HIV Attachment Inhibitor to Treat Human Immunodeficiency Virus 1 (HIV-1) Infections

Infection, Human Immunodeficiency Virus Clinical Trial

Official title:

A Phase IIb Randomized, Controlled, Partially-Blinded Trial to Investigate Safety, Efficacy and Dose-Response of BMS-663068 in Treatment-experienced HIV-1 Subjects, Followed by an Open-Label Period on the Recommended Dose

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01384734
• Other study ID #: 205889
• Secondary ID: AI438-011
• Status: Completed
• Phase: Phase 2
• Start date: July 26, 2011
• Est. completion date: May 12, 2017

Study information

• Verified date: August 2018
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the safety, efficacy, tolerability and pharmacokinetics of four doses of BMS-663068 with Raltegravir (RAL) + Tenofovir Disoproxil Fumarate (TDF). At least 1 dose of BMS-663068 can be identified which is safe, well tolerated, and efficacious when combined with RAL + TDF for treatment-experienced HIV-1 infected subjects. PHENOSENSE® is a registered trademark of Monogram Biosciences.

Description:

Masking: Double-blind for BMS-6630368 treatment groups until the Week 24 Primary Endpoint analysis, then open label. The reference groups is all open-label.

Arms: 5 (4 BMS-663068 treatment groups and 1 reference group)

Intervention Model: Parallel (with unblinding after the Week 24 primary endpoint analysis)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 254
• Est. completion date: May 12, 2017
• Est. primary completion date: February 18, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Plasma HIV-1 RNA = 1000 copies/ml at Screening

• Treatment experience with antiretroviral therapies (excluding integrase inhibitors)

• Screening PHENOSENSE Entry indicating BMS-626529 inhibitory concentration (IC)50 < 0.1 µM

• Cluster of differentiation (CD)4+ T-cell count > 50 cells/mm3

Exclusion Criteria:

• History (or evidence at Screening) of genotypic resistance to any component of the study regimen [ Tenofovir Disoproxil Fumarate (TDF), Atazanavir (ATV), Raltegravir (RAL)]

• Certain laboratory and electrocardiogram (ECG) values

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Immunologic Deficiency Syndromes
• Infection
• Infection, Human Immunodeficiency Virus

Intervention

Drug:
• BMS-663068 400 mg
Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose
• BMS-663068 800 mg
Tablets, Oral, 800 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose
• BMS-663068 600 mg
Tablets, Oral, 600 mg, once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose
• BMS-663068 1200 mg
Tablets, Oral, 1200 mg, once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose
• Raltegravir 400 mg
Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose
• Tenofovir 300 mg
Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose
• Ritonavir 100 mg
Tablets, Oral, 100 mg, Once daily, 96 weeks
• Atazanavir 300 mg
Capsules, Oral, 300 mg, Once daily, 96 weeks

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Ciudad de Buenos Aires	Buenos Aires
Argentina	GSK Investigational Site	Córdoba
Argentina	GSK Investigational Site	Rosario
Argentina	GSK Investigational Site	Rosario	Santa Fe
Colombia	GSK Investigational Site	Bogota
Colombia	GSK Investigational Site	Bogotá
Colombia	GSK Investigational Site	Bogoto
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Bonn	Nordrhein-Westfalen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	München
Mexico	GSK Investigational Site	Aguascalientes
Mexico	GSK Investigational Site	DF
Mexico	GSK Investigational Site	Distrito Federal
Mexico	GSK Investigational Site	Guadalajara	Jalisco
Mexico	GSK Investigational Site	Mexico City
Mexico	GSK Investigational Site	San Luis Potosi	San Luis Potosí
Mexico	GSK Investigational Site	Zapopan	Jalisco
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
Peru	GSK Investigational Site	Lima
Peru	GSK Investigational Site	Lima
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Constanta
Romania	GSK Investigational Site	Craiova
Romania	GSK Investigational Site	Iasi
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Smolensk
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
South Africa	GSK Investigational Site	Dundee	KwaZulu- Natal
South Africa	GSK Investigational Site	Durban
South Africa	GSK Investigational Site	Johannesburg
South Africa	GSK Investigational Site	Observatory, Cape Town
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Córdoba
Spain	GSK Investigational Site	Madrid
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Coral Gables	Florida
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Longview	Texas
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
ViiV Healthcare

Countries where clinical trial is conducted

United States,  Argentina,  Colombia,  Germany,  Mexico,  Peru,  Romania,  Russian Federation,  South Africa,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) < 50 Copies Per Milliliter (c/mL) at Week 24	Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Week 24 using the Food and Drug Administration (FDA) snapshot algorithm was assessed to evaluate the antiviral activity. Treatment comparisons were not performed as this was an estimation study. Response rates were tabulated by treatment arm with exact Clopper-Pearson binomial 95 percentage confidence intervals (CI). Virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment within the snapshot window of the visit of interest. Intent-To-Treat-Exposed (ITT-E) Population includes all randomized participants who received at least one dose of study treatment.	Week 24
Primary	Number of Participants With Serious Adverse Events (SAE) and Discontinuation Due to AEs up to Week 24	Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or suspected transmission of an infectious agent via the study drug were categorized as SAE. AEs leading to discontinuation of study therapy were also reported as safety assessment. Safety population included all participants who received at least one dose of study treatment. Summaries of SAEs and AEs leading to discontinuation or withdrawal through Week 24 included AEs with onset on or after the start of study treatment (i.e. study date of first study treatment intake) up to and including the end of the Week 24 visit snapshot window.	Up to Week 24
Secondary	Change From Monotherapy Baseline in log10 HIV RNA of the Monotherapy Period	Change from monotherapy Baseline in log10 HIV RNA to assess the antiviral activity of temsavir following administration of selected doses of FTR administered orally to HIV-1-infected participants for 7 days. 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 value at indicated time point minus Baseline value. ITT-E Monotherapy Population comprised of participants that were randomized and participated in the monotherapy sub-study and received at least one dose of FTR Monotherapy. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).	Baseline and up to Day 8 of the monotherapy period
Secondary	Maximum Decrease From Monotherapy Baseline in log10 Plasma HIV-1 RNA	Maximum decrease from monotherapy Baseline in log10 plasma HIV-1 RNA during monotherapy to assess the antiviral activity of temsavir following administration of selected doses of FTR administered orally to HIV-1-infected participants for 7 days. 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 value at indicated time point minus Baseline value. The data for monotherapy nadir has been presented where nadir represents the maximum decrease from Baseline.	Baseline and up to Day 8 of the monotherapy period
Secondary	Percentage of Participants With Plasma HIV-1 RNA < 50 c/mL at Day 8 of the Monotherapy Period	Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Baseline of combination therapy was assessed to evaluate the antiviral activity of four doses of FTR. Baseline of combination therapy was the Day 1 of the combination therapy. Virologic success or failure was determined using the non-missing viral load value at Baseline of combination therapy. The assessment closest to the window target Study Day was used for the analysis. Only those participants with data available at the specified time points were analyzed.	Up to Day 8 of the monotherapy period
Secondary	Number of Participants With SAE and Discontinuation Due to AEs During Monotherapy Period	Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or suspected transmission of an infectious agent via the study drug were categorized as SAE. AEs leading to discontinuation of study therapy were also reported as safety assessment.	Up to Day 8 of the monotherapy period
Secondary	Change From Monotherapy Baseline in Cluster of Differentiation (CD)4+ and CD8+ T-cell Counts During Monotherapy	Blood was collected and CD4+ and CD8+ cell count assessment was done by flow cytometery and was carried out at Baseline (Day 1) to evaluate the immunological activity of multiple doses of FTR. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and the values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed.	Baseline and Day 8
Secondary	Change From Monotherapy Baseline in CD4+ and CD8+ T-cell Proportion During Monotherapy	Blood was collected and CD4+ and CD8+ proportion assessment was done by flow cytometery and was carried out at Baseline (Day 1) to evaluate the immunological activity of multiple doses of FTR. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and the values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed.	Baseline and Day 8
Secondary	Percentage of Participants With Plasma HIV-1 RNA < 50 c/mL at Primary Study	Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Weeks 48 and 96 using the FDA snapshot algorithm was assessed to evaluate the antiviral activity. Treatment comparisons were not performed as this was an estimation study. Response rates were tabulated by treatment arm with exact Clopper-Pearson binomial 95 percentage CI. Virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment within the snapshot window of the visit of interest.	Weeks 48 and 96
Secondary	Number of Participants With SAE and Discontinuation Due to AEs During Primary Study	Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or suspected transmission of an infectious agent via the study drug were categorized as SAE. AEs leading to discontinuation of study therapy were also reported as safety assessment. Safety Population comprised of participants who received at least one dose of study treatment. Summaries of SAEs and AEs leading to discontinuation or withdrawal through Week X (where X = 48 or 96) included AEs with onset on or after the start of study treatment (i.e. study date of first study treatment intake) up to and including the end of the Week 48 and 96 visit snapshot window.	Weeks 48 and 96
Secondary	Change From Baseline in CD4+ T-cell Count	Blood was collected and CD4+ cell count assessment by flow cytometery was carried out at Baseline (Day 1), Weeks 24, 48 and 96 to evaluate the immunological activity of multiple doses of BMS-663068/GSK3684934. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and those values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).	Baseline and Weeks 24, 48 and 96
Secondary	Number of Participants With Newly-emergent Genotypic Substitutions at Week 24	Participants who administered antiretroviral (ARV) with virologic failure (VF) were assessed. Genotypic substitution included assessment of Reverse Transcriptase (RT) substitution, Protease Inhibitor (PI) substitution and Integrase RAL substitution as per International Acquired Immune Deficiency Syndrome (AIDS) Society-USA (IAS-USA) list. ITT-E Resistance Tested through Week 24 population included participants who met the criteria for Resistance testing, and the confirmatory value or value at discontinuation occurred at or before the end of the Week 24 Snapshot analysis window. The criteria for resistance tested was participant who had virologic failure or met the following criteria a) Participants who achieved viral suppression (plasma HIV-1 RNA < 50 c/mL) and have confirmed plasma HIV-1 RNA >= 400 c/mL at any time during the study. b) Participants who were discontinued before achieving viral suppression (plasma HIV-1 RNA < 50 c/mL) after Week 8 with last plasma HIV-1 RNA >=400 c/mL.	Up to Week 24
Secondary	Number of Participants With Newly-emergent Genotypic Substitutions at Week 48	Participants who administered ARV with VF were assessed. Genotypic substitution included assessment of RT substitution, PI substitution and Integrase RAL substitution as per IAS-USA list. ITT-E Resistance Tested through Week 48 population included participants who met the criteria for Resistance testing, and the confirmatory value or value at discontinuation occurred at or before the end of the Week 48 Snapshot analysis window. The criteria for resistance tested was participant who had virologic failure or the following criteria a) Participants who achieved viral suppression (plasma HIV-1 RNA < 50 c/mL) and have confirmed plasma HIV-1 RNA >= 400 c/mL at any time during the study. b) Participants who were discontinued before achieving viral suppression (plasma HIV-1 RNA < 50 c/mL) after Week 8 with last plasma HIV-1 RNA >=400 c/mL.	Up to Week 48
Secondary	Number of Participants With Newly-emergent Genotypic Substitutions at Week 96	Participants who administered ARV with VF were assessed. Genotypic substitution included assessment of RT substitution, PI substitution and Integrase RAL substitution as per IAS-USA list. ITT-E Resistance Tested through Week 96 population included participants who met the criteria for Resistance testing, and the confirmatory value or value at discontinuation occurred at or before the end of the Week 96 Snapshot analysis window. The criteria for resistance tested was participants with virologic failure or the following criteria a) Participants who achieved viral suppression (plasma HIV-1 RNA < 50 c/mL) and have confirmed plasma HIV-1 RNA >= 400 c/mL at any time during the study. b) Participants who were discontinued before achieving viral suppression (plasma HIV-1 RNA < 50 c/mL) after Week 8 with last plasma HIV-1 RNA >=400 c/mL.	Up to Week 96
Secondary	Maximum Change From Baseline in Inhibitory Concentration at 50% (IC50) Fold Change Among Participants With VF at Week 24	Virologic failure is defined clinically as confirmed plasma HIV-1 RNA >= 50 copies/mL at Week 24 or later or virologic rebound defined as confirmed HIV-1 RNA >=50 copies/mL at any time after prior confirmed suppression to <50 copies/mL OR confirmed >1 log10 copies/mL increase in HIV-1 RNA at any time above nadir level where nadir was >= 50 copies/mL . The phenotypic resistance to a drug is defined as a fold change (i.e, ratio of the IC50 of the clinical isolate to the IC50 of the reference strain) greater than the cut-off for reduced susceptibility. Maximum change from Baseline in Temsavir IC50 fold change based on all on-treatment values has been presented. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and those values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants available at the specified time points were analyzed.	Baseline and up to Week 24
Secondary	Change From Baseline in IC50 Fold Change Among Participants With VF at Week 48	Virologic failure is defined clinically as confirmed plasma HIV-1 RNA >= 50 copies/mL at Week 24 or later or later or virologic rebound defined as confirmed HIV-1 RNA >=50 copies/mL at any time after prior confirmed suppression to <50 copies/mL OR confirmed >1 log10 copies/mL increase in HIV-1 RNA at any time above nadir level where nadir was >= 50 copies/mL. The phenotypic resistance to a drug is defined as a fold change (i.e, ratio of the IC50 of the clinical isolate to the IC50 of the reference strain) greater than the cut-off for reduced susceptibility. Maximum change from Baseline in Temsavir IC50 fold change based on all on-treatment values has been presented. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and those values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants available at the specified time points were analyzed.	Baseline and up to Week 48
Secondary	Change From Baseline in IC50 Fold Change Among Participants With VF at Week 96	Virologic failure is defined clinically as confirmed plasma HIV-1 RNA >= 50 copies/mL at Week 24 or later or virologic rebound defined as confirmed HIV-1 RNA >=50 copies/mL at any time after prior confirmed suppression to <50 copies/mL OR confirmed >1 log10 copies/mL increase in HIV-1 RNA at any time above nadir level where nadir was >= 50 copies/mL. The phenotypic resistance to a drug is defined as a fold change (i.e, ratio of the IC50 of the clinical isolate to the IC50 of the reference strain) greater than the cut-off for reduced susceptibility. Maximum change from Baseline in Temsavir IC50 fold change based on all on-treatment values has been presented. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and those values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants available at the specified time points were analyzed.	Baseline and up to Week 96