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

• BMS-955176 (Drug): HIV Maturation Inhibitor
• Atazanavir (ATV) (Drug): Atazanavir
• Ritonavir (RTV) (Drug): Ritonavir
• Dolutegravir (DTG) (Drug): Dolutegravir
• Tenofovir (TDF) (Drug): Tenofovir

Primary outcomes

• 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.
• 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.

Secondary outcomes

• 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 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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.
• 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.
• 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).
• 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.
• 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).

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• 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 (Primary), Number, Percentage of participants: Stage 1: BMS-955176 120 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 73.7 (56.9 to 86.6); Stage 1: TDF 300 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 60.0 (42.1 to 76.1)
• Percentage of Participants With Plasma HIV-1 RNA <40 c/mL at Week 24-Stage 2 (Primary)
• Percentage of Participants With Plasma HIV-1 RNA <40 c/mL at Weeks 48 and 96-Stage 1 (Secondary), Number, Percentage of participants: Stage 1: BMS-955176 120 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 75.0 (34.9 to 96.8); Stage 1: TDF 300 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 66.7 (29.9 to 92.5)
• Percentage of Participants With Plasma HIV-1 RNA <40 c/mL at Weeks 48 and 96-Stage 2 (Secondary)
• Percentage of Participants With HIV-1 RNA <200 c/mL at Weeks 24, 48 and 96-Stage 1 (Secondary), Number, Percentage of participants: Stage 1: BMS-955176 120 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 93.8 (79.2 to 99.2); Stage 1: TDF 300 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 89.7 (72.6 to 97.8)
• Percentage of Participants With HIV-1 RNA <200 c/mL at Weeks 24, 48 and 96-Stage 2 (Secondary)
• Change From Baseline in Logarithm to the Base 10 (log10) HIV-1 RNA Over Time-Stage 1 (Secondary), Mean, log10 c/mL: Stage 1: BMS-955176 120 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD -4.232 +/- 0.8779; Stage 1: TDF 300 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD -4.050 +/- 1.3413
• Change From Baseline in log10 HIV-1 RNA Over Time-Stage 2 (Secondary)
• Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Count Over Time-Stage 1 (Secondary), Mean, Cells per microliter: Stage 1: BMS-955176 120 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 57.6 +/- 93.54; Stage 1: TDF 300 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 26.7 +/- 83.30
• Change From Baseline in CD4+ Cell Count Over Time-Stage 2 (Secondary)
• Change From Baseline in Percentage of CD4+ Cells Over Time-Stage 1 (Secondary), Mean, Percentage of CD4+ cells: Stage 1: BMS-955176 120 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 1.94 +/- 2.701; Stage 1: TDF 300 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 1.82 +/- 2.152
• Change From Baseline in Percentage of CD4+ Cells Over Time-Stage 2 (Secondary)
• Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation (AELD)-Stage 1 (Secondary), Count of participants, Participants: Stage 1: BMS-955176 120 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 4; Stage 1: TDF 300 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 3
• Number of Participants With SAEs and AELDs-Stage 2 (Secondary)
• Number of Participants With Occurrence of New Acquired Immunodeficiency Syndrome (AIDS) Defining Events-Stage 1 (Secondary), Count of participants, Participants: Stage 1: BMS-955176 120 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 1; Stage 1: TDF 300 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD 0
• Number of Participants With Occurrence of New AIDS Defining Events-Stage 2 (Secondary)
• Maximum Observed Concentration (Cmax) for BMS-955176-Stage 1 (Secondary)
• Cmax for BMS-955176-Stage 2 (Secondary)
• Time of Maximum Observed Plasma Concentration (Tmax) for BMS-955176-Stage 1 (Secondary)
• Tmax for BMS-955176-Stage 2 (Secondary)
• 8 more outcome measures not shown.

Adverse events

Time frame: Adverse events (AEs) and serious adverse events (SAEs) were collected from the start of study treatment until Week 96.

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2015-01-28)
• Statistical Analysis Plan (PDF, 2017-11-09)

• GSK Clinical Trials, Study director, ViiV Healthcare