Attachment Inhibitor Comparison in Heavily Treatment Experienced Patients

HIV Infections Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02362503
• Other study ID #: 205888
• Secondary ID: AI438-0472014-00
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: February 23, 2015
• Est. completion date: December 31, 2025

Study information

• Verified date: January 2024
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 371
• Est. completion date: December 31, 2025
• Est. primary completion date: August 18, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• BMS-663068
BMS-663068

Other:
• Placebo
Placebo

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autónoma de Buenos Aires	Buenos Aires
Argentina	GSK Investigational Site	Cordoba	Córdova
Argentina	GSK Investigational Site	Cordoba	Córdova
Argentina	GSK Investigational Site	Rosario	Santa Fe
Australia	GSK Investigational Site	Darlinghurst	New South Wales
Australia	GSK Investigational Site	Melbourne	Victoria
Belgium	GSK Investigational Site	Antwerpen
Belgium	GSK Investigational Site	Brussels
Brazil	GSK Investigational Site	Belo Horizonte
Brazil	GSK Investigational Site	Campinas	São Paulo
Brazil	GSK Investigational Site	Curitiba	Paraná
Brazil	GSK Investigational Site	Porto Alegre	Rio Grande Do Sul
Brazil	GSK Investigational Site	Ribeirao Preto
Brazil	GSK Investigational Site	Rio de Janeiro
Brazil	GSK Investigational Site	Salvador
Brazil	GSK Investigational Site	Sao Paulo	São Paulo
Brazil	GSK Investigational Site	Sao Paulo	São Paulo
Brazil	GSK Investigational Site	Sao Paulo	São Paulo
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Ottawa	Ontario
Canada	GSK Investigational Site	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Vancouver	British Columbia
Canada	GSK Investigational Site	Vancouver
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago
Chile	GSK Investigational Site	Santiago Centro	Región Metro De Santiago
Chile	GSK Investigational Site	Temuco
Colombia	GSK Investigational Site	Bogota
Colombia	GSK Investigational Site	Bogotá
Colombia	GSK Investigational Site	Cali, Valle Del Cauca
France	GSK Investigational Site	Bordeaux cedex
France	GSK Investigational Site	Marseille
France	GSK Investigational Site	Nantes
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris cedex 10
France	GSK Investigational Site	Paris Cedex 12
France	GSK Investigational Site	Paris cedex 20
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Dortmund	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Freiburg	Baden-Wuerttemberg
Germany	GSK Investigational Site	München
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Thessaloniki
Ireland	GSK Investigational Site	Dublin
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Modena
Italy	GSK Investigational Site	Monza
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Torino	Piemonte
Mexico	GSK Investigational Site	Chihuahua
Mexico	GSK Investigational Site	Ciudad de Mexico
Mexico	GSK Investigational Site	Ciudad de México	Estado De México
Mexico	GSK Investigational Site	Distrito Federal
Mexico	GSK Investigational Site	Guadalajara	Jalisco
Mexico	GSK Investigational Site	Mexico
Netherlands	GSK Investigational Site	Utrecht
Peru	GSK Investigational Site	Iquitos	Loreto
Peru	GSK Investigational Site	Lima
Peru	GSK Investigational Site	Lima
Peru	GSK Investigational Site	Lima
Peru	GSK Investigational Site	Lima
Poland	GSK Investigational Site	Szczecin
Poland	GSK Investigational Site	Warszawa
Portugal	GSK Investigational Site	Lisboa
Portugal	GSK Investigational Site	Lisbon
Puerto Rico	GSK Investigational Site	San Juan
Romania	GSK Investigational Site	Bucharest
Russian Federation	GSK Investigational Site	Irkutsk
Russian Federation	GSK Investigational Site	Krasnodar
South Africa	GSK Investigational Site	Benoni	Gauteng
South Africa	GSK Investigational Site	Bloemfontein	Free State
South Africa	GSK Investigational Site	Cape Town
South Africa	GSK Investigational Site	Dundee	KwaZulu- Natal
South Africa	GSK Investigational Site	Durban
South Africa	GSK Investigational Site	Johannesburg	Gauteng
South Africa	GSK Investigational Site	Observatory	Western Province
South Africa	GSK Investigational Site	Port Elizabeth	Eastern Cape
Spain	GSK Investigational Site	Badalona, Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Seville, Sevilla
Taiwan	GSK Investigational Site	Taipei
United Kingdom	GSK Investigational Site	Bournemouth
United Kingdom	GSK Investigational Site	Leicestershire
United Kingdom	GSK Investigational Site	London
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Bellaire	Texas
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Bronx	New York
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Fort Pierce	Florida
United States	GSK Investigational Site	Hillsborough	New Jersey
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Manhasset	New York
United States	GSK Investigational Site	New Haven	Connecticut
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Newark	New Jersey
United States	GSK Investigational Site	Oakland Park	Florida
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Palm Springs	California
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	Savannah	Georgia
United States	GSK Investigational Site	Southfield	Michigan
United States	GSK Investigational Site	Tulsa	Oklahoma
United States	GSK Investigational Site	Washington	District of Columbia
United States	GSK Investigational Site	Washington	District of Columbia
United States	GSK Investigational Site	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
ViiV Healthcare

Countries where clinical trial is conducted

United States,  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, 

References & Publications (1)

Kozal M, Aberg J, Pialoux G, Cahn P, Thompson M, Molina JM, Grinsztejn B, Diaz R, Castagna A, Kumar P, Latiff G, DeJesus E, Gummel M, Gartland M, Pierce A, Ackerman P, Llamoso C, Lataillade M; BRIGHTE Trial Team. Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2020 Mar 26;382(13):1232-1243. doi: 10.1056/NEJMoa1902493. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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