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Attachment Inhibitor Comparison in Heavily Treatment Experienced Patients

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ClinicalTrials.gov Identifier: NCT02362503
Recruitment Status : Active, not recruiting
First Posted : February 13, 2015
Results First Posted : September 18, 2018
Last Update Posted : August 6, 2019
Sponsor:
Information provided by (Responsible Party):
ViiV Healthcare

Tracking Information
First Submitted Date  ICMJE February 9, 2015
First Posted Date  ICMJE February 13, 2015
Results First Submitted Date  ICMJE August 2, 2018
Results First Posted Date  ICMJE September 18, 2018
Last Update Posted Date August 6, 2019
Actual Study Start Date  ICMJE February 23, 2015
Actual Primary Completion Date August 18, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 20, 2018)
Mean Change in Logarithm to the Base 10 (log10) HIV-1 Ribonucleic Acid (RNA) From Day 1 at Day 8-Randomized Cohort [ Time Frame: Day 1 and Day 8 ]
Plasma samples were collected for analysis of HIV-1 RNA. Mean change in log10 HIV-1 RNA from Day 1 was estimated using analysis of covariance (ANCOVA) with log10 HIV-1 RNA change from Day 1 at Day 8 as dependent variable, treatment (fostemsavir or placebo) as an independent variable, and Day 1 log10 HIV-1 RNA as a continuous covariate. Change from Day 1 was calculated as value at Day 8 minus value at Day 1. The analysis was performed on Intent-to-Treat Exposed (ITT-E) Population which comprised of all randomized participants who received at least one dose of study treatment. Missing HIV-1 RNA values at Day 8 were imputed using (a) Day 1 Observation Carried Forward (D1OCF) for participants without a value during blinded treatment (i.e, imputing a zero change from Day 1) or (b) Last Observation Carried Forward (LOCF) for participants with an early value during blinded treatment before the Day 8 analysis visit window.
Original Primary Outcome Measures  ICMJE
 (submitted: February 12, 2015)
The efficacy of BMS-663068, relative to placebo, is assessed using the mean change in log10 HIV-1 RNA from Day 1(baseline) to Day 8 as determined by maximum likelihood methods. [ Time Frame: At day 8 ]
At day 8 follow the start of Blinded BMS-663068 (or Placebo) + optimized background therapy (OBT)
Change History Complete list of historical versions of study NCT02362503 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 20, 2018)
  • Percentage of Participants With HIV-1 RNA Decreases From Day 1 That Exceed 0.5 log10 c/mL and 1.0 log10 c/mL at Day 8-Randomized Cohort [ Time Frame: Day 1 and Day 8 ]
    The percentage of participants in the Randomized Cohort with HIV-1 RNA decreases from Day 1 that exceed 0.5 log10 c/mL and 1.0 log10 c/mL at Day 8 was determined by comparing HIV-1 RNA Day 1 measurement of each participant to their Day 8 measurement. This was an ITT analysis that classified participants without HIV-1 RNA at Day 1 or Day 8 as failures. The percentage of responders along with 95% confidence interval based on Wilson score is presented.
  • Percentage of Participants With HIV-1 RNA <40 c/mL at Weeks 24 and 48-Randomized Cohort [ Time Frame: Weeks 24 and 48 ]
    The durability of response (that is, the number of participants achieving HIV-1 RNA <40 c/mL) at Weeks 24 and 48 of open-label fostemsavir plus OBT in the Randomized Cohort was assessed using the Food and Drug Administration (FDA) snapshot algorithm in which participants without HIV-1 RNA at Weeks 24 and 48 or those who changed OBT due to lack of efficacy through Weeks 24 and 48 were counted as failures. The percentage of participants in the Randomized Cohort who achieved virologic success (HIV-1 RNA <40 c/mL) at Weeks 24 and 48 is presented along with 95% Wilson confidence interval. All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
  • Number of Participants With On-treatment Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation (AELD)-Randomized Cohort [ Time Frame: Up to Week 48 analysis cut-off date ]
    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; an important medical event that may jeopardize the participant or require intervention. Number of participants with on-treatment SAEs and AEs leading to withdrawal of study treatment is presented. SAEs and AELDs were collected in Safety Population which comprised of all participants who received at least one dose of study treatment. All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
  • Number of Participants With Toxicity Grade Increase in Clinical Chemistry Results to Grade 3-4 Relative to Baseline-Randomized Cohort [ Time Frame: Baseline and up to Week 48 analysis cut-off date ]
    Laboratory toxicities were graded for severity according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) grading system: Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (potentially life-threatening). Baseline is defined as the latest pre-dose assessment. The number of participants with clinical chemistry toxicity grade increase to Grade 3-4 at anytime post-Baseline relative to Baseline is presented. Only participants with data available at the specified time points were analyzed (represented by n=X in category titles). All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
  • Number of Participants With Toxicity Grade Increase in Hematology Results to Grade 3-4 Relative to Baseline-Randomized Cohort [ Time Frame: Baseline and up to Week 48 analysis cut-off date ]
    Laboratory toxicities were graded for severity according to the DAIDS grading system: Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (potentially life-threatening). Baseline is defined as the latest pre-dose assessment. The number of participants with hematology toxicity grade increase to Grade 3-4 at anytime post-Baseline relative to Baseline is presented. Only participants with data available at the specified time points were analyzed (represented by n=X in category titles). All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
  • Number of Participants With Centers for Disease Control (CDC) Class C Events-Randomized Cohort [ Time Frame: Up to Week 48 analysis cut-off date ]
    Disease progression during open label fostemsavir plus OBT was assessed based on the occurrence of new AIDS defining events (CDC Class C events) or death. The number of participants with on-treatment CDC Class C AIDS events is presented. All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
  • Change From Day 1 in Cluster of Differentiation (CD) 4+ T-cell Count at Day 8-Randomized Cohort [ Time Frame: Day 1 and Day 8 ]
    CD4+ T- cell counts were assessed by flow cytometry. Mean change in CD4+ T- cell count from Day 1 at Day 8 was analyzed using one-way ANCOVA with change of CD4+ cell counts from Day 1 at Day 8 as the dependent variable, treatment (fostemsavir or placebo) as an in-dependent variable, and Day 1 CD4+ cell count as a continuous covariate. Change from Day 1 was calculated as value at Day 8 minus value at Day 1. Missing CD4+ cell count values at Day 8 were imputed using (a) D1OCF for participants without a value during blinded treatment (i.e., imputing a zero change from Day 1), or (b) LOCF for participants with an early value during blinded treatment before the Day 8 analysis visit window.
  • Change in CD4+ T- Cell Count Percentage From Day 1 at Day 8-Randomized Cohort [ Time Frame: Day 1 and Day 8 ]
    CD4+ T- cell counts were assessed by flow cytometry. Mean change in CD4+ T- cell count percentage from Day 1 at Day 8 was analyzed using one-way ANCOVA with change of CD4+ cell count percentage from Day 1 at Day 8 as the dependent variable, treatment (fostemsavir or placebo) as an independent variable, and Day 1 CD4+ cell count percentage as a continuous covariate. Change from Day 1 was calculated as value at Day 8 minus value at Day 1. Missing CD4+ cell count values at Day 8 were imputed using (a) D1OCF for participants without a value during blinded treatment (ie, imputing a zero change from Day 1), or (b) LOCF for participants with an early value during blinded treatment before the Day 8 analysis visit window.
  • Change From Baseline in log10 HIV-1 RNA for Fostemsavir When Given With OBT Through Week 48-Randomized Cohort [ Time Frame: Baseline and up to Week 48 ]
    Blood samples were collected for the analysis of HIV-1 RNA. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment. Change from Baseline was calculated as the value at post-dose visit minus the value at Baseline. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles). All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
  • Change From Baseline in CD4+ T- Cell Count Through Week 48-Randomized Cohort [ Time Frame: Baseline and up to Week 48 ]
    CD4+ T- cell counts were assessed by flow cytometry. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment. Change from Baseline was calculated as the value at post-dose visit minus the value at Baseline. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles). All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
  • Change From Baseline in CD4+ T- Cell Count Percentage Through Week 48 [ Time Frame: Baseline and up to Week 48 ]
    CD4+ T- cell counts were assessed by flow cytometry. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment. Change from Baseline was calculated as the value at post-dose visit minus the value at Baseline. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles). All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
  • Number of Participants With Treatment-emergent Viral Genotypic Substitution of Interest in the GP160 Domain as a Measure of Genotypic Resistance-Randomized Cohort [ Time Frame: Week 48 ]
    Plasma samples were collected for drug resistance testing. Participants with emergent viral genotypic substitutions of interest in GP160 domain was identified by next-generation sequencing (NGS) assay. Virologic failure (VF) Population comprised of all participants with available phenotypic and genotypic resistance data meeting at the time protocol defined virologic failure (PDVF) was met. Criteria for PDVF was a) Confirmed, or last available prior to discontinuation, HIV-1 RNA >=400 c/mL at any time after prior confirmed suppression to <400 c/mL prior to Week 24 or Confirmed, or last available prior to discontinuation, >1 log10 c/mL increase in HIV-1 RNA at any time above nadir level where nadir is >=40 c/mL prior to Week 24. b) Confirmed, or last available prior to discontinuation, HIV-1 RNA >=400 c/mL at or after Week 24. All participants received fostemsavir during open-label period irrespective of original randomization; hence, combined totals for Randomized Cohort is presented.
  • Number of Participants With Indicated Fold Change Ratio (FCR) Using the Monogram PhenoSense Entry Assay-Randomized Cohort [ Time Frame: Week 48 ]
    The phenotypic resistance to a drug is defined in terms of a fold change (FC) in IC50s, ie, the ratio of the 50% inhibitory concentration (IC50) of the clinical isolate to the IC50 of a reference strain (wild type control). FCR was calculated as FC at PDVF divided by Baseline FC. The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. FCR<1 indicates that FC is smaller on-treatment than at Baseline. FCR >3 indicates that on-treatment FC is 3 times greater than it was at Baseline. All the participants received fostemsavir during open-label period irrespective of the original arms to which they were randomized; hence, combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 12, 2015)
  • The proportion of subjects with HIV-1 RNA decreases from baseline that exceed 0.5 log10 c/mL and 1 log10 c/mL [ Time Frame: week 24 ]
    The proportion of subjects with HIV-1 RNA decreases from baseline that exceed 0.5 log10 c/mL and 1 log10 c/mL is determined by comparing each subject's HIV-1 RNA baseline measurement to their Day 8 measurement. Subjects without data at Day 8 are classified as failures
  • The durability of response (HIV-1 RNA < 40 c/mL) at Week 24 of OBT is assessed using the FDA snapshot algorithm [ Time Frame: week 24 ]
  • The frequency of Serious Adverse Event (SAEs), Adverse Event (AEs) leading to discontinuation, and Grade 3-4 laboratory abnormalities during OBT are tabulated from Case Report Forms (CRFs) and laboratory data [ Time Frame: week 24 ]
  • Disease progression during OBT is assessed using the occurrence of new AIDS defining events (CDC Class C events) or death as tabulated from CRFs [ Time Frame: week 24 ]
  • Drug resistance is assessed through phenotypic and genotypic resistance testing of isolates from subjects identified as meeting the criteria for virologic failure [ Time Frame: week 24 ]
  • The changes in CD4+ T-cells counts and percentages, for BMS-663068 and placebo when given with failing background therapies, are determined using the mean changes from baseline (Day 1) to Day 8 [ Time Frame: week 24 ]
  • The changes from baseline in HIV-1 RNA, CD4+ cell counts, and percentage of CD4+ T-cells, for BMS-663068 when given with OBT, are assessed using laboratory results collected through Week 24 [ Time Frame: week 24 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Attachment Inhibitor Comparison in Heavily Treatment Experienced Patients
Official Title  ICMJE A Multi-arm, Phase 3, Randomized, Placebo Controlled, Double Blind Clinical Trial to Investigate the Efficacy and Safety of Fostemsavir (BMS-663068/GSK3684934) in Heavily Treatment Experienced Subjects Infected With Multi-drug Resistant HIV-1 (BRIGHTE Study)
Brief Summary The purpose of this study is to determine whether the BMS Attachment Inhibitor (BMS-663068) is effective in the treatment of heavily treatment experienced HIV-1 patients with multi-drug resistance.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE HIV Infections
Intervention  ICMJE
  • Drug: BMS-663068
    BMS-663068
  • Other: Placebo
    Placebo
Study Arms  ICMJE
  • Experimental: A1: BMS-663068
    Phase 1: BMS-663068 600 mg tablets orally twice daily for 8 days. Phase 2: BMS-663068 600 mg tablets orally twice daily for 48 weeks or longer.
    Intervention: Drug: BMS-663068
  • Active Comparator: B1: Placebo + BMS-663068
    Phase 1: Placebo twice daily for 8 days. Phase 2: BMS-663068 600 mg tablets orally twice daily for 48 weeks or longer.
    Interventions:
    • Drug: BMS-663068
    • Other: Placebo
  • Experimental: BMS-663068
    BMS-663068 600 mg tablets orally twice daily for 48 weeks or longer.
    Intervention: Drug: BMS-663068
Publications * Not Provided

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 20, 2018)
371
Original Estimated Enrollment  ICMJE
 (submitted: February 12, 2015)
401
Estimated Study Completion Date  ICMJE December 31, 2024
Actual Primary Completion Date August 18, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Men and non-pregnant women with chronic HIV-1 infection
  • Antiretroviral-experienced with documented historical or baseline resistance, intolerability, and/or contraindications to antiretrovirals in at least three classes
  • Failing current antiretroviral regimen with a confirmed plasma HIV-1 RNA ≥ 400 c/mL (first value from Investigator, second from Screening labs)
  • Must have ≤ 2 classes with at least 1 but no more than 2 fully-active antiretrovirals remaining which can be effectively combined to form a viable new regimen, based on current and/or documented historical resistance testing and tolerability and safety
  • Able to receive ≥ 1 fully active approved antiretroviral as part of the OBT from Day 9 onwards in the Randomized Cohort
  • Subjects without any remaining fully active approved antiretroviral may be enrolled in the Non-Randomized Cohort

Exclusion Criteria:

  • Chronic untreated Hepatitis B virus (HBV) (however, patients with chronic treated HBV are eligible)
  • HIV-2 infection
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 7 x ULN
  • Alkaline Phosphatase > 5 x ULN
  • Bilirubin ≥ 1.5 x Upper limit of normal (ULN) (unless subject is currently on atazanavir and has predominantly unconjugated hyperbilirubinemia)
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,   Australia,   Belgium,   Brazil,   Canada,   Chile,   Colombia,   France,   Germany,   Greece,   Ireland,   Italy,   Mexico,   Netherlands,   Peru,   Poland,   Portugal,   Puerto Rico,   Romania,   Russian Federation,   South Africa,   Spain,   Taiwan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02362503
Other Study ID Numbers  ICMJE 205888
AI438-047 ( Other Identifier: Bristol-Myers Squibb )
2014-002111-41 ( EudraCT Number )
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 Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials ViiV Healthcare
PRS Account ViiV Healthcare
Verification Date July 2019

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