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

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

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

Study Overview

• Status: Completed
• Conditions: HIV Infections; Infection, Human Immunodeficiency Virus
• Intervention / Treatment: Drug: Ritonavir; Drug: Emtricitabine; Drug: BMS-955176; Drug: Placebo matching with BMS-955176; Drug: Atazanavir; Drug: Tenofovir

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A-Group 1: BMS-955176 (5 mg) or Placebo; 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; BMS-955176; Drug: Placebo matching with BMS-955176; Placebo matching with BMS-955176
Experimental: Part A-Group 2: BMS-955176 (10 mg) or Placebo; 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; BMS-955176; Drug: Placebo matching with BMS-955176; Placebo matching with BMS-955176
Experimental: Part A-Group 3: BMS-955176 (20 mg) or Placebo; 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; BMS-955176; Drug: Placebo matching with BMS-955176; Placebo matching with BMS-955176
Experimental: Part A-Group 4: BMS-955176 (40 mg) or Placebo; 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; BMS-955176; Drug: Placebo matching with BMS-955176; Placebo matching with BMS-955176
Experimental: Part B-Group 5: BMS-955176 + Atazanavir; 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; BMS-955176; Drug: Atazanavir; Atazanavir
Experimental: Part B-Group 6: BMS-955176 + Atazanavir + Ritonavir; 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: Ritonavir; Ritonavir; Drug: BMS-955176; BMS-955176; Drug: Atazanavir; Atazanavir
Experimental: Part B-Group 7: Atazanavir+Ritonavir+Tenofovir+Emtricitabine; 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: Ritonavir; Ritonavir; Drug: Emtricitabine; Emtricitabine; Drug: Atazanavir; Atazanavir; Drug: Tenofovir; Tenofovir
Experimental: Part C-Group 8: BMS-955176 (40 mg) or Placebo; 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; BMS-955176; Drug: Placebo matching with BMS-955176; Placebo matching with BMS-955176
Experimental: Part A-Group 9: BMS-955176 (80 mg) or Placebo; 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; BMS-955176; Drug: Placebo matching with BMS-955176; Placebo matching with BMS-955176
Experimental: Part A-Group 10: BMS-955176 (120 mg) or Placebo; 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; BMS-955176; Drug: Placebo matching with BMS-955176; Placebo matching with BMS-955176
Experimental: Part A-Group 11 (Optional): BMS-955176 (≤120 mg) or Placebo; 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; BMS-955176; Drug: Placebo matching with BMS-955176; Placebo matching with BMS-955176
Experimental: Part B-Group 12: BMS-955176 (80 mg) + Atazanavir; 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; BMS-955176; Drug: Atazanavir; Atazanavir
Experimental: Part C-Group 13: BMS-955176 (120 mg) or Placebo; 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; BMS-955176; Drug: Placebo matching with BMS-955176; Placebo matching with BMS-955176

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: ViiV Healthcare
• Collaborators: GlaxoSmithKline

Publications and helpful links

General Publications

• Hwang C, Schurmann D, Sobotha C, Boffito M, Sevinsky H, Ray N, Ravindran P, Xiao H, Keicher C, Huser A, Krystal M, Dicker IB, Grasela D, Lataillade M. Antiviral Activity, Safety, and Exposure-Response Relationships of GSK3532795, a Second-Generation Human Immunodeficiency Virus Type 1 Maturation Inhibitor, Administered as Monotherapy or in Combination With Atazanavir With or Without Ritonavir in a Phase 2a Randomized, Dose-Ranging, Controlled Trial (AI468002). Clin Infect Dis. 2017 Aug 1;65(3):442-452. doi: 10.1093/cid/cix239.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2013
• Primary Completion (Actual): November 29, 2014
• Study Completion (Actual): November 29, 2014

Study Registration Dates

• First Submitted: March 1, 2013
• First Submitted That Met QC Criteria: March 1, 2013
• First Posted (Estimate): March 4, 2013

Study Record Updates

• Last Update Posted (Actual): November 25, 2019
• Last Update Submitted That Met QC Criteria: November 4, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Tenofovir; Emtricitabine; Ritonavir; Atazanavir Sulfate; BMS-955176
• Other Study ID Numbers: 206739; 2012-004124-38 (EudraCT Number); AI468-002 (Other Identifier: Bristol-Myers Squibb)