Strategy-confirming Study of BMS-955176 to Treat HIV-1 Infected Treatment-experienced Adults

Phase 2

Terminated

Conditions: HIV Infections

Interventions: Drug: BMS-955176
Drug: Atazanavir (ATV)
Drug: Ritonavir (RTV)
Drug: Dolutegravir (DTG)
Drug: Tenofovir (TDF)

Registration Number: NCT02386098

Lead Sponsor: ViiV Healthcare

Brief Summary: The purpose of this study is to evaluate whether the combination of BMS-955176 with atazanavir (ATV) \[with or without ritonavir (RTV)\] and dolutegravir (DTG) is efficacious, safe, and well-tolerated in HIV-1 infected treatment experienced adults.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 86

Inclusion Criteria

Men and non-pregnant women, at least 18 years of age
Antiretroviral treatment-experienced, defined as having documented evidence of having failed 1 or 2 regimens that include 2 or 3 classes of antiretroviral (ARV) (with or without documented resistance)
CD4+ T-cell count > 50 cells/mm3
Screening genotype/phenotype indicating susceptibility to study drugs (unboosted ATV, FC < 2.2; DTG; TDF)

Exclusion Criteria

Antiretroviral treatment-experienced adults who have failed > 2 ARV regimens
Resistance or partial resistance to any study drug determined by tests at Screening
Historical or documented genotypic and/or phenotypic drug resistance testing showing certain resistance mutations to ATV, TDF, RAL, Protease Inhibitors, and certain TAMs
Chronic hepatitis B virus (HBV)/ hepatitis C virus (HCV)
Blood tests that indicate normal liver function
Hemoglobin < 8.0 g/dL, Platelets < 50,000 cells/mm3

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1: BMS-955176 + ATV + RTV + DTG	Atazanavir (ATV)	BMS-955176 at 120 mg tablet per day + Atazanavir boosted with ritonavir (ATV/r) 300/100 mg tablets per day + DTG 50 mg tablet per day, orally
Arm 1: BMS-955176 + ATV + RTV + DTG	Dolutegravir (DTG)	BMS-955176 at 120 mg tablet per day + Atazanavir boosted with ritonavir (ATV/r) 300/100 mg tablets per day + DTG 50 mg tablet per day, orally
Arm 2: TDF + ATV + RTV + DTG	Tenofovir (TDF)	TDF 300 mg tablet per day + ATV/r at 300/100 mg tablets per day + DTG 50 mg per day, orally
Arm 2: TDF + ATV + RTV + DTG	Dolutegravir (DTG)	TDF 300 mg tablet per day + ATV/r at 300/100 mg tablets per day + DTG 50 mg per day, orally
Arm 3: BMS-955176 + ATV + DTG	Dolutegravir (DTG)	BMS-955176 at 120 mg tablet per day + ATV at 400 mg tablet per day + DTG at 50 mg tablet per day, orally
Arm 2: TDF + ATV + RTV + DTG	Atazanavir (ATV)	TDF 300 mg tablet per day + ATV/r at 300/100 mg tablets per day + DTG 50 mg per day, orally
Arm 1: BMS-955176 + ATV + RTV + DTG	Ritonavir (RTV)	BMS-955176 at 120 mg tablet per day + Atazanavir boosted with ritonavir (ATV/r) 300/100 mg tablets per day + DTG 50 mg tablet per day, orally
Arm 2: TDF + ATV + RTV + DTG	Ritonavir (RTV)	TDF 300 mg tablet per day + ATV/r at 300/100 mg tablets per day + DTG 50 mg per day, orally
Arm 5: TDF + ATV + RTV + DTG	Atazanavir (ATV)	TDF 300 mg tablet per day + ATV/r at 300/100 mg tablets per day + DTG 50 mg per day, orally
Arm 5: TDF + ATV + RTV + DTG	Dolutegravir (DTG)	TDF 300 mg tablet per day + ATV/r at 300/100 mg tablets per day + DTG 50 mg per day, orally
Arm 4: BMS-955176 + ATV + DTG	Dolutegravir (DTG)	BMS-955176 at 180 mg tablet per day + ATV at 400 mg tablet per day + DTG at 50 mg tablet per day, orally
Arm 3: BMS-955176 + ATV + DTG	Atazanavir (ATV)	BMS-955176 at 120 mg tablet per day + ATV at 400 mg tablet per day + DTG at 50 mg tablet per day, orally
Arm 4: BMS-955176 + ATV + DTG	Atazanavir (ATV)	BMS-955176 at 180 mg tablet per day + ATV at 400 mg tablet per day + DTG at 50 mg tablet per day, orally
Arm 5: TDF + ATV + RTV + DTG	Ritonavir (RTV)	TDF 300 mg tablet per day + ATV/r at 300/100 mg tablets per day + DTG 50 mg per day, orally
Arm 5: TDF + ATV + RTV + DTG	Tenofovir (TDF)	TDF 300 mg tablet per day + ATV/r at 300/100 mg tablets per day + DTG 50 mg per day, orally
Arm 1: BMS-955176 + ATV + RTV + DTG	BMS-955176	BMS-955176 at 120 mg tablet per day + Atazanavir boosted with ritonavir (ATV/r) 300/100 mg tablets per day + DTG 50 mg tablet per day, orally
Arm 3: BMS-955176 + ATV + DTG	BMS-955176	BMS-955176 at 120 mg tablet per day + ATV at 400 mg tablet per day + DTG at 50 mg tablet per day, orally
Arm 4: BMS-955176 + ATV + DTG	BMS-955176	BMS-955176 at 180 mg tablet per day + ATV at 400 mg tablet per day + DTG at 50 mg tablet per day, orally

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Plasma HIV-1 RNA <40 c/mL at Week 24-Stage 2	Week 24	Blood samples were planned to be collected for quantitative analysis of plasma HIV-1 RNA. The analysis was not performed in Stage 2 due to early termination of the study during Stage 1.
Percentage of Participants With Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <40 Copies Per Milliliter (c/mL) at Week 24-Stage 1	Week 24	Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. Percentage of participants with plasma HIV-1 RNA \<40 c/mL at Week 24 was assessed using the Food and Drug Administration (FDA) snapshot algorithm which used the last on-treatment plasma HIV-1 RNA measurement, within an FDA-specified visit window (18 to 30 weeks), to determine response. Analysis was performed on the modified intent to treat (mITT) Population which comprised of all randomized participants who received atleast one dose of BMS-955176 or TDF.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Plasma HIV-1 RNA <40 c/mL at Weeks 48 and 96-Stage 1	Weeks 48 and 96	Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. Response was assessed using the last plasma HIV-1 RNA value in the predefined visit window to classify a participant's response status. The percentage of responders with HIV-1 RNA \<40 c/mL at Weeks 48 and 96 using mITT Population (observed) which consisted of participants in the mITT Population excluding participants who had no HIV-1 RNA result data in the assessment visit windows due to discontinuation and who discontinued on or after the date of site notification of study termination by the sponsor (October 10, 2016) is presented. The study was terminated early during the primary end point analysis of Stage 1; hence, data was not collected for Week 96 analysis.
Percentage of Participants With Plasma HIV-1 RNA <40 c/mL at Weeks 48 and 96-Stage 2	Weeks 48 and 96	Blood samples were planned to be collected for quantitative analysis of plasma HIV-1 RNA. The analysis was not performed in Stage 2 due to early termination of the study during Stage 1.
Percentage of Participants With HIV-1 RNA <200 c/mL at Weeks 24, 48 and 96-Stage 1	Weeks 24, 48 and 96	Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. Response was assessed using the last plasma HIV-1 RNA value in the predefined visit window to classify a participant's response status. The percentage of responders with HIV-1 RNA \<200 c/mL at Weeks 24, 48 and 96 using mITT Population (observed) which consisted of participants in the mITT Population excluding participants who had no HIV-1 RNA result data in the assessment visit windows due to discontinuation and who discontinued on or after the date of site notification of study termination by the sponsor (October 10, 2016) is presented. The study was terminated early during the primary end point analysis of Stage 1; hence, data was not collected for Week 96 analysis.
Percentage of Participants With HIV-1 RNA <200 c/mL at Weeks 24, 48 and 96-Stage 2	Weeks 24, 48 and 96	Blood samples were planned to be collected for quantitative analysis of plasma HIV-1 RNA. The analysis was not performed in Stage 2 due to early termination of the Study during Stage 1.
Change From Baseline in log10 HIV-1 RNA Over Time-Stage 2	Baseline and up to Week 96	This end point was not evaluated in Stage 2 due to early termination of the study during Stage 1.
Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Count Over Time-Stage 1	Baseline and up to Week 72	The CD4+ cell count was assessed using flow cytometry. Baseline is the last value on or before the start of study treatment. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates data was not available. The standard deviation could not be calculated as a single participant was analyzed at the specified time point.
Change From Baseline in CD4+ Cell Count Over Time-Stage 2	Baseline and up to Week 96	This end point was not evaluated in Stage 2 due to early termination of the study during Stage 1.
Change From Baseline in Percentage of CD4+ Cells Over Time-Stage 1	Baseline and up to Week 72	The percentage of CD4+ cells was assessed using flow cytometry. Baseline is the last value on or before the start of study treatment. Change from Baseline was calculated as the value at specified visit minus the Baseline value. NA indicates data was not available. The standard deviation could not be calculated as a single participant was analyzed at the specified time point.
Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation (AELD)-Stage 1	Up to Week 96	An SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization or causes prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or medical events that may jeopardize the participant or require intervention (medical or surgical) to prevent one of the outcomes mentioned before. The number of participants with SAEs and AELDs are presented.
Number of Participants With SAEs and AELDs-Stage 2	Up to Week 96	This end point was not evaluated in Stage 2 due to early termination of the study during Stage 1.
Cmax for BMS-955176-Stage 2	Week 2 (pre-dose, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 8, 12 hours post-dose and 24 hours [morning pre-dose])	This end point was not evaluated, as the resulting information would only have been needed to help confirm the dose for Stage 2 (which never opened due to the early termination of the study in Stage 1).
Tmax for BMS-955176-Stage 2	Week 2 (pre-dose, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 8, 12 hours post-dose and 24 hours [morning pre-dose])	This end point was not evaluated, as the resulting information would only have been needed to help confirm the dose for Stage 2 (which never opened due to the early termination of the study in Stage 1).
Observed Plasma Concentration at the End of a Dosing Interval (Ctau) for BMS-955176-Stage 1	Week 2 (pre-dose, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 8, 12 hours post-dose and 24 hours [morning pre-dose])	PK assessments were planned to be performed; however, it was not performed due to the early termination of the study in Stage 1.
Change From Baseline in Logarithm to the Base 10 (log10) HIV-1 RNA Over Time-Stage 1	Baseline and up to Week 72	Blood samples were collected for analysis of HIV-1 RNA. Baseline is the last value on or before the start of study treatment. Change from Baseline was calculated as the value at specified visit minus the Baseline value. Change from Baseline in plasma HIV-1 RNA (log10) is summarized over time for the mITT Population using observed values, which excluded participants without HIV-1 RNA result data in the assessment visit windows due to discontinuation and who discontinued on or after the date of site notification of study termination by the sponsor (10 October 2016). NA indicates data was not available. The standard deviation could not be calculated as a single participant was analyzed at the specified time point.
Number of Participants With Occurrence of New Acquired Immunodeficiency Syndrome (AIDS) Defining Events-Stage 1	Up to Week 96	The occurrence of new AIDS defining events that is, Centers for Disease Control (CDC) Class C events in participants is presented.
Number of Participants With Occurrence of New AIDS Defining Events-Stage 2	Up to Week 96	This end point was not evaluated in Stage 2 due to early termination of the study during Stage 1.
Change From Baseline in Percentage of CD4+ Cells Over Time-Stage 2	Baseline and up to Week 96	This end point was not evaluated in Stage 2 due to early termination of the study during Stage 1.
Maximum Observed Concentration (Cmax) for BMS-955176-Stage 1	Week 2 (pre-dose, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 8, 12 hours post-dose and 24 hours [morning pre-dose])	The pharmacokinetic (PK) assessments were planned to be performed on PK Population, which comprised of all treated participants who had any available concentration-time data; however, it was not performed due to the early termination of the study in Stage 1.
Time of Maximum Observed Plasma Concentration (Tmax) for BMS-955176-Stage 1	Week 2 (pre-dose, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 8, 12 hours post-dose and 24 hours [morning pre-dose])	PK assessments were planned to be performed; however, it was not performed due to the early termination of the study in Stage 1.
Area Under the Concentration-time Curve in One Dosing Interval (AUC[Tau]) for BMS-955176-Stage 1	Week 2 (pre-dose, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 8, 12 hours post-dose and 24 hours [morning pre-dose])	PK assessments were planned to be performed; however, it was not performed due to the early termination of the study in Stage 1.
Ctau for BMS-955176-Stage 2	Week 2 (pre-dose, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 8, 12 hours post-dose and 24 hours [morning pre-dose])	This end point was not evaluated, as the resulting information would only have been needed to help confirm the dose for Stage 2 (which never opened due to the early termination of the study in Stage 1).
Observed Pre-dose Plasma Concentration (C0) for BMS-955176-Stage 1	Week 2 (pre-dose, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 8, 12 hours post-dose and 24 hours [morning pre-dose])	PK assessments were planned to be performed; however, it was not performed due to the early termination of the study in Stage 1.
C0 for BMS-955176-Stage 2	Week 2 (pre-dose, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 8, 12 hours post-dose and 24 hours [morning pre-dose])	This end point was not evaluated, as the resulting information would only have been needed to help confirm the dose for Stage 2 (which never opened due to the early termination of the study in Stage 1).
AUC(Tau) for BMS-955176-Stage 2	Week 2 (pre-dose, 1, 2, 2.5, 3, 4, 4.5, 5, 6, 8, 12 hours post-dose and 24 hours [morning pre-dose])	This end point was not evaluated, as the resulting information would only have been needed to help confirm the dose for Stage 2 (which never opened due to the early termination of the study in Stage 1).
Number of Participants With Emergence of HIV Drug Resistance-Stage 1	Up to Week 96	Emergence of drug resistance was planned to be assessed using the most current version of International AIDS Society-United States of America (IAS-USA); however, it was not assessed due to the early termination of the study in Stage 1.
Number of Participants With Emergence of HIV Drug Resistance-Stage 2	Up to Week 96	This end point was not evaluated, as the resulting information would only have been needed to help assess the risk for Stage 2 (which never opened due to the early termination of the study in Stage 1).