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Dose-finding Study of BMS-955176 to Treat HIV-1 Infected Treatment-naive Adults

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ClinicalTrials.gov Identifier: NCT02415595
Recruitment Status : Terminated (The trial ended early due to GI intolerability and treatment-emergent resistance.)
First Posted : April 14, 2015
Results First Posted : September 19, 2018
Last Update Posted : September 19, 2018
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare

Tracking Information
First Submitted Date  ICMJE March 11, 2015
First Posted Date  ICMJE April 14, 2015
Results First Submitted Date  ICMJE August 20, 2018
Results First Posted Date  ICMJE September 19, 2018
Last Update Posted Date September 19, 2018
Actual Study Start Date  ICMJE May 12, 2015
Actual Primary Completion Date May 26, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 20, 2018)
Number of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <40 Copies Per Milliliter (c/mL) at Week 24 Using Food and Drug Administration (FDA) Snapshot Algorithm [ Time Frame: Week 24 ]
Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. The antiviral efficacy was determined by the number of participants with plasma HIV 1 RNA <40 c/mL at Week 24 using the FDA snapshot algorithm. This 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 mITT Population, which comprised of randomized participants who received at least 1 dose of BMS-955176/GSK3532795 or EFV.
Original Primary Outcome Measures  ICMJE
 (submitted: April 9, 2015)
Proportion of subjects taking BMS-955176 or EFV, each in combination with TDF/FTC, with plasma HIV-1 ribonucleic acid (RNA) < 40 c/mL at Week 24 [ Time Frame: Week 24 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 20, 2018)
  • Number of Participants With Plasma HIV-1 RNA < 40 c/mL at Weeks 48 and 96 Using FDA Snapshot Algorithm [ Time Frame: Weeks 48 and 96 ]
    Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. The antiviral efficacy was determined by the number of participants with plasma HIV 1 RNA <40 c/mL at Weeks 48 and 96 using the FDA snapshot algorithm. This used the last on-treatment plasma HIV-1 RNA measurement within an FDA-specified visit window to determine response. The analysis was performed 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 (10 October 2016). The data was not collected for Week 96 analysis; as the study was terminated early. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).
  • Number of Participants With Plasma HIV-1 RNA < 200 c/mL at Week 24 Using FDA Snapshot Algorithm [ Time Frame: Week 24 ]
    Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. The antiviral efficacy was determined by the number of participants with plasma HIV-1 RNA <200 c/mL at Week 24 using the FDA snapshot algorithm. This used the last on-treatment plasma HIV-1 RNA measurement within an FDA-specified visit window to determine response.
  • Number of Participants With Plasma HIV-1 RNA < 200 c/mL at Weeks 48 and 96 [ Time Frame: Weeks 48 and 96 ]
    Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. The antiviral efficacy was determined by the number of participants with plasma HIV-1 RNA <200 c/mL at Weeks 48 and 96 using the FDA snapshot algorithm. This used the last on-treatment plasma HIV-1 RNA measurement within an FDA-specified visit window to determine response. The analysis was performed 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 (10 October 2016). The data was not collected for Week 96 analysis; as the study was terminated early. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).
  • Number of Participants With Newly Emergent Genotypic Resistance Using All On-treatment Isolates [ Time Frame: Week 24 ]
    The emergence of genotypic resistance among samples selected for drug resistance testing were assessed by searching for all reverse transcriptase substitutions and protease inhibitor substitutions listed in the International Acquired Immunodeficiency Syndrome (AIDS) Society-United States of America (IAS-USA) list of HIV-1 drug resistance mutations. The outcome was originally designed to be assessed up to 96 weeks of treatment, but it was analyzed up to Week 24 as the study was terminated early. The emergence of genotypic resistance is presented for participants in the mITT Population who had Baseline and on-treatment genotypic resistance testing and who had successful sequencing.
  • Number of Participants With Newly Emergent Phenotypic Resistance Using All On-treatment Isolates [ Time Frame: Week 24 ]
    Phenotypic resistance to a drug is defined as a fold change (i.e., ratio of the 50% inhibitory concentration (IC50) of the clinical isolate to the IC50 of the reference strain) which is greater than the cut-off for reduced susceptibility. Emergent phenotypic resistance to BMS-955176/GSK3532795 was defined as a Baseline fold change IC50<= 3 and an on-treatment fold change IC50>3. The number of participants with newly emergent phenotypic resistance is presented for participants in the mITT Population who had Baseline and on-treatment phenotypic resistance testing. The outcome was originally designed to be assessed up to 96 weeks of treatment, but it was analyzed up to Week 24 as the study was terminated early.
  • Change From Baseline in Logarithm to the Base 10 (log10) HIV-1 RNA Over Time [ Time Frame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84 ]
    Blood samples were collected for analysis of HIV-1 RNA. Values obtained at Day 1 were considered as Baseline value. Change from Baseline was calculated as value at indicated time point minus 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). Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.
  • Change From Baseline in Cluster of Differentiation (CD)4+ Thymus (T)-Cell Counts Over Time [ Time Frame: Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84 ]
    CD4+ T-cell counts was assessed using flow cytometry. Values obtained at Day 1 were considered as Baseline value. Change from Baseline was calculated as value at indicated time point minus Baseline value. Change from Baseline in CD4+T- cell counts 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). Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.
  • Change From Baseline in the Percentage of CD4+ T-cells Over Time [ Time Frame: Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84 ]
    CD4+ T-cell counts overall was assessed using flow cytometry. Values obtained at Day 1 were considered as Baseline value. Change from Baseline was calculated as value at indicated time point minus Baseline value. Change from Baseline in percentage of CD4+T- cell counts 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). Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.
  • Number of Participants With Serious Adverse Events (SAEs) and Adverse Events Leading to Discontinuation (AELD) [ Time Frame: Up to Week 96 ]
    Any untoward medical occurrence that at any dose: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention were categorized as SAE. Number of participants with SAEs and AELDs is summarized.
  • Number of Participants With at Least One Centers for Disease Control (CDC) Class C Events [ Time Frame: Up to Week 96 ]
    The occurrence of new AIDS defining events that is CDC class C events is presented.
  • Maximum Observed Plasma Concentration (Cmax), Observed Pre-dose Plasma Concentration (C0) and Observed Plasma Concentration at the End of a Dosing Interval (Ctau) of BMS-955176/GSK3532795 [ Time Frame: Pre-dose (morning) and at 0.5, 1, 1.5, 2, 4, 4.5, 5, 6, 8, 12 (evening pre-dose) and 24 hours (morning pre-dose) at Week 2 (Days 12 to 16) ]
    Serial blood samples were collected at indicated time points for intensive pharmacokinetic (PK) assessment. The PK assessments were performed on evaluable PK Population, a sub-population which included all treated participants who had adequate PK profiles.
  • Time of Maximum Observed Plasma Concentration (Tmax) of BMS-955176/GSK3532795 [ Time Frame: Pre-dose (morning) and 0.5, 1, 1.5, 2, 4, 4.5, 5, 6, 8, 12 (evening pre-dose) and 24 hours (morning pre-dose) at Week 2 (Days 12 to 16) ]
    Serial blood samples were collected at indicated time points for intensive PK assessment.
  • Area Under the Concentration-time Curve in One Dosing Interval (AUC [Tau]) of BMS-955176/GSK3532795 [ Time Frame: Pre-dose (morning) and at 0.5, 1, 1.5, 2, 4, 4.5, 5, 6, 8, 12 (evening pre-dose) and 24 hours (morning pre-dose) at Week 2 (Days 12 to 16) ]
    Serial blood samples were collected at indicated time points for intensive PK assessment.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2015)
  • The antiviral efficacy of BMS-955176 and EFV by determining the proportion of subjects with plasma HIV-1 RNA < 40 c/mL [ Time Frame: At Weeks 48 and 96 ]
  • The antiviral efficacy of BMS-955176 and EFV by determining the proportion of subjects with plasma HIV-1 RNA < 200 c/mL [ Time Frame: At Weeks 24, 48 and 96 ]
  • The emergence of HIV drug resistance among samples selected for drug resistance testing will be assessed using the most recent version of the International AIDS Society (IAS)-USA list of HIV-1 drug resistance mutations [ Time Frame: At Weeks 24, 48 and 96 ]
    Samples meeting the criteria below will be selected for the drug resistance testing, and will tabulated by the number of unique subjects with mutations listed in the most recent version of the IAS-USA list of HIV-1 drug resistance mutations:
    1. Confirmed > 1 log10 c/mL increase in HIV-1 RNA at any time above nadir level where nadir is ≥ 40 c/mL
    2. HIV-1 RNA ≥ 40 c/mL if prior suppression < 40 c/mL
    3. Confirmed HIV-1 RNA ≥ 400 c/mL after Week 24
    4. Failure to suppress last HIV-1 RNA to < 400 c/mL within Week 24, 48, or 96 week snapshot window
  • Safety and tolerability of BMS-955176 in treatment-naïve subjects by measuring frequency of serious adverse events (SAEs) and adverse events (AEs) leading to discontinuation [ Time Frame: At Weeks 24, 48 and 96 ]
  • Disease progression as measured by the occurrence of new AIDS defining events (CDC Class C events) [ Time Frame: At Weeks 24, 48 and 96 ]
  • Maximum observed plasma concentration (Cmax) of BMS-955176 [ Time Frame: At week 24 ]
  • Time of maximum observed plasma concentration (Tmax) of BMS-955176 [ Time Frame: At week 24 ]
  • Observed plasma concentration at the end of a dosing interval (Ctau) of BMS-955176 [ Time Frame: At week 24 ]
  • Observed pre-dose plasma concentration (C0) of BMS-955176 [ Time Frame: At week 24 ]
  • Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-955176 [ Time Frame: At week 24 ]
  • Efficacy: Mean changes from baseline in log10 HIV-1 RNA of BMS-955176 and EFV [ Time Frame: At Weeks 24, 48 and 96 ]
  • Efficacy: Mean changes in CD4+ T-cell counts of BMS-955176 and EFV [ Time Frame: At Weeks 24, 48 and 96 ]
  • Efficacy: Percentage of CD4+ T-cells of BMS-955176 and EFV [ Time Frame: At Weeks 24, 48 and 96 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose-finding Study of BMS-955176 to Treat HIV-1 Infected Treatment-naive Adults
Official Title  ICMJE A Phase 2b Randomized, Active-Controlled, Double-Blind Trial to Investigate Safety, Efficacy, and Dose-response of BMS-955176, Given on a Backbone of Tenofovir/Emtricitabine, in Treatment-Naive HIV-1 Infected Adults
Brief Summary The purpose of this study is to find at least one dose of BMS-955176 that will be safe, effective and tolerable for HIV-1 infected treatment naive adults.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Infection, Human Immunodeficiency Virus
Intervention  ICMJE
  • Drug: BMS-955176
    HIV Maturation Inhibitor
  • Drug: EFV
    EFV
  • Drug: TDF/FTC
    TDF/FTC
Study Arms  ICMJE
  • Experimental: Arm 1: BMS-955176 60 mg + TDF/FTC
    BMS-955176 at 60 mg active dose per day + BMS-955176 placebo matching 120 mg + efavirenz (EFV) placebo matching 600 mg + tenofovir/emtricitabine (TDF/FTC) 300/200 mg per day, orally
    Interventions:
    • Drug: BMS-955176
    • Drug: TDF/FTC
  • Experimental: Arm 2: BMS-955176 120 mg + TDF/FTC
    BMS-955176 placebo matching 60 mg + BMS-955176 at 120mg active dose per day + EFV placebo matching 600mg + TDF/FTC 300/200mg per day, orally
    Interventions:
    • Drug: BMS-955176
    • Drug: TDF/FTC
  • Experimental: Arm 3: BMS-955176 180 mg + TDF/FTC
    BMS-955176 at 60mg active dose per day + BMS-955176 at 120mg active dose per day + EFV placebo matching 600mg + TDF/FTC at 300/200mg per day, orally
    Interventions:
    • Drug: BMS-955176
    • Drug: TDF/FTC
  • Active Comparator: Arm 4: EFV + TDF/FTC
    BMS-955176 placebo matching 60mg + BMS-955176 placebo matching 120mg + EFV at 600mg per day + TDF/FTC 300/200mg per day
    Interventions:
    • Drug: EFV
    • Drug: TDF/FTC
Publications * Morales-Ramirez J, Bogner JR, Molina JM, Lombaard J, Dicker IB, Stock DA, DeGrosky M, Gartland M, Pene Dumitrescu T, Min S, Llamoso C, Joshi SR, Lataillade M. Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial. PLoS One. 2018 Oct 23;13(10):e0205368. doi: 10.1371/journal.pone.0205368. eCollection 2018.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: August 20, 2018)
210
Original Estimated Enrollment  ICMJE
 (submitted: April 9, 2015)
200
Actual Study Completion Date  ICMJE August 21, 2017
Actual Primary Completion Date May 26, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

  • Men and non-pregnant women, at least 18 years of age
  • Antiretroviral treatment-naïve; defined as no current or previous exposure to > 1 week of an antiretroviral drug
  • Plasma HIV-1 RNA ≥ 1000 copies/mL
  • CD4 T-cell count > 200 cells/mm3

Exclusion Criteria:

  • Resistance or partial resistance to any study drug determined by tests at Screening
  • Current or historical genotypic and/or phenotypic drug resistance testing showing certain resistance mutations to EFV, TDF, FTC, Protease Inhibitors
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Canada,   Chile,   France,   Germany,   Italy,   Mexico,   Poland,   South Africa,   Spain,   United Kingdom,   United States
Removed Location Countries Puerto Rico,   Thailand
 
Administrative Information
NCT Number  ICMJE NCT02415595
Other Study ID Numbers  ICMJE 205891
2013-005487-26 ( EudraCT Number )
AI468-038 ( Other Identifier: Bristol-Myers Squibb )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party ViiV Healthcare
Study Sponsor  ICMJE ViiV Healthcare
Collaborators  ICMJE GlaxoSmithKline
Investigators  ICMJE
Study Director: GSK Clinical Trials ViiV Healthcare
PRS Account ViiV Healthcare
Verification Date August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP