Time of maximum observed plasma concentration 
- AUC(TAU) 
Area under the concentration-time curve in one dosing interval 
- AUC(0-24h) Area under the concentration-time curve over a 24-hour period following       
the AM dose (PM for Group 2) on Day 8 
- Css,avg  
Average steady-state plasma concentration, calculated as AUC(0-24h)/24 
- T-HALF  
Terminal half-life (after last dose only) 
- CLT/F  
Apparent total body clearance (after last dose only) 
- Vz/F  
Apparent volume of distribution based on the terminal phase (after last 
dose only) 
- AI  
Accumulation index; ratio of AUC(TAU) at steady-state to AUC(TAU) after 
the first dose 
- Protein 
Percent of BMS-626529 that are bound to total plasma proteins 
  binding (%) 
- IQ  
Inhibitory quotient, calculated as the ratio of BMS-626529 in vivo 
exposure to in vitro measured protein binding adjusted EC90. The 
following in vivo exposure measures will be used in evaluating IQ: 
Cmax, composite Ctrough and Css,avg. 
Protein binding adjusted EC90 for BMS-626529 will be derived from phenotypically 
measured individual EC50 values at baseline using the following formula: 
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Protein binding adjusted EC90 (ng/mL) = sc × mw × EC50 (M) / fu  
 
where sc is a scale factor relating EC50 to EC90 (sc = 5.5);  
fu is the mean estimated unbound faction of BMS-626529 in vivo;  
mw is the molecular weight of BMS-626529 free base (473.48 g/mole);  
IC50 from monogram = EC50 
Individual subject pharmacokinetic parameter values will be derived by non 
compartmental methods by a validated pharmacokinetic analysis program. 
Pharmacodynamic Endpoint(s) 
Pharmacodynamic assessment will be based on change in HIV RNA. Additionally, 
CD4+ and CD8+ lymphocyte counts and percents will be assessed. 
Analyses 
Demographics and Baseline Characteristics 
Frequency distributions of gender and race will be tabulated. Summary statistics for age, 
body weight, height, and Body Mass Index (BMI) will be tabulated. 
Safety Analyses 
All recorded adverse events will be listed and tabulated by system organ class, preferred 
term and treatment. Vital signs and clinical laboratory test results will be listed and 
summarized by treatment. Any significant physical examination findings, and clinical 
laboratory results will be listed. ECG readings will be evaluated by the investigator and 
abnormalities, if present, will be listed. 
Efficacy Analyses 
Not Applicable. 
Pharmacokinetic Analyses 
The multiple-dose pharmacokinetics of BMS-626529 and RTV following administration of 
BMS-663068 with or without RTV will be described by summary statistics (mean, SD, 
CV, median, minimum, maximum, geometric mean, geometric CV) for the 
pharmacokinetic parameters by regimen group, study day, dose time (AM or PM, 
Groups 1, 3, 4 and 5 only for BMS-626529; Groups 1 and 3 only for RTV), antiretroviral 
treatment history (ARV naive, ARV experienced, and combined [ARV naive + ARV 
experienced]).
To assess the dependency on regimen, scatter plots of BMS-626529 Cmax, AUC(TAU), 
AUC(0-24h), and composite Ctrough versus regimen group will be provided by dose 
time on Day 1 and on Day 8 (Groups 1, 3, 4 and 5 only). Time to steady-state will be 
evaluated by summary statistics of individual Ctrough (following AM doses except Group 
2) by study day and by plot of geometric mean Ctrough versus study day. 
Protein binding (%) for BMS-626529 will be summarized for all data, by sampling time 
and by regimen group. Inhibitory Quotient (IQ) of Cmax (on Day 8 following AM 
regimens except Group 2), composite Ctrough and Css,avg of BMS-626529 will be 
summarized and tabulated by regimen group. 
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Point estimates and 90% confidence intervals will be constructed for accumulation 
indices (ratio of Day 8 [AM doses except Group 2] vs. Day 1 for AUC(TAU), Cmax and 
Ctrough) by regimen group. These estimates will be generated using a mixed-effect 
model fitted to log-transformed data with study day as a fixed effect, and subject as 
random effect. Point estimates and 90% confidence intervals for differences at the log-
scale will be exponentiated to obtain estimates and confidence intervals for ratios of 
geometric means in the original scale. No adjustments will be made for multiplicity. 
Similar analysis will be used to access the effect of RTV on PK exposure of 
BMS-626529, by comparing the exposure of BMS-626529 in group 3 vs. group 5 and 
group 4 vs. group 5 with regimen groups as a fixed effect in the general linear models. 
The effects of diurnal PK variation (PM vs. AM) will also be assessed by a mixed-effect 
model for Groups 1, 3, 4 and 5 only with time point (PM or AM) as a fixed effect and 
subject as random effect. 
Pharmacodynamic Analyses 
Although the final decision on the further evaluation of BMS-663068 will be a broader 
scientific assessment of its benefit/risk profile, including consideration of safety and other 
endpoints as previously outlined, plus relevant information external to this trial, a mean 
decrease from baseline in HIV RNA of at least 1 log10 on Day 9 within any one regimen 
group may suggest that that dose of BMS-663068 is sufficiently active against HIV. 
The magnitude of the change in log10 HIV RNA levels will be assessed by summarizing 
changes from baseline, including 90% confidence intervals, at study day 2 through day 
11 and at day 15, by regimen group and antiretroviral treatment history (ARV naive, ARV 
experienced, and combined [ARV naive + ARV experienced]). The primary assessment 
of the antiviral activity of BMS-663068 will be based on the log10 change from baseline 
in HIV RNA to Day 9. To assess the dependency on dose, scatter plots of log10 change 
from baseline in HIV RNA at Day 9 versus dose will be provided. Two groups t-test will 
be used to test the differences in mean log10 decrease in HIV RNA at Day 9 between 
two regimen groups by antiretroviral treatment history (ARV naive, ARV experienced, 
and combined [ARV naive + ARV experienced]). Each individual’s maximum log10 
decrease from baseline in HIV RNA will be summarized by regimen group, antiretroviral 
treatment history (ARV naive, ARV experienced, and combined [ARV naive + ARV 
experienced]), and frequency distributions for maximum log10 decrease from baseline in 
HIV RNA will be provided by regimen group, antiretroviral treatment history (ARV naive, 
ARV experienced, and combined [ARV naive + ARV experienced]). Additional analysis 
of HIV RNA beyond day 9 may be requested if HIV RNA continue to decline beyond Day 
9 in the majority of individuals. 
Pharmacokinetics/ Pharmacodynamic Analyses 
The effect of BMS-626529 on PD measures (i.e., HIV RNA and CD4+ and CD8+ T 
lymphocyte counts and percents and the corresponding changes in these parameters 
from baseline) will be assessed by summary statistics. Scatter plots will be used to 
assess the relationship between the changes from baseline in plasma HIV RNA and 
protein binding adjusted BMS-626529 EC90 (determined from Day 1 sample), a 
threshold of EC90 may be determined based on this scatter plot and summary statistics 
will be provided for the changes from baseline in plasma HIV RNA by group, excluding 
subjects with EC90 above this threshold.  
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Scatter plots will also be used to assess the relationship between the changes from 
baseline in plasma HIV RNA and BMS-626529 exposure parameters, and to assess the 
correlation between log10 changes from baseline in HIV RNA and IQs. 
Outcomes Research Analyses 
Not applicable. 
Other Analyses 
Summary statistics for exploratory biomarkers, such as but not limited to those stated in 
sections 6.6 and 6.9 of the protocol, and corresponding changes from baseline, or 
percent changes from baseline as appropriate, will be tabulated by regimen group, study 
day and time point. Possible associations between changes in exploratory biomarkers of 
interest and BMS-663068 dose or exposure will be explored graphically and by suitable 
statistical models, if appropriate. Some nonlinear models, such as but not limited to 
generalized least squares, will also be explored. Ad-hoc statistical analysis would be 
considered but are not in the scope of this analysis plan. 
Interim Analyses 
Data Summaries were added: 
- 
on 50% of the sample size, including data up to day 15 for HIV RNA and CD4 
- 
on 75% of the sample size, including data up to day 15 for HIV RNA and CD4 
- 
on 100% of the sample size, including data up to day 15 for HIV RNA and CD4 
No data summary on 25% of the sample was performed as no datasets were available 
at that time. 
These summaries will only include patients with (either HIV or CD) data on day 15. 
The final analysis will contain all data (up to trial termination) for all subjects. 
The TLFs for these intermediate analyses are identified in this SAP with “+IA” in the TLF 
title. 
3.2 Changes to the planned analysis 
Only Clade B subjects will be included in the PD analysis population.  This is because, 
based on in vitro data, PD and PK/PD analyses from non-Clade B subjects is anticipated 
to be substantially different from that of Clade B HIV.  
For the inferential statistics in the PD analysis, the between-group comparison of the 
changes from baseline by means of a t-test is replaced by an ANCOVA model in order to 
correct for baseline (including baseline as a covariate in the model).  This was done 
based on the EMEA Points to consider on adjustment for baseline covariates. 
3.3 Further specifications 
Stratification factor:
In case of a discrepancy between the recorded actual stratification and the stratification 
used for IVRS central randomization, the actual stratification as reported on the CRF 
randomization page will be used in the statistical analysis. 
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4
ANALYSIS DETAILS 
All results will be presented per treatment group, unless specified otherwise. Listings will 
be ordered by treatment group, subject and time point (if applicable). The analysis 
population will be indicated in a subtitle. 
4.1 General characteristics
The statistical analysis will be done for the safety population. 
As descriptive statistics the mean, standard error, standard deviation, 90% confidence 
interval of the mean, minimum, maximum and median will be calculated. 
4.1.1
Allocation 
Listing GEN 1: Allocation: Randomization list 
Listing of medication numbers, subject numbers, prior antiretroviral treatment history 
(stratification factor), date of randomization, treatment groups, country and site. Both the 
actual stratification factor and the one used for randomization will be listed, and the 
difference will be flagged.  
4.1.2
Investigator information 
Table GEN 1: Countries and sites: Tabulation 
Tabulation of the number of subjects per country and site per treatment group and 
overall.
4.1.3
Subject disposition 
Table GEN 2: Subject disposition: Descriptive statistics of the number of days in 
trial 
Descriptive statistics of the number of days in trial per treatment group and per visit. 
Table GEN 3: Subject disposition: Tabulation
Tabulation of number of subjects (per treatment group and overall): 
- 
screened (i.e., who signed an ICF) 
- 
not randomized and not treated 
- 
randomized and not treated 
- 
treated (= safety population) 
- 
in the PD population 
- 
in the PK population 
- 
in the PK/PD population. 
Listing GEN 2: Subject disposition: number of days in trial 
Listing per subject of the number of days in trial for each visit, together with the actual 
visit dates and the trial termination date (= date of last contact). 
Listing GEN 3: Subject disposition: trial phases 
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Listing per subject of the analysis phases in the trial, together with the start and end 
dates of each phase. 
Listing GEN 4: Subject disposition: first and last contact in the trial 
Date of first visit in the trial, date of last visit in the trial, date of last trial termination. 
Analysis population = all screened subjects. 
4.1.4
Trial termination 
Table GEN 4: Trial termination: tabulation 
Tabulation per treatment group (and total) of completions/discontinuations, and the 
reasons for discontinuation. 
Listing GEN 5: Trial termination 
Listing per subject of the reason for completion/discontinuation, the number of days in 
trial at trial termination.  
4.1.5
Protocol deviations 
Protocol deviations will not be included in the database, and therefore not included in the 
analysis either. Medical Writing will receive a list of deviations from Data Management to 
include in the CSR. 
Listing GEN 6: No-treatment subjects 
Listing of the no-treatment subjects and the reason of being a no-treatment subject. 
4.1.6
In- and exclusion criteria 
Listing GEN 7: In- and exclusion criteria (violations) 
Only criteria that are not met will be listed. 
4.1.7
Demographic data and baseline disease characteristics  
Demographic parameters only listed:
- 
subject initials 
- 
date of signing informed consent 
- 
date of signing pharmacogenetic informed consent 
- 
date of birth 
Continuous demographic parameters:
- 
age at screening (years)  
- 
height (cm) at screening 
- 
weight (kg) at screening 
- 
body mass index BMI = (weight in kg) / (height in m)² (kg/m²), as calculated 
automatically in the eCRF. 
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Categorical demographic parameters:
- 
sex 
- 
race 
- 
drug abuse (urine drug screen) 
Continuous baseline disease parameters:
- 
baseline CD4+ and CD8+ counts 
- 
baseline HIV-1 RNA results 
- 
baseline log10 HIV-1 RNA results 
- 
duration of HIV infection (=baseline date - date of first confirmed positive HIV test+1) 
- 
Baseline envelope phenotype at day 1 
- 
EC50 and PBA EC90  
Categorical baseline disease parameters:
- 
baseline HIV-1 RNA results (<5.000, [5.000-10.000[, [10.000-100.000[, 100.000)
- 
baseline CD4+ and CD8+ counts (<200, [200-500[, 500)
- 
Hepatitis infection status: 
- 
Hepatitis C antibody 
- 
Hepatitis B surface antigen 
- 
HIV Serology screen 
- 
ART treatment history (+date of first ARV intake and date of last ARV intake prior to 
screening) 
- 
ART naïve / experienced (stratification factor) 
- 
Exposed to HIV attachment inhibitor 
Analysis:
Table GEN 5: Demographic data: descriptive statistics 
Continuous parameters: descriptive statistics per treatment group and overall. 
Categorical parameters: tabulation per treatment group and overall.  
For each population. 
Listing GEN 8: Demographic data 
Listing per subject of all demographic parameters. 
Table GEN 6: Baseline disease characteristics: descriptive statistics
Continuous parameters: descriptive statistics per treatment group and overall. 
Categorical parameters: tabulation per treatment group and overall.  
For each population. 
Listing GEN 9: Baseline disease characteristics 
Listing per subject of all baseline disease characteristics and date of first confirmed 
positive HIV-1 test. 
Listing GEN 10: RT/Pol genotype 
Listing per subject of all RT/Pol genotype data (including HIV RT and Pol genotypic 
resistance mutations). 
Listing GEN 11: Envelope phenotype 
Listing per subject of baseline envelope phenotype (EC50 and PBA EC90) at day 1. 
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4.1.8
Baseline physical examination 
Table GEN 7: Physical examinations: tabulation 
Tabulation per treatment group and overall. 
Listing GEN 12: Physical examinations: abnormalities 
Listing of the baseline physical examination results of abnormal findings only. 
4.1.9
Concomitant therapy 
Treatments will be reported in each analysis phase during which they were applied. I.e., 
a non-treatment-emergent allocation. The analysis phases are defined in §2.3.1, and the 
allocation algorithm in case of missing data is discussed in §2.4.
Concomitant therapies are coded using WHO-DRUG. In the tabulation, the generic term 
will be used. The ATC classification will not be used for analysis. 
Table GEN 8: Concomitant therapies: tabulation 
Tabulation of the generic terms per phase, treatment group and overall. 
Listing GEN 13: Concomitant therapies 
Listing per subject of all concomitant therapy data. 
4.1.10 Diagnostic and medical treatment procedures 
Table GEN 9: Diagnostic and medical treatment procedures: tabulation 
Tabulation of the medical treatment used by the patients. 
Listing GEN 14: Diagnostic and medical treatment procedures 
Listing per subject of all medical treatment data.  
4.1.11 Medical/Surgical history and concomitant diseases 
Listing GEN 15: Medical history 
Listing per subject of the (abnormal) medical history data (i.e., condition no longer 
present). 
Listing GEN 16: Concomitant diseases 
Listing per subject of the (abnormal) concomitant diseases data (i.e., condition still 
present). 
4.1.12 Exposure 
Parameters:
- 
total treatment duration = date of last drug administration – date of first drug 
administration + 1 day 
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Analysis:
Table GEN 10: Exposure: tabulation 
Frequency tabulation per treatment group of the total treatment duration of BMS-663068 
and ritonavir. 
Listing GEN 17: Exposure 
Listing per subject of all medications, number of units and times of intake per phase. 
Listing GEN 18: Exposure: breakfast 
Listing per subject of the start and stop time of breakfast. 
Listing GEN 19: Exposure: snacks 
Listing per subject of the start and stop time of the snack. 
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4.2  Pharmacokinetics 
The final statistical analysis will be done on the Pharmacokinetics population. 
Table PK 1: Actual PK blood sampling times 
The actual blood sampling times relative to BMS-663068 administration will be tabulated 
by subject, day and group. 
Table PK 2: BMS-626529 plasma concentrations 
Individual values and descriptive statistics of BMS-626529 plasma concentration vs. the 
theoretical sampling time will be tabulated by regimen group, by day, by dosing time 
(groups 1, 3, 4 and 5). Descriptive statistics will be provided overall and by antiretroviral 
treatment history (ARV naïve or ARV experienced). 
Table PK 3: Ritonavir plasma concentrations 
Individual values and descriptive statistics of Ritonavir plasma concentration vs. the 
theoretical sampling time will be tabulated by regimen group, by day, by dosing time 
(groups 1 and 3). Descriptive statistics will be provided overall and by antiretroviral 
treatment history (ARV naïve or ARV experienced). 
Figure PK 1: Average BMS-626529 plasma concentration vs. time profiles 
Arithmetic mean (±SD if possible) of BMS-626529 plasma concentration vs. time profiles 
on linear and log linear scales, all regimens groups in the same graph (with different 
symbols), one graph by day, overall and by ARV history. 
Figure PK 2: Individual BMS-626529 plasma concentration vs. time profiles, by 
regimen group 
Spaghetti plots of individual BMS-626529 plasma concentration vs. time profiles on 
linear and log linear scales, all subjects in the same graph, one graph by regimen group 
and by day, solid lines for ARV naïve and dashed lines for ARV experienced. 
Figure PK 3: Individual BMS-626529 plasma concentration vs. time profiles, by 
subject
Individual BMS-626529 plasma concentration vs. time profiles on linear and log linear 
scales, one graph by subject (with indication of the ARV history), all days in the same 
graph.
Figure PK 4: Average ritonavir plasma concentration vs. time profiles 
Arithmetic mean (±SD if possible) of ritonavir plasma concentration vs. time profiles on 
linear and log linear scales, all regimens groups in the same graph (with different 
symbols), one graph by day, overall and by ARV history. 
Figure PK 5: Individual ritonavir plasma concentration vs. time profiles, by 
regimen group 
Spaghetti plots of individual BMS-626529 plasma concentration vs. time profiles on 
linear and log linear scales, all subjects in the same graph, one graph by regimen group 
and by day, solid lines for ARV naïve and dashed lines for ARV experienced. 
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Figure PK 6: Individual ritonavir plasma concentration vs. time profiles, by subject 
Individual ritonavir plasma concentration vs. time profiles on linear and log linear scales, 
one graph by subject (with indication of the ARV history), all days in the same graph. 
Table PK 4: BMS-626529 pharmacokinetic parameters 
Individual values and descriptive statistics of BMS-626529 plasma pharmacokinetic 
parameters (including protein binding and IQs) will be tabulated by regimen group, by 
day and by dosing time where applicable. Descriptive statistics will be provided overall 
and by antiretroviral treatment history (ARV naïve or ARV experienced). 
Table PK 5: Ritonavir pharmacokinetic parameters 
Individual values and descriptive statistics of ritonavir plasma pharmacokinetic 
parameters will be tabulated by regimen group, by day and by dosing time where 
applicable. Descriptive statistics will be provided overall and by antiretroviral treatment 
history (ARV naïve or ARV experienced). 
Figure PK 7: Dependency on regimen of BMS-626529 pharmacokinetic parameters 
Scatter plots of BMS-626529 Cmax, AUC(TAU), AUC(0-24h) and Ctrough versus 
regimen groups, one graph by day (Day 1 and Day 8) and by dosing time (where 
applicable). Different symbols for ARV naïve and ARV experienced subjects. 
Figure PK 8: Dependency on regimen of ritonavir pharmacokinetic parameters 
Scatter plots of ritonavir Cmax, AUC(TAU), AUC(0-24h) and Ctrough versus regimen 
groups, one graph by day (Day 1 and Day 8) and by dosing time (where applicable). 
Different symbols for ARV naïve and ARV experienced subjects. 
Figure PK 9: Steady-state assessment for BMS-626529 plasma concentration
Geometric mean of BMS-626529 Ctrough concentration vs. study day, all regimens 
groups in the same graph (with different symbols), overall and by ARV history. 
Figure PK 10: Steady-state assessment for ritonavir plasma concentration  
Geometric mean of ritonavir Ctrough concentration vs. study day, all regimens groups in 
the same graph (with different symbols), overall and by ARV history. 
Table PK 6: Statistical assessment of the accumulation of plasma BMS-626529 
Point estimates and 90% confidence intervals for the ratios of Day 8 vs. Day 1 for 
AUC(TAU), Cmax and Ctrough, One sub-table for each regimen group. 
Table PK 7: Statistical assessment of the effect of RTV on BMS-626529 
pharmacokinetic parameters 
Point estimates and 90% confidence intervals for the ratios of group 3 versus group 5 
and group 4 versus group 5 for AUC(TAU), Cmax and Ctrough (separate assessment 
after morning and evening administration). One sub-table for each comparison 
Table PK 8: Statistical assessment of the diurnal variation of BMS-626529 
pharmacokinetic parameters 
Point estimates and 90% confidence intervals for the ratios of PM versus AM 
administration for AUC(TAU), Cmax and Ctrough. One sub-table for each regimen 
group.
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4.3 Pharmacodynamics       
The statistical analysis will be done for the Pharmacodynamic population. 
4.3.1
Primary parameter: Log10 HIV RNA  
The primary pharmacodynamic parameter is the change from baseline in log10 HIV RNA 
to day 9. No imputation will be perfomed in case of a missing value on day 9. All other 
time points will be regarded as secondary. Baseline is defined as day 1 predose.  In 
case this is missing, the last non-missing assessment prior to first study medication 
intake will be used. 
As descriptive statistics the mean, standard error, standard deviation, 90% confidence 
interval of the mean, minimum, maximum and median will be calculated. 
For the quarterly summaries, all data up to and including day 15 will be included. 
Assessments:
HIV-1 RNA analysis. Values below the limit of detection will be imputed by the value of 
the detection limit. This will be flagged in the listing. 
Parameters:
- 
HIV RNA viral load 
- 
log10 HIV RNA viral load 
- 
changes from baseline in log10 HIV RNA (especially to day 9) 
- 
largest decrease in log10 HIV RNA from day 2 up to and including day 15 (nadir) 
- 
day when this largest decrease was achieved (day 2 up to and including day 15) 
Analysis:
Figure PD 1: HIV log10  RNA: Subject profile plots of the actual values (+IA) 
Subject profile plot of the actual values over time. Each subject is represented by a line, 
showing data from day 1 (predose) up till day 15. Regimen groups will be differentiated 
by different line colours and symbols. The Y-axis with the viral load will use a log10 
scale. Solid symbols are used for viral loads under the detection limit. 
Table PD 1: HIV RNA and HIV log10 RNA: Descriptive statistics of the actual 
values (+IA) 
Descriptive statistics of the actual values (in original units as well as log10 transformed) 
per time point and per regimen group. 
Figure PD 2: HIV log10 RNA: Subject profile plots of the changes from baseline 
(+IA)
Subject profile plot of the changes from baseline over time. Each subject is represented 
by a line, showing data from day 1 (predose) up till day 15. Regimen groups will be 
differentiated by different line colours and symbols. The Y-axis will show a horizontal 
reference line at 0 (= no change). Solid symbols are used for viral loads under the 
detection limit. 
Figure PD 3: HIV log10 RNA: Mean plot of the changes from baseline (+IA) 
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Mean plot (with 90% CI) of the changes from baseline over time. Each regimen is 
represented by a line, showing data from day 1 (predose) up till day 15. Regimen groups 
will be differentiated by different line colours and symbols. The Y-axis will show a 
horizontal reference line at 0 (= no change). 
Figure PD 4: HIV log10 RNA: Median plot of the changes from baseline (+IA) 
Median plot of the changes from baseline over time. Each regimen is represented by a 
line, showing data from day 1 (predose) up till day 15. Regimen groups will be 
differentiated by different line colours and symbols. The Y-axis will show a horizontal 
reference line at 0 (= no change). 
Figure PD 5: HIV log10 RNA: Scatter plots
Scatter plots of log10 change from baseline in HIV RNA at day 9 versus baseline. 
Regimen groups will be differentiated by different plot symbols. 
Table PD 2: HIV log10 RNA: Descriptive statistics of the changes from baseline 
(+IA)
Descriptive statistics per time point, per regimen group of the changes from baseline.  
Table PD 3: HIV log10 RNA: Inferential statistics of the changes from baseline 
(+IA)
Between-treatment comparison: ANCOVA to test the difference in mean log10 decrease 
in HIV RNA at day 9 between 2 regimen groups, including baseline as a covariate.  No 
correction for multiplicity will be done. Also 90% confidence intervals of the mean 
treatment difference will be calculated. This analysis will be replicated including ARV 
history. The interaction between treatment and ARV history will be tested, and dropped 
from the model if p<0.10. 
Within-group comparison versus baseline: paired t-test. 
Table PD 4: HIV log10 RNA: Categorized changes from baseline (+IA) 
Categories for the change in log10 HIV RNA per time point with following categories:  
- 
decrease >3 log,  
- 
decrease ]2-3] log,  
- 
decrease ]1-2] log,  
- 
decrease ]0.5-1] log,  
- 
decrease ]0-0.5] log  
- 
no change or increase.  
Frequency tabulation per time point and per regimen group. 
Table PD 5: HIV log10 RNA: Descriptive statistics on maximum log10 decrease from 
baseline in HIV RNA (+IA) 
Descriptive statistics of the maximum log10 decrease from baseline in HIV RNA by   
regimen group.
Table PD 6: HIV log10 RNA: Inferential statistics on maximum log10 decrease from 
baseline in HIV RNA (+IA) 
Between-group comparisons: ANCOVA to test the difference in mean log10 decrease in 
HIV RNA at day 9 between 2 regimen groups, including baseline as a covariate. No 
correction for multiplicity will be done. This analysis will be replicated including ARV 
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history. The interaction between treatment and ARV history will be tested, and dropped 
from the model if p<0.10. 
Within-group comparison versus baseline: paired t-test.  
Figure PD 6: HIV log10 RNA: Scatter plot of the maximum change from baseline in 
HIV RNA 
Scatter plot of maximum log10 HIV RNA decrease from baseline versus the baseline 
log10 HIV RNA.  
Table PD 7: HIV log10 RNA: Categorized maximum change from baseline (+IA) 
Categories for the maximum change in log10 HIV RNA with following categories:  
- 
decrease >3 log,  
- 
decrease ]2-3] log,  
- 
decrease ]1-2] log,  
- 
decrease ]0.5-1] log,  
- 
decrease ]0-0.5] log  
- 
no change or increase.  
Frequency tabulation per regimen group. 
Table PD 8: HIV log10 RNA: Day of maximum log10 decrease from baseline in HIV 
RNA
Frequency table of the day of reaching the maximum log10 decrease from baseline in HIV 
RNA by regimen group. 
Analysis per ARV treatment history:
Plots and descriptive statistics will be created for treatment-naïve and treatment-
experienced subjects separately, and will be presented next to one another. 
Table PD 9: HIV RNA and HIV log10 RNA: Descriptive statistics of the actual values 
by ARV treatment history (+IA) 
See Table PD 1. 
Figure PD 7: HIV log10 RNA: Scatter plot of change from baseline in HIV log10 RNA
on Day 9 vs. Envelope Phenotype (Protein Binding Adjusted EC90) on Day 1 
separated by ARV experience 
Scatter plots of log10 change from baseline in HIV RNA at day 9 versus Protein Binding 
Adjusted EC90 of envelope phenotype at baseline separately by the ARV experience. 
Different plot symbols for the treatment regimens. 
Perform a linear regression of log10 change on the Protein Binding Adjusted EC90, 
separated by the ARV experience, and provide the estimate and test results on the 
coefficient of the slope of the Protein Binding Adjusted EC90. 
Figure PD 8: HIV log10 RNA: Mean plot of the changes from baseline by ARV 
treatment history (+IA) 
Figure PD 9: HIV log10 RNA: Median plot of the changes from baseline by ARV 
treatment history (+IA) 
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Table PD 10: HIV log10 RNA: Descriptive statistics of the changes from baseline by 
ARV treatment history (+IA) 
See Table PD 2. 
Table PD 11: HIV log10 RNA: Inferential statistics of the changes from baseline by 
ARV treatment history (+IA) 
See Table PD 3. 
Table PD 12: HIV log10 RNA: Categorized changes from baseline by ARV 
treatment history (+IA) 
See Table PD 4. 
Table PD 13: HIV log10 RNA: Descriptive statistics on maximum log10 decrease from 
baseline in HIV RNA by ARV treatment history (+IA) 
See Table PD 5. 
Table PD 14: HIV log10 RNA: Inferential statistics on maximum log10 decrease from 
baseline in HIV RNA by ARV treatment history (+IA) 
See Table PD 6. 
Figure PD 10: HIV log10 RNA: Scatter plot of the maximum change from baseline in 
HIV RNA by ARV treatment history 
Scatter plot of maximum log10 HIV RNA decrease from baseline versus the baseline 
log10 HIV RNA, separately by ARV treatment history category. Graphs will be presented 
next to one another. 
Figure PD 11: HIV log10 RNA: Scatter plot of maximum HIV log10 RNA decrease 
from baseline vs. Envelope Phenotype (Protein Binding Adjusted EC90) on Day 1 
separated by ARV experience 
Scatter plots of maximum log10 HIV RNA decrease from baseline versus Protein Binding 
Adjusted EC90 of envelope phenotype  on Day 1 separately by the ARV experience. 
Different plot symbols for the treatment regimens. 
Perform a linear regression of log10 change on the Protein Binding Adjusted EC90, 
separated by the ARV experience, and provide the estimate and test results on the 
coefficient of the slope of the Protein Binding Adjusted EC90. 
Table PD 15: HIV log10 RNA: Categorized maximum change from baseline by 
ARV treatment history (+IA) 
See Table PD 4. 
Table PD 16: HIV log10 RNA: Day of maximum log10 decrease from baseline in HIV 
RNA by ARV treatment history 
Analysis listing:
Listing PD 1: HIV RNA viral load data (+IA) 
Listing of all viral load data per subject and per treatment group. A flag will be added to 
indicate the timepoint of achieving an absolute HIV RNA nadir or <50c/ml or <400</ml. 
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4.3.2
CD4+ and CD8+ counts and percentages 
As descriptive statistics the mean, standard error, standard deviation, 90% confidence 
interval, minimum, maximum and median of the parameters will be calculated. 
Baseline = day 1 predose. 
Assessments:
- 
CD4+ and CD8+ counts and percentages 
Parameters:
- 
actual values 
- 
changes from baseline 
Analysis:
Figure PD 12: CD4+ and CD8+: Subject profile plots of the actual values (+IA) 
Subject profile plot of the actual values over time. Each subject is represented by a line, 
showing data from day 1 (predose) up till day 15. Regimen groups will be differentiated 
by different line colours and symbols.  
Table PD 17: CD4+ and CD8+: Descriptive statistics of the actual values 
Descriptive statistics of the actual values (counts and percents) per treatment group and 
per time point. 
Figure PD 13: CD4+ and CD8+: Subject profile plots of the changes from baseline 
(+IA)
Subject profile plot of the changes from baseline over time. Each subject is represented 
by a line, showing data from day 1 (predose) up till day 15. Regimen groups will be 
differentiated by different line colours and symbols. The Y-axis will show a horizontal 
reference line at 0 (= no change). 
Figure PD 14: CD4+ and CD8+: Mean plot of the changes from baseline (+IA) 
Mean plot (with 90% CI) of the changes from baseline over time. Each regimen is 
represented by a line, showing data from day 1 (predose) up till day 15. Regimen groups 
will be differentiated by different line colours and symbols. The Y-axis will show a 
horizontal reference line at 0 (= no change). 
Figure PD 15: CD4+ and CD8+: Median plot of the changes from baseline (+IA) 
Median plot of the changes from baseline over time. Each regimen is represented by a 
line, showing data from day 1 (predose) up till day 15. Regimen groups will be 
differentiated by different line colours and symbols. The Y-axis will show a horizontal 
reference line at 0 (= no change). 
Table PD 18: CD4+ and CD8+: Descriptive statistics of changes from baseline (+IA) 
Descriptive statistics of the changes from baseline per treatment group and per time 
point. No inferential statistics are planned. 
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Table PD 19: CD4+ and CD8+: Cross-tabulation of time points versus baseline 
For CD4+, CD8+ cell counts: cross-tabulation per treatment group of each time point 
versus baseline of the categories < 200, 200-500,  500. 
Analysis per ARV treatment history:
Plots and descriptive statistics will be created for treatment-naïve and treatment-
experienced subjects separately, and will be presented next to one another. 
Table PD 20: CD4+ and CD8+: Descriptive statistics of the actual values by ARV 
treatment history 
Figure PD 16: CD4+ and CD8+: Mean plot of the changes from baseline by ARV 
treatment history (+IA) 
Figure PD 17: CD4+ and CD8+: Median plot of the changes from baseline by ARV 
treatment history (+IA) 
Table PD 21: CD4+ and CD8+: Descriptive statistics of changes from baseline by 
ARV treatment history (+IA) 
See Table PD 18. 
Table PD 22: CD4+ and CD8+: Cross-tabulation of time points versus baseline by 
ARV treatment history 
Analysis listing:
Listing PD 2: CD4+ and CD8+ data 
Listing of all CD4+, CD8+ data per subject and per treatment group. 
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4.4    Pharmacokinetics/pharmacodynamics relation 
The statistical analysis will be done for the Pharmacokinetics/pharmacodynamics 
population.
As descriptive statistics the mean, standard error, standard deviation, 90% confidence 
interval of the mean, minimum, maximum and median will be calculated. 
Assessments:
- 
BMS-626529 plasma concentration 
- 
BMS-626529 EC50
- 
BMS-626529 EC90 (generated with standard conversion factor applied to measured 
EC50)
- 
BMS-626529 Protein Binding Adjusted EC90
- 
BMS-626529 IQs  
- 
HIV RNA plasma HIV RNA 
Parameters
- 
Largest decrease in plasma HIV RNA (days 2 up to and including day 15) 
Analysis:
Figure PK/PD 1: PK/PD: scatter plot of changes from baseline in plasma HIV RNA 
and RNA nadir versus Protein Binding Adjusted BMS-626529 EC90
Scatter plots will be made to assess the relationship between the log10 changes from 
baseline in plasma HIV RNA at day 9 and RNA nadir vs Protein Binding Adjusted BMS-
626529 EC90.
Table PK/PD 1: PK/PD: Descriptive statistics of changes from baseline of plasma 
HIV RNA 
A threshold will be determined based on the scatter plot in Table PK/PD1. Descriptive 
statistics will be provided for the changes from baseline in plasma HIV RNA and log10 
HIV RNA by treatment group, per time point and ARV treatment history, excluding 
subjects with Protein Binding Adjusted EC90 above the previously defined threshold. 
Figure PK/PD 2: PK/PD: scatter plot of changes from baseline in CD4+ and CD8+ 
cell counts versus Protein Binding Adjusted BMS-626529EC90 and versus PK 
parameters
Scatter plots will be made to assess the relationship between the changes from baseline 
in CD4+ and CD8+ cell counts and Protein Binding Adjusted BMS-626529 EC90 and 
versus PK parameters.
Figure PK/PD 3: PK/PD: scatter plot of changes from baseline in plasma HIV RNA 
and RNA nadir versus BMS-626529 Iqs and versus PK parameters 
To assess the relationship between the log10 changes from baseline in plasma HIV 
RNA at day 9 vs BMS-626529 IQs, scatter plots of log10 changes from baseline in 
plasma HIV RNA and RNA nadir versus BMS-626529 IQs and versus PK parameters 
will be made. Also the correlation between log10 changes from baseline in HIV RNA and 
RNA nadir vs IQs  and vs PK parameters will be presented in a footnote of the graph. 
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Listing PK/PD 1: HIV RNA and PK parameters 
Listing of the HIV RNA decrease and the PK parameters per treatment group. 
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4.5 Safety
The safety analysis will be done for the safety population. 
The safety analysis will not present subgroup analyses by ARV treatment history. 
4.5.1
Adverse events 
Treatment-emergent principle:
An AE will only be reported in the phase where it started, and not in subsequent phases 
if the AE continues to be present. The reporting (analysis) phases are defined in §2.3.1,
and the allocation algorithm in case of missing data is discussed in §2.4.
Worst-case principle:
When cross tabulating AE preferred terms versus an AE attribute (e.g., severity), the 
worst-case is always applied within each analysis phase. I.e., when a subject has two 
times the same AE preferred term in the same analysis phase, then the subject is 
reported only once: only with the worst severity. If this happens in two different analysis 
phases, the AE is reported twice: once in each analysis phase. This worst-case principle 
is not applied to the number of events. All events will be shown. 
Definitions:
Tabulations will show: 
-
N = the number of subjects. In case a subject has multiple events of the same AE 
preferred term in the same reporting (analysis) phase, then the subject will only be 
counted once.
-
% = percentage of N relative to the total number of subjects in the reporting 
(analysis) phase. 
Other derived parameters: 
- 
AE preferred term = ‘NONE’: the subject does not have an AE in the reporting 
(analysis) phase 
- 
onset day = AE start date – analysis reference date + 1 (and is only defined when 
both dates are completely known) 
- 
duration  
= AE stop date – AE start date + 1 (in case both dates are completely known) 
= trial termination date – AE start date + 1 (in case the start date is completely 
known, and the AE has not resolved yet at the end of the study. These observations 
will be flagged in the listing, e.g., as “>x days” instead of just “x days”.) 
= missing in all other cases. 
Coding:
Adverse event verbatims were coded using the MedDRA dictionary. The tabulations will 
show the system organ class and the preferred term. 
Analysis:
The screening analysis phase will only be listed, unless specified otherwise. 
Table SAF 1: Adverse events: Summary table 
Tabulation per treatment group and per analysis phase (screening, treatment, follow-up, 
treatment and follow up) of the total number (and %) of subjects: 
- 
with data; 
- 
with at least one treatment-emergent AE; 
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- 
with at least one treatment-emergent SAE; 
- 
with at least one treatment-emergent AE leading to death; 
- 
with at least one mild (grade1) treatment-emergent AE; 
- 
with at least one moderate (grade2) treatment-emergent AE; 
- 
with at least one severe (grade3) treatment-emergent AE; 
- 
with at least one very severe (grade4) treatment-emergent AE; 
- 
with at least one severe or very severe (grade 3-4) treatment-emergent AE; 
- 
with at least one treatment emergent AE for which the study treatment was 
permanently stopped; 
- 
with at least one treatment emergent AE for which the study treatment was 
temporarily stopped; 
- 
with at least one treatment emergent  AE that is thought to be related to treatment; 
Table SAF 2: Adverse events: Tabulation of all events 
Tabulation of treatment emergent AE preferred terms per body class, per analysis phase 
and per treatment group. 
Table SAF 3: Adverse events: Tabulation per intensity 
Cross-tabulation of treatment emergent AE preferred terms versus their intensity. 
Exclude the ‘NONE’ from this table. Use the worst-case intensity per treatment emergent 
AE per subject. Per analysis phase and per treatment group. 
Table SAF 4: Adverse events: Tabulation per action taken against study treatment 
Tabulation of treatment emergent  AE preferred terms versus the action taken against 
the study treatment. Exclude the ‘NONE’ from this table. Use the worst-case per 
treatment emergent AE per subject. Per analysis phase and per treatment group. 
Part A): considering the action taken towards BMS-663068 
Part B): considering the action taken towards Ritonavir 
Table SAF 5: Adverse events: Tabulation of all treatment-related adverse events 
Tabulation of treatment emergent AE preferred terms per body class, per analysis phase 
and per treatment group. Selecting only the treatment emergent AE that were treatment-
related. 
Table SAF 6: Adverse events: Tabulation of the intensity of all treatment-related 
adverse events 
Cross-tabulation per analysis phase of treatment emergent AE preferred terms versus 
their intensity. Per body class and per treatment group. Use the worst-case intensity per 
treatment emergent AE per subject and per analysis phase, selecting only the AEs that 
were treatment-related. 
Table SAF 7: Adverse events: Tabulation of the intensity of all not treatment-
related adverse events 
Cross-tabulation per analysis phase of treatment emergent AE preferred terms versus 
their intensity. Per body class and per treatment group. Use the worst-case intensity per 
treatment emergent AE per subject and per analysis phase, selecting only the AEs that 
were not treatment-related. 
Analysis listings:
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Listing SAF 1: Adverse events: Summary listing of all events (+IA) 
Listing per subject of the treatment emergent AE preferred term, start and stop date with 
onset day and duration and the outcome (in case of serious adverse events), intensity, 
relation to the study treatment, action taken regarding the study treatment, concomitant 
therapy started because of the AE, and a seriousness flag.  
In such a way that all information fits on one single line for each AE. 
Listing SAF 2: Adverse events: All events 
Listing per subject of the AE verbatim / preferred (coded) term / system organ class, 
start and stop date with onset day and duration and the outcome, intensity, relation to 
the study treatment, action taken regarding the study treatment, concomitant therapy 
started because of the AE, and a seriousness flag together with its details 
(hospitalization, life-threatening,…). 
Listing SAF 3: Adverse events: Death (+IA) 
Listing of all AEs resulting in death. 
Listing SAF 4: Adverse events: Serious events (+IA) 
Listing of all serious AEs. 
Listing SAF 5: Adverse events: Events for which the study or the study treatment 
were permanently discontinued (+IA) 
Listing of the AEs for which the study treatment was permanently discontinued, or for 
which the study was discontinued. 
4.5.2
Laboratory safety: hematology and biochemistry 
The analysis will be done on SI-converted values only. 
Abnormality codes:
All values will be classified according to the test’s normal ranges as below, within or 
above normal range. Values equal to the normal limits are still considered normal. 
Worst-case abnormality
Per test and per subject, a worst-case post-baseline will be derived. This worst-case is 
defined as: 
- 
(B) Below normal: at least one post-baseline assessment is below normal range, and 
no post-baseline assessment is above normal range. 
- 
(A) Above normal: at least one post-baseline assessment is above normal range, 
and no post-baseline assessment is below normal range. 
- 
(W) Within normal: all post-baseline assessments are within normal range. 
- 
(A+B) Both above and below normal: at least one post-baseline assessment is below 
normal range, and another post-baseline assessment above normal range. 
- 
(M) Missing, when there are no post-baseline assessments. 
Local lab data and unscheduled visits  (if any) are normally only listed but shall be used 
in the determination of the worst-case abnormality. Thus, all post-baseline lab results will 
be used for this worst-case. 
Parameters to analyse:
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- 
raw (observed) values; 
- 
changes from reference; 
- 
abnormality codes per time point 
- 
worst-case on-treatment abnormality code 
The reference assessment (baseline) will be the measurement the closest –but prior– to 
the first medication intake, and shown as ‘Imputed Baseline’ in the tables. As only 
measurements from the central lab will be considered for this, the reference assessment 
visit will usually be the screening visit, unless a pre-dose unscheduled assessment 
occurs after the screening assessment. The data from SYNLAB on day -1 will not be 
used as a reference. 
Analysis:
Table SAF 8: Laboratory safety: Descriptive statistics of the actual values 
Descriptive statistics of the actual values, sorted per test, per time point and per 
treatment group. 
Table SAF 9: Laboratory safety: Descriptive statistics of the changes from baseline 
Descriptive statistics of the changes from baseline, sorted per test, per time point and 
per treatment group. 
Table SAF 10: Laboratory safety: Shift table of the abnormalities at each time point 
versus baseline
Frequency table showing per test, per time point and per treatment group the number of 
subjects in each of the possible combinations of normal regions at the two time points 
(from below normal to within normal, from above normal to above normal, etc.). I.e., the 
change from baseline in abnormality code. 
Table SAF 11: Laboratory safety: Shift table of the worst-case abnormalities versus 
baseline
Frequency table showing per test and per treatment group the worst-case on-treatment 
abnormality code, cross-tabulated versus the baseline abnormality code. 
Listing SAF 6: Laboratory safety: All test results 
Listing per treatment group, per subject and per time point of all test results, flagging out-
of-normal values. Flag the samples for which the subject had not been fasting for at least 
7 hours prior to sampling. 
Listing SAF 7: Laboratory safety: Abnormal test results 
Listing per treatment group, per subject and per time point of all test results, selecting 
only the out-of-normal values. Flag the samples for which the subject had not been 
fasting for at least 7 hours prior to sampling. 
Listing SAF 8: Laboratory safety: pregnancy tests 
Listing of the pregnancy tests per treatment group. 
Listing SAF 9: Laboratory safety: Comments 
Listing of the lab comments. 
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4.5.3
Urinalysis
Table SAF 12: Laboratory safety: Cross-tabulation of the urinalysis results against 
baseline 
Cross-tabulation per test, per time point and per treatment group of the urinalysis results  
against the baseline results. 
Listing SAF 10: Laboratory safety: Urinalysis results 
Listing of the urinalysis test results per subject. 
4.5.4
ECG
Reference time point:
The reference assessment (baseline) will be the measurement the closest –but prior– to 
the first medication intake (=imputed baseline). If there are two assessments on day -1 
(i.e. a ‘day -1’ assessment and an ‘unscheduled’ assessment), the unscheduled 
assessment will be taken as a baseline since this was a re-test of the day -1 
assessment. 
Parameter definitions:
The following measurements will be analysed: 
- 
HR (bpm); 
- 
PR (ms); 
- 
QT (ms) 
- 
QRS (ms); 
- 
uncorrected QT (ms); 
The following HR-based corrections of the QT interval will be analysed: 
- 
Bazett’s square-root corrected QT[1]: QTcB (ms) = QT (ms) 
60
)
(bpm
HR
- 
Fridericia’s cube-root corrected QT[2]: QTcF (ms) = QT (ms) 
 3
60
)
(bpm
HR
If RR is missing, but HR is available from the same ECG reading, the following 
replacement will be made in the above formulas.  
60
)
(
)
(
1000
bpm
HR
ms
RR

Corrected QT (QTc) will always be re-computed if already provided. Provided QTcs will 
only be listed. 
If HR is missing, it will be calculated using RR (if available) and rounded to the integer 
value (see formula above). HR from the vital signs part (i.e., pulse) will not be used in 
this ECG analysis part. Recalculated HR values will be flagged in the listing. 
Any roundings will be performed after computation of the applicable parameters, and 
before any further handling. 
Abnormalities for the actual values:
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The actual values will be categorized into abnormalities using the normal ranges defined 
in the table below. Values equal to the boundaries are still considered normal. 
Parameter 
Lower limit 
Upper limit 
HR, bpm 
55 and change of < -15 
100 and change of > +30 
PR, ms 
NAP
200
QRS, ms 
50
120
)ROORZLQJ,&+(WKHDFWXDOYDOXHVRIWKHuncorrected as well as the corrected 
QTs ZLOODOVREHFDWHJRULVHGLQWR
ืPV
@@PV
@@PV
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Abnormalities on the changes from baseline (QT and QTc parameters):
Abnormalities on the change from baseline will only be defined for corrected QT, as 
follows:
 30 ms; 
 
]30 ; 60] ms; 
 
> 60 ms. 
Only increases by > 30 ms will be considered as abnormalities.  
Note: the QTc definitions for abnormalities follow the ICH E14 guidance[3]. 
Worst-case abnormality for HR, QRS and PR intervals:
Per parameter and per subject, a worst-case post-baseline will be derived. This worst-
case is defined as: 
- 
(B) Below normal: at least one post-baseline assessment is below normal range, and 
no post-baseline assessment is above normal range. 
- 
(A) Above normal: at least one post-baseline assessment is above normal range, 
and no post-baseline assessment is below normal range. 
- 
(W) Within normal: all post-baseline assessments are within normal range. 
- 
(A+B) Both above and below normal: at least one post-baseline assessment is below 
normal range, and another post-baseline assessment above normal range. 
- 
(M) Missing, when there are no post-baseline assessments. 
All post-baseline assessments will be included in this derivation; also possible 
unscheduled assessments. 
Worst-case abnormality for QT and QTc intervals:
Per parameter and per subject, a worst-case post-baseline will be derived. This worst-
case is defined as the highest QT(c) value. This worst-case will be derived for both the 
absolute values as well as the changes from baseline. All post-baseline assessments 
will be included in this derivation; also possible unscheduled assessments. 
Parameters to analyze:
- 
actual values;  
- 
changes from baseline; 
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- 
abnormality classifications for the actual values; 
- 
abnormality classification for the increases from baseline (only QT and QTc); 
- 
worst-case abnormalities.  
Analysis:
Table SAF 13: ECG: Descriptive statistics of actual values 
Descriptive statistics per parameter, per time point and per treatment group of actual 
(raw) values.
Figure SAF 1: ECG: Mean plot of the changes from baseline 
Mean plot (with SE bars) of the changes from baseline over time. Each regimen is 
represented by a line, showing data from imputed baseline up till day 15. Regimen 
groups will be differentiated by different line colours and symbols. The Y-axis will show a 
horizontal reference line at 0 (= no change). 
Separate plot for each parameter. 
Figure SAF 2: ECG: Scatter plot of the actual QT(c) interval versus the plasma 
concentration
Scatter plots of the QT and QTc values at day 8 versus the BMS-626529 plasma levels 
at day 8. Different plot symbols for the treatment regimens. 
Figure SAF 3: ECG: Scatter plot of the changes from baseline in QT(c) interval 
versus the plasma concentration 
Scatter plots of the change from baseline in QT and QTc at day 8 versus the BMS-
626529 plasma levels at day 8. Different plot symbols for the treatment regimens. 
Perform a linear regression of the change from baseline in QT and QTc on the plasma 
levels, and provide the estimate and test results on the coefficient of the slope. 
Add a horizontal reference line at change=0. 
Figure SAF 4: ECG: Plots of mean QT and QTc and mean BMS-626529 
concentration versus time since dosing 
Plot per treatment regimen of the mean (without SE) change in QT and QTc, together 
with the mean BMS-626529 concentration. The left vertical axis should provide the 
change from baseline in QT or QTc, and the right vertical axis should provide the plasma 
levels.
Table SAF 14: ECG: Descriptive statistics of changes from baseline 
Descriptive statistics per parameter, per time point and per treatment group of the 
changes from baseline.  
Table SAF 15: ECG: Shift-table per time point of QRS and PR intervals 
)UHTXHQF\WDEOHVKRZLQJSHUSDUDPHWHUSHUWLPHSRLQWDQGSHUWUHDWPHQWWKHQXPEHURI
VXEMHFWVLQHDFKRIWKHSRVVLEOHFRPELQDWLRQVRIQRUPDOUHJLRQVDWWKHWZRWLPHSRLQWV
IURPEHORZQRUPDOWRZLWKLQQRUPDOIURPDERYHQRUPDOWRDERYHQRUPDOHWF,HWKH
FKDQJHIURPEDVHOLQHLQDEQRUPDOLW\FRGH
Table SAF 16: ECG: Shift-table of the worst-case QRS and PR intervals 
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)UHTXHQF\WDEOHVKRZLQJSHUSDUDPHWHUDQGSHUWUHDWPHQWJURXSWKHZRUVWFDVHRQ
WUHDWPHQWDEQRUPDOLW\FRGHFURVVWDEXODWHGYHUVXVWKHEDVHOLQHDEQRUPDOLW\FRGH
Table SAF 17: ECG: Shift-table per time point of QT and QTc intervals 
)UHTXHQF\WDEOHVKRZLQJSHUSDUDPHWHUSHUWLPHSRLQWDQGSHUWUHDWPHQWWKHQXPEHURI
VXEMHFWVLQHDFKRIWKHSRVVLEOHFRPELQDWLRQVRIYDOXHVDWWKHWZRWLPHSRLQWV,HWKH
FKDQJHIURPEDVHOLQHLQDEQRUPDOLW\FRGHRQWKHUDZYDOXHV
Table SAF 18: ECG: Shift-table of the worst-case QT and QTc intervals 
)UHTXHQF\WDEOHVKRZLQJSHUSDUDPHWHUDQGSHUWUHDWPHQWJURXSWKHZRUVWFDVHRQ
WUHDWPHQWDEQRUPDOLW\FRGHRIWKHUDZYDOXHVFURVVWDEXODWHGYHUVXVWKHEDVHOLQH
DEQRUPDOLW\FRGH
Table SAF 19: ECG: Tabulation per time point of changes in QT and QTc intervals 
)UHTXHQF\WDEOHVKRZLQJSHUSDUDPHWHUSHUWLPHSRLQWDQGSHUWUHDWPHQWWKHQXPEHURI
VXEMHFWVLQHDFKRIWKHSRVVLEOHFKDQJHIURPEDVHOLQHFDWHJRULHV
Table SAF 20: ECG: Tabulation of the worst-case change in QT and QTc intervals 
)UHTXHQF\WDEOHVKRZLQJSHUSDUDPHWHUDQGSHUWUHDWPHQWJURXSWKHZRUVWFDVHRQ
WUHDWPHQWFKDQJHIURPEDVHOLQHFDWHJRU\
Analysis listings:
Listing SAF 11: ECG: Actually measured intervals 
Listing of ECG parameters (date/time performed, actual values, changes from baseline 
and abnormality codes). 
Listing SAF 12: ECG: Morphology results 
Listing of ECG morphology results. 
Listing SAF 13: ECG: abnormalities 
- 
Abnormalities reported by ECG reader; 
- 
Abnormalities in ECG parameters (i.e. based on arithmetic criteria at start of this 
section). 
4.5.5
Vital signs 
Parameters:
- 
pulse (bpm): if the pulse is taken from the ECG HR, then this will be flagged in the 
listing. 
- 
systolic blood pressure (mmHg) 
- 
diastolic blood pressure (mmHg) 
- 
Body temperature (°C) 
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- 
Weight (kg)  
- 
Respiratory rate (bpm) 
Note that vital signs can be taken in seated or supine (5 minutes) conditions, but this is 
not recorded in the eCRF. 
Parameter definitions:
Normal ranges, applied to the vital signs parameters are listed below. Values equal to 
the limits of the normal range are still considered to be normal. There are no normal 
ranges for the body weight. 
Parameter
Lower limit 
Upper limit 
Pulse, bpm 
 Value < 55 and change < -15 
Value > 100 and change > 30 
DBP, mmHg 
Value < 55 and change < -20 
Value > 90 and change > 20 
SBP, mmHg 
Value < 90 and change < -10 
Value > 140 and change > 10 
Temperature, °C 
36.0
Value > 37.5 (99.5 °F),
or change > 1.7 (3 °F) 
Respiratory rate, bpm 
8
Value > 16 or change > 10 
Worst-case abnormality
Per parameter and per subject, a worst-case post-baseline will be derived. This worst-
case is defined as: 
- 
(B) Below normal: at least one post-baseline assessment is below normal range, and 
no post-baseline assessment is above normal range. 
- 
(A) Above normal: at least one post-baseline assessment is above normal range, 
and no post-baseline assessment is below normal range. 
- 
(W) Within normal: all post-baseline assessments are within normal range. 
- 
(A+B) Both above and below normal: at least one post-baseline assessment is below 
normal range, and another post-baseline assessment above normal range. 
- 
(M) Missing, when there are no post-baseline assessments. 
This worst-case derivation will use all post-baseline assessments, including unscheduled 
time points. 
Parameters to analyse:
- 
raw (observed) values; 
- 
changes from reference; 
- 
abnormality codes per time point 
- 
worst-case on-treatment abnormality code  
The baseline reference time point is last available measurement before first medication 
intake (=imputed baseline).  
Analysis:
Table SAF 21: Vital signs: Descriptive statistics of actual values 
Descriptive statistics per parameter, per time point and per treatment group of actual 
(raw) values.
Figure SAF 5: Vital signs: Mean plot of the changes from baseline 
Mean plot (with SE bars) of the changes from baseline over time. Each regimen is 
represented by a line, showing data from imputed baseline up till day 8. Regimen groups 
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will be differentiated by different line colours and symbols. The Y-axis will show a 
horizontal reference line at 0 (= no change). 
Separate plot for each parameter. 
Figure SAF 6: Vital signs: Plots of mean vital signs and mean BMS-626529 
concentration versus time since dosing 
Plot per treatment regimen of the mean (without SE) change in vital signs, together with 
the mean BMS-626529 concentration. The left vertical axis should provide the change 
from baseline in vital signs, and the right vertical axis should provide the plasma levels. 
Table SAF 22: Vital signs: Descriptive statistics of changes from baseline 
Descriptive statistics per parameter, per time point and per treatment group of the 
changes from baseline.  
Table SAF 23: Vital signs: Tabulation per time point of the abnormalities 
Frequency tabulation per parameter, per time point and per treatment group of the 
abnormality codes. 
Table SAF 24: Vital signs: Tabulation of the worst-case abnormalities 
Tabulation per parameter and per treatment group of the worst-case on-treatment 
abnormalities.
Analysis listings:
Listing SAF 14: Vital signs: Actually measurements 
Listing of VS parameters (date/time performed, actual values, changes from baseline 
and abnormality codes). 
Values outside the normal ranges will be flagged, as well as pulse measurements taken 
from the ECG HR. 
Listing SAF 15: Vital signs: Abnormalities 
Listing of raw values, changes from baseline and the abnormality codes for observations 
outside the normal range. 
This listing will select only the values outside of the normal range. 
4.5.6
Physical examinations 
Listing SAF 16: Physical examination: Abnormalities 
Listing showing the abnormal physical examination results only.  
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5
REFERENCES 
1.
H C Bazett: An analysis of the time-relations of electrocardiogram; Heart 
1920; 7: 353 – 370. 
2. 
L S Fridericia: Die systolendauer im elektrokardiogramm bei normalen 
menschen und bei herzkranken; Acta Med Scand 1920; 15: 335 – 642. 
3. 
ICH E14 The clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs. ICH Step 4: Note for 
guidance on the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs. London, May 2005. 
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