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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
Last Update Posted : July 10, 2018
Sponsor:
Information provided by (Responsible Party):
ViiV Healthcare

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.

Condition or disease Intervention/treatment Phase
Infection, Human Immunodeficiency Virus Drug: BMS-663068 Other: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 371 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multi-arm Phase 3 Randomized Placebo Controlled Double Blind Clinical Trial to Investigate the Efficacy and Safety of BMS-663068 in Heavily Treatment Experienced Subjects Infected With Multi-drug Resistant HIV-1
Actual Study Start Date : February 23, 2015
Actual Primary Completion Date : August 18, 2016
Estimated Study Completion Date : April 15, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
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.
Drug: BMS-663068
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.
Drug: BMS-663068
BMS-663068

Other: Placebo
Placebo

Experimental: BMS-663068
BMS-663068 600 mg tablets orally twice daily for 48 weeks or longer.
Drug: BMS-663068
BMS-663068




Primary Outcome Measures :
  1. Mean change in 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. Participants with missing Day 1 HIV-1 RNA values were not analyzed.


Secondary Outcome Measures :
  1. 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. Only participants with data available at the specified time points were analyzed.

  2. 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.

  3. 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.

  4. Number of participants with 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. Change from Baseline is the value at post-dose visit minus Baseline value. The number of participants with clinical chemistry results 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).

  5. Number of participants with 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. Change from Baseline is the value at post-dose visit minus Baseline value. The number of participants with hematology results 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)

  6. 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 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.

  7. 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 was 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 counts 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), and (b) LOCF for participants with an early value during blinded treatment before the Day 8 analysis visit window. Only those participants with data available at the specified time points were analyzed.

  8. Percentage change from Day 1 in CD4+ T- cell count at Day 8-Randomized Cohort [ Time Frame: Day 1 and Day 8 ]
    CD4+ T- cell counts was assessed by flow cytometry. Mean percentage 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 counts 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), and (b) LOCF for participants with an early value during blinded treatment before the Day 8 analysis visit window. Only those participants with data available at the specified time points were analyzed.

  9. 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).

  10. 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 was 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).

  11. Percentage change from Baseline in CD4+ T- cell count through Week 48 [ Time Frame: Baseline and up to Week 48 ]
    CD4+ T- cell counts was assessed by flow cytometry. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment. Percentage change from Baseline was calculated as the [(value at post-dose visit minus the value at Baseline)/Baseline] multiplied by 100. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

  12. 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 emergent drug resistance testing. The number of participants with emergent viral genotypic substitutions of interest in the GP160 domain was identified by the 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. The 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.

  13. 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. Only participants available at the specified time point was analyzed.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02362503


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Sponsors and Collaborators
ViiV Healthcare
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT02362503     History of Changes
Other Study ID Numbers: 205888
AI438-047 ( Other Identifier: Bristol-Myers Squibb )
First Posted: February 13, 2015    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: July 2018

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases