Study to Evaluate a HIV Drug for the Treatment of HIV Infection

Study Overview
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Brief Summary
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The primary purpose of this study is to study the safety and tolerability of a HIV drug and to evaluate a decrease of HIV-1 virus level in blood after treatments in HIV-1 infected patients

Detailed Description
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Masking: Open-Part B. Double Blind-Parts A and C Gender: Both female and male participants for Parts A and C. Male participants for Part B. HIV = Human Immunodeficiency Virus RNA = Ribonucleic acid

Official Title
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Randomized, Placebo-Controlled, Multiple-Dose Study to Evaluate the Pharmacodynamics, Safety and Pharmacokinetics of BMS-955176 (Double-Blinded) and BMS-955176 With Atazanavir +/- Ritonavir (Open-Labeled) in HIV-1 Infected Subjects

Conditions
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Infection, Human Immunodeficiency Virus, HIV Infections

Intervention / Treatment
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* Drug: BMS-955176
* Drug: Placebo matching with BMS-955176
* Drug: Atazanavir
* Drug: Ritonavir
* Drug: Tenofovir
* Drug: Emtricitabine


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. Inclusion Criteria: Age 18-55 years inclusive Men and women: (Parts A and C); men only (Part B) Women of childbearing potential (WOCBP) must not be pregnant and nursing BMI: 18.0-35.0 kg/m2 Subjects are infected with HIV-1 (clades B or C) and meet following criteria at the screening: i) Plasma HIV-1 RNA ≥5,000 copies/mL; ii) Antiretroviral treatment naive (defined as <1 week of ARV treatment) or ART-experienced (protease inhibitor and/or maturation inhibitor naive); iii) Subjects are not eligible for HIV-1 treatment based on the United States Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents or have declined initiation of cART iv) CD4+ lymphocyte measurement ≥200 cells/μL; v) In Parts A and B, all subjects are infected with HIV-1 clade B vi) In Part C, all subjects are infected with HIV-1 clade C Exclusion Criteria: History of genotypic and/or phenotypic drug resistance testing showing resistance to protease inhibitors Any significant acute or chronic medical illness which is not stable or is not controlled with medication or not consistent with HIV-1 infection Receive antiretroviral treatment within 12 weeks prior to screening Currently co-infected with hepatitis C or hepatitis B Previously received an HIV maturation inhibitor or HIV protease inhibitor Current or recent (within 3 months of study drug administration) gastrointestinal disease Any major surgery within 4 weeks of study drug administration Acute diarrhea lasting ≥1 day, within 3 weeks prior to randomization Subjects with history of Gilbert's syndrome Subjects previously received an HIV maturation inhibitor or HIV protease inhibitor A personal history of clinically relevant cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de pointes. A personal or family history of long QT syndrome Patients 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 maturation inhibitor and/or ATV Any gastrointestinal surgery that could impact upon the absorption of study drug Smoking >10 cigarettes per day PR ≥210 msec; QRS ≥120 msec; QT ≥500 msec; and QTcF ≥470 msec for women and ≥450 msec for men Evidence of second or third degree heart block prior to study drug Absolute Neutrophil Count <(ANC) 0.7 x lower limit of normal (LLN) Hemoglobin <0.8 x LLN Alanine aminotransferase (ALT) >1.25 x upper limit of normal (ULN) Aspartate aminotransferase (AST) >1.25 x ULN Total Bilirubin >1.25 x ULN Creatinine clearance <60 mL/mim Positive urine screen for drugs of abuse without a valid prescription (subjects positive for cannabinoids and/or amphetamines will be included) Positive blood screen for hepatitis C virus (HCV) RNA, hepatitis B surface antigen (consistent with active or chronic hepatitis B), or HIV-2 antibody History of any significant drug allergy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A-Group 1: BMS-955176 (5 mg) or Placebo<br>BMS-955176 5 mg solution by mouth once daily for 10 days OR Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Placebo matching with BMS-955176<br>* Placebo matching with BMS-955176<br>|
| Experimental: Part A-Group 2: BMS-955176 (10 mg) or Placebo<br>BMS-955176 10 mg solution by mouth once daily for 10 days OR Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Placebo matching with BMS-955176<br>* Placebo matching with BMS-955176<br>|
| Experimental: Part A-Group 3: BMS-955176 (20 mg) or Placebo<br>BMS-955176 20 mg solution by mouth once daily for 10 days OR Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Placebo matching with BMS-955176<br>* Placebo matching with BMS-955176<br>|
| Experimental: Part A-Group 4: BMS-955176 (40 mg) or Placebo<br>BMS-955176 40 mg solution by mouth once daily for 10 days OR Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Placebo matching with BMS-955176<br>* Placebo matching with BMS-955176<br>|
| Experimental: Part B-Group 5: BMS-955176 + Atazanavir<br>BMS-955176 40 mg solution by mouth once daily for 28 days Atazanavir 2 x 200 mg capsules by mouth once daily for 28 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Atazanavir<br>* Atazanavir<br>|
| Experimental: Part B-Group 6: BMS-955176 + Atazanavir + Ritonavir<br>BMS-955176 40 mg solution by mouth once daily for 28 days Atazanavir 1 x 300 mg capsules by mouth once daily for 28 days Ritonavir 1 x 100 mg tablet by mouth once daily for 28 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Atazanavir<br>* Atazanavir<br>Drug: Ritonavir<br>* Ritonavir<br>|
| Experimental: Part B-Group 7: Atazanavir+Ritonavir+Tenofovir+Emtricitabine<br>Atazanavir 1 x 300 mg capsule by mouth once daily for 28 days Ritonavir 1 x 100 mg tablet by mouth once daily for 28 days Tenofovir 1 x 300 mg tablet by mouth once daily for 28 days Emtricitabine 1 x 200 mg capsule once daily for 28 days | Drug: Atazanavir<br>* Atazanavir<br>Drug: Ritonavir<br>* Ritonavir<br>Drug: Tenofovir<br>* Tenofovir<br>Drug: Emtricitabine<br>* Emtricitabine<br>|
| Experimental: Part C-Group 8: BMS-955176 (40 mg) or Placebo<br>BMS-955176 40 mg solution by mouth once daily for 10 days OR Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Placebo matching with BMS-955176<br>* Placebo matching with BMS-955176<br>|
| Experimental: Part A-Group 9: BMS-955176 (80 mg) or Placebo<br>BMS-955176 80 mg solution by mouth once daily for 10 days OR Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Placebo matching with BMS-955176<br>* Placebo matching with BMS-955176<br>|
| Experimental: Part A-Group 10: BMS-955176 (120 mg) or Placebo<br>BMS-955176 120 mg solution by mouth once daily for 10 days OR Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Placebo matching with BMS-955176<br>* Placebo matching with BMS-955176<br>|
| Experimental: Part A-Group 11 (Optional): BMS-955176 (≤120 mg) or Placebo<br>BMS-955176 ≤120 mg solution by mouth once daily for 14 days OR Placebo matching with BMS-955176 0 mg solution by mouth once daily for 14 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Placebo matching with BMS-955176<br>* Placebo matching with BMS-955176<br>|
| Experimental: Part B-Group 12: BMS-955176 (80 mg) + Atazanavir<br>BMS-955176 80 mg solution by mouth once daily for 28 days Atazanavir 2 x 200 mg capsules by mouth once daily for 28 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Atazanavir<br>* Atazanavir<br>|
| Experimental: Part C-Group 13: BMS-955176 (120 mg) or Placebo<br>BMS-955176 120 mg solution by mouth once daily for 10 days OR Placebo matching with BMS-955176 0 mg solution by mouth once daily for 10 days | Drug: BMS-955176<br>* BMS-955176<br>Drug: Placebo matching with BMS-955176<br>* Placebo matching with BMS-955176<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma Log10 HIV-1 Ribonucleic Acid (RNA) Levels From Baseline to Day 11 | Antiviral activity of BMS-955176 was estimated by measuring the plasma HIV-1 RNA levels in the HIV-1 infected participants. Change in the plasma HIV-1 RNA levels were measured in the participants infected with HIV-1 clade B and C who received BMS-955176 monotherapy. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values. | Baseline (Day 1) and Day 11 after the final dose with BMS-955176 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach Maximum Plasma Concentration (Tmax) - Part A and C | Time to reach the maximum plasma concentration was directly determined from concentration time data. | Pre-dose Day 1 and Day 10 | 
| Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to SAEs, Adverse Events (AEs), and Discontinuations Due to AEs During the Study | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. | Day 1 to end of the study (Day 42) | 
| Maximum Decline From Baseline in Log10 HIV-1 RNA - Part A and C | Antiviral activity of BMS-955176 was estimated by measuring the plasma HIV-1 RNA levels in the HIV-1 infected participants. Maximum decline from Baseline in the plasma HIV-1 RNA levels were measured in the participants infected with HIV-1 clade B and C. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values. | Baseline (Day 1) up to Day 24 | 
| Maximum Decline From Baseline in Log10 HIV-1 RNA - Part B | Antiviral activity of BMS-955176 was estimated by measuring the plasma HIV-1 RNA levels in the HIV-1 infected participants. Maximum decline from Baseline in the plasma HIV-1 RNA levels were measured in the participants infected with HIV-1 clade B and C. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values. | Baseline (Day 1) up to Day 42 | 
| Time to Maximum Decline in Log 10 HIV-1 RNA - Part A and C | Antiviral activity of BMS-955176 was estimated by measuring the plasma HIV-1 RNA levels in the HIV-1 infected participants. Time to maximum decline in the plasma HIV-1 RNA levels were measured in the participants infected with HIV-1 clade B and C. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values. | Baseline (Day 1) up to Day 24 | 
| Time to Maximum Decline in Log 10 HIV-1 RNA - Part B | Antiviral activity of BMS-955176 was estimated by measuring the plasma HIV-1 RNA levels in the HIV-1 infected participants. Time to maximum decline in the plasma HIV-1 RNA levels were measured in the participants infected with HIV-1 clade B and C. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values. | Baseline (Day 1) up to Day 42 | 
| Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Counts - Part A and C | Change in the CD4+ and CD8+ cell counts from Baseline were measured in the participants infected with HIV-1 clade B and C who received BMS-955176 + ATV or BMS-955176 + ATV + RTV therapy. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values. | Baseline (Day 1) up to Day 24 | 
| Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Counts - Part B | Change in the CD4+ and CD8+ cell counts from Baseline were measured in the participants infected with HIV-1 clade B and C who received BMS-955176 + ATV or BMS-955176 + ATV + RTV therapy. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values. | Baseline (Day 1) up to Day 42 | 
| Percent Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Percent - Part A and C | Percent Change in the CD4+ and CD8+ cell counts from Baseline were measured in the participants infected with HIV-1 clade B and C who received BMS-955176 + ATV or BMS-955176 + ATV + RTV therapy. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values. | Baseline (Day 1) up to Day 24 | 
| Percent Change From Baseline in Cluster of Differentiation (CD) 4+ and CD8+ Lymphocyte Percent - Part B | Percent Change in the CD4+ and CD8+ cell counts from Baseline were measured in the participants infected with HIV-1 clade B and C who received BMS-955176 + ATV or BMS-955176 + ATV + RTV therapy. Baseline was Day 1. Change from Baseline was post-Baseline individual values minus Baseline values. | Baseline (Day 1) up to Day 42 | 
| Time to Reach Maximum Plasma Concentration (Tmax) - Part B | Tmax was directly determined from concentration time data. | Pre-dose Day 1 and Day 28 | 
| Maximum Observed Plasma Concentrations (Cmax) - Part A and C | Cmax was defined as the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. | Pre-dose Day 1 and Day 10 | 
| Plasma Concentration 24 Hours Post-Dose (C24) - Part A and C | C24 was defined as the plasma concentration of BMS-955176 at 24 hours post-dose. | 24 hours post-dose | 
| Maximum Observed Plasma Concentrations (Cmax) - Part B | Cmax was defined as the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. | Pre-dose Day 1 and Day 28 | 
| Plasma Concentration 24 Hours Post-Dose (C24) - Part B | C24 was defined as the plasma concentration of BMS-955176 at 24 hours post-dose. | 24 hours post-dose | 
| Area Under The Plasma Concentration - Time Curve Over the Dosing Interval (AUC([Tau]) - Part A and C | AUC(tau) was defined as the area under the plasma concentration - time curve over the dosing interval. | Pre-dose Day 1 and Day 10 | 
| Area Under The Plasma Concentration - Time Curve Over the Dosing Interval (AUC[Tau]) - Part B | AUC(tau) was defined as the area under the plasma concentration - time curve over the dosing interval. | Pre-dose Day 1 and Day 28 | 
| Accumulation Index (AI): Part A and C | Accumulation index was calculated by dividing the AUC(tau) or Cmax or C24 of BMS-955176 on Day 10 by the AUC(TAU) or Cmax or C24, respectively, of BMS-955176 on Day 1. | Baseline and Day 10 | 
| Apparent Total Body Clearance: Part A and C | Apparent total body clearance was derived by non-compartmental methods, using a validated pharmacokinetic (PK) analysis program: KineticaTM 5.0 within eToolbox (version 2.7). | Baseline (Day 1) to Day 10 | 
| Degree of Fluctuation (DF): Part A and C | DF was calculated as the difference between Cmax and Cmin divided by Css-avg. DF was derived by non-compartmental methods, using a validated pharmacokinetic (PK) analysis program: KineticaTM 5.0 within eToolbox (version 2.7). | Baseline (Day 1) to Day 10 | 
| Average Observed Plasma Concentration at Steady State (Css-avg): Part A and C | Css-avg was calculated by the quotient of AUC(TAU) and the dosing interval (24 h). Css-avg was derived by non-compartmental methods, using a validated pharmacokinetic (PK) analysis program: KineticaTM 5.0 within eToolbox (version 2.7). | Baseline (Day 1) to Day 10 | 
| Plasma Half-life: Part A and C | Half-life of the terminal log-linear phase, (T-half), was calculated as natural logarithm of 2 (ln2)/λ, where λ is the absolute value of the slope of the terminal log-linear phase. T-half was derived by non-compartmental methods, using a validated pharmacokinetic (PK) analysis program: KineticaTM 5.0 within eToolbox (version 2.7). | Baseline (Day 1) to Day 10 | 
| Number of Participants With Clinically Significant Grade 3/4 Laboratory Abnormalities From Baseline | Laboratory abnormalities were determined and graded using the Division of Acquired Immune Deficiency Syndrome (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, version 1.0, December 2004. | Day 1 to up to end of the study (Day 42) | 
| Number of Participants With Clinically Significant Changes in Heart Rate | Heart rate was measured after the participants had been seated quietly for at least 5 minutes. Criteria used to determine heart rate that are outside of a pre-specified range, where changes from Baseline are based on matched postural positions and are calculated as parameter value - Baseline parameter value: Value >100 and change from Baseline > 30, or Value < 55 and change from Baseline < -15. | Day 1 to end of the study (Day 42) | 
| Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) | Participants with out of range ECG intervals were summarized. Criteria used to determine ECG results that are outside of a pre-specified range: PR (milliseconds [msec]): Value >200; QRS (msec): Value >120; QT (msec): Value >500 or change from Baseline >30; corrected QT interval Fridericia's formula (QTcF) (msec): Value >450 or change from Baseline >30. | Day 1 to end of the study (Day 42) | 
| Number of Participants With Abnormal Changes in Physical Examination | Participants with abnormal changes in physical examination is presented. | Day 1 to end of the study (Day 42) | 
| Number of Participants With Clinically Significant Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Systolic BP (millimeter of mercury [mmHg]): value >140 and change from Baseline >20, or value <90 and change from Baseline <-20; Diastolic BP (mmHg): value >90 and change from Baseline >10, or value <55 and change from Baseline <-10. | Day 1 to end of the study (Day 42) |