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

Study Overview
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Brief Summary
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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.

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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: BMS-955176
* Drug: Atazanavir (ATV)
* Drug: Ritonavir (RTV)
* Drug: Dolutegravir (DTG)
* Drug: Tenofovir (TDF)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: BMS-955176 + ATV + RTV + DTG<br>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 | Drug: BMS-955176<br>* HIV Maturation Inhibitor<br>Drug: Atazanavir (ATV)<br>* Atazanavir<br>Drug: Ritonavir (RTV)<br>* Ritonavir<br>Drug: Dolutegravir (DTG)<br>* Dolutegravir<br>|
| Other: Arm 2: TDF + ATV + RTV + DTG<br>TDF 300 mg tablet per day + ATV/r at 300/100 mg tablets per day + DTG 50 mg per day, orally | Drug: Atazanavir (ATV)<br>* Atazanavir<br>Drug: Ritonavir (RTV)<br>* Ritonavir<br>Drug: Dolutegravir (DTG)<br>* Dolutegravir<br>Drug: Tenofovir (TDF)<br>* Tenofovir<br>|
| Experimental: Arm 3: BMS-955176 + ATV + DTG<br>BMS-955176 at 120 mg tablet per day + ATV at 400 mg tablet per day + DTG at 50 mg tablet per day, orally | Drug: BMS-955176<br>* HIV Maturation Inhibitor<br>Drug: Atazanavir (ATV)<br>* Atazanavir<br>Drug: Dolutegravir (DTG)<br>* Dolutegravir<br>|
| Experimental: Arm 4: BMS-955176 + ATV + DTG<br>BMS-955176 at 180 mg tablet per day + ATV at 400 mg tablet per day + DTG at 50 mg tablet per day, orally | Drug: BMS-955176<br>* HIV Maturation Inhibitor<br>Drug: Atazanavir (ATV)<br>* Atazanavir<br>Drug: Dolutegravir (DTG)<br>* Dolutegravir<br>|
| Other: Arm 5: TDF + ATV + RTV + DTG<br>TDF 300 mg tablet per day + ATV/r at 300/100 mg tablets per day + DTG 50 mg per day, orally | Drug: Atazanavir (ATV)<br>* Atazanavir<br>Drug: Ritonavir (RTV)<br>* Ritonavir<br>Drug: Dolutegravir (DTG)<br>* Dolutegravir<br>Drug: Tenofovir (TDF)<br>* Tenofovir<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Week 24 | 
| Percentage of Participants With Plasma HIV-1 RNA <40 c/mL at Week 24-Stage 2 | 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. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Plasma HIV-1 RNA <40 c/mL at Weeks 48 and 96-Stage 1 | 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. | Weeks 48 and 96 | 
| Percentage of Participants With Plasma HIV-1 RNA <40 c/mL at Weeks 48 and 96-Stage 2 | 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. | Weeks 48 and 96 | 
| Percentage of Participants With HIV-1 RNA <200 c/mL at Weeks 24, 48 and 96-Stage 1 | 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. | Weeks 24, 48 and 96 | 
| Percentage of Participants With HIV-1 RNA <200 c/mL at Weeks 24, 48 and 96-Stage 2 | 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. | Weeks 24, 48 and 96 | 
| Change From Baseline in Logarithm to the Base 10 (log10) HIV-1 RNA Over Time-Stage 1 | 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. | Baseline and up to Week 72 | 
| Change From Baseline in log10 HIV-1 RNA Over Time-Stage 2 | This end point was not evaluated in Stage 2 due to early termination of the study during Stage 1. | Baseline and up to Week 96 | 
| Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Count Over Time-Stage 1 | 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. | Baseline and up to Week 72 | 
| Change From Baseline in CD4+ Cell Count Over Time-Stage 2 | This end point was not evaluated in Stage 2 due to early termination of the study during Stage 1. | Baseline and up to Week 96 | 
| Change From Baseline in Percentage of CD4+ Cells Over Time-Stage 1 | 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. | Baseline and up to Week 72 | 
| Change From Baseline in Percentage of CD4+ Cells Over Time-Stage 2 | This end point was not evaluated in Stage 2 due to early termination of the study during Stage 1. | Baseline and up to Week 96 | 
| Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation (AELD)-Stage 1 | 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. | Up to Week 96 | 
| Number of Participants With SAEs and AELDs-Stage 2 | This end point was not evaluated in Stage 2 due to early termination of the study during Stage 1. | Up to Week 96 | 
| Number of Participants With Occurrence of New Acquired Immunodeficiency Syndrome (AIDS) Defining Events-Stage 1 | The occurrence of new AIDS defining events that is, Centers for Disease Control (CDC) Class C events in participants is presented. | Up to Week 96 | 
| Number of Participants With Occurrence of New AIDS Defining Events-Stage 2 | This end point was not evaluated in Stage 2 due to early termination of the study during Stage 1. | Up to Week 96 | 
| Maximum Observed Concentration (Cmax) for BMS-955176-Stage 1 | 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. | 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]) | 
| Cmax for BMS-955176-Stage 2 | 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). | 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]) | 
| Time of Maximum Observed Plasma Concentration (Tmax) for BMS-955176-Stage 1 | PK assessments were planned to be performed; however, it was not performed due to the early termination of the study in 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]) | 
| Tmax for BMS-955176-Stage 2 | 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). | 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]) | 
| Observed Plasma Concentration at the End of a Dosing Interval (Ctau) for BMS-955176-Stage 1 | PK assessments were planned to be performed; however, it was not performed due to the early termination of the study in 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]) | 
| Ctau for BMS-955176-Stage 2 | 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). | 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]) | 
| Observed Pre-dose Plasma Concentration (C0) for BMS-955176-Stage 1 | PK assessments were planned to be performed; however, it was not performed due to the early termination of the study in 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]) | 
| C0 for BMS-955176-Stage 2 | 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). | 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]) | 
| Area Under the Concentration-time Curve in One Dosing Interval (AUC[Tau]) for BMS-955176-Stage 1 | PK assessments were planned to be performed; however, it was not performed due to the early termination of the study in 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]) | 
| AUC(Tau) for BMS-955176-Stage 2 | 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). | 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]) | 
| Number of Participants With Emergence of HIV Drug Resistance-Stage 1 | 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. | Up to Week 96 | 
| Number of Participants With Emergence of HIV Drug Resistance-Stage 2 | 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). | Up to Week 96 |