Attachment Inhibitor Comparison in Heavily Treatment Experienced Patients

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: BMS-663068
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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)

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A1: BMS-663068<br>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<br>* BMS-663068<br>|
| Active Comparator: B1: Placebo + BMS-663068<br>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<br>* BMS-663068<br>Other: Placebo<br>* Placebo<br>|
| Experimental: BMS-663068<br>BMS-663068 600 mg tablets orally twice daily for 48 weeks or longer. | Drug: BMS-663068<br>* BMS-663068<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Logarithm to the Base 10 (log10) HIV-1 Ribonucleic Acid (RNA) From Day 1 at Day 8-Randomized Cohort | 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. | Day 1 and Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Day 1 and Day 8 | 
| Percentage of Participants With HIV-1 RNA <40 c/mL at Weeks 24, 48 and 96-Randomized Cohort | The durability of response (that is, the number of participants achieving HIV-1 RNA <40 c/mL) at Weeks 24, 48 and 96 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, 48 and 96 or those who changed OBT due to lack of efficacy through Weeks 24, 48 and 96 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, 48 and 96 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. | At Weeks 24, 48 and 96 | 
| Number of Participants With On-treatment Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation (AELD)-Randomized Cohort | 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. | Up to Week 96 analysis cut-off date | 
| Number of Participants With Toxicity Grade Increase in Clinical Chemistry Results to Grade 3-4 Relative to Baseline-Randomized Cohort | 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. 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. | Baseline and up to Week 96 analysis cut-off date | 
| Number of Participants With Toxicity Grade Increase in Hematology Results to Grade 3-4 Relative to Baseline-Randomized Cohort | 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. 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. | Baseline and up to Week 96 analysis cut-off date | 
| Number of Participants With Centers for Disease Control (CDC) Class C Events-Randomized Cohort | 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. | Up to Week 96 analysis cut-off date | 
| Change From Day 1 in Cluster of Differentiation (CD) 4+ T-cell Count at Day 8-Randomized Cohort | 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. | Day 1 and Day 8 | 
| Change in CD4+ T- Cell Count Percentage From Day 1 at Day 8-Randomized Cohort | 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. | Day 1 and Day 8 | 
| Change From Baseline in log10 HIV-1 RNA for Fostemsavir When Given With OBT Through Week 96-Randomized Cohort | 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. 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. | Baseline and at Day 8, Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84 and 96 | 
| Change From Baseline in CD4+ T- Cell Count Through Week 96-Randomized Cohort | 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. | Baseline and at Day 8, Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84 and 96 | 
| Change From Baseline in CD4+ T- Cell Count Percentage Through Week 96 | Percentage 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. | Baseline and at Day 8, Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84 and 96 | 
| Number of Participants With Treatment-emergent Viral Genotypic Substitution of Interest in the GP160 Domain as a Measure of Genotypic Resistance-Randomized Cohort | 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. Protocol defined virologic failure (PDVF) through Week 96 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. | Week 96 | 
| Number of Participants With Indicated Fold Change Ratio (FCR) Using the Monogram PhenoSense Entry Assay-Randomized Cohort | The phenotypic resistance to a drug is defined in terms of a fold change (FC) in IC50s, i.e., 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. | Week 96 |