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

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

Official Title
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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

Conditions
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Infection, Human Immunodeficiency Virus

Intervention / Treatment
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* Drug: BMS-663068 400 mg
* Drug: BMS-663068 800 mg
* Drug: BMS-663068 600 mg
* Drug: BMS-663068 1200 mg
* Drug: Raltegravir 400 mg
* Drug: Tenofovir 300 mg
* Drug: Ritonavir 100 mg
* Drug: Atazanavir 300 mg


Participation Criteria
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Eligibility Criteria
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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

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: BMS-663068 (400mg) + Raltegravir + Tenofovir<br>Treatment Group 1 | Drug: BMS-663068 400 mg<br>* Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>Drug: Raltegravir 400 mg<br>* Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>Drug: Tenofovir 300 mg<br>* Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>|
| Experimental: Arm B: BMS-663068 (800 mg) + Raltegravir + Tenofovir<br>Treatment Group 2 | Drug: BMS-663068 800 mg<br>* Tablets, Oral, 800 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>Drug: Raltegravir 400 mg<br>* Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>Drug: Tenofovir 300 mg<br>* Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>|
| Experimental: Arm C: BMS-663068 (600 mg) + Raltegravir + Tenofovir<br>Treatment Group 3 | Drug: BMS-663068 600 mg<br>* Tablets, Oral, 600 mg, once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>Drug: Raltegravir 400 mg<br>* Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>Drug: Tenofovir 300 mg<br>* Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>|
| Experimental: Arm D: BMS-663068 (1200 mg) + Raltegravir + Tenofovir<br>Treatment Group 4 | Drug: BMS-663068 1200 mg<br>* Tablets, Oral, 1200 mg, once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>Drug: Raltegravir 400 mg<br>* Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>Drug: Tenofovir 300 mg<br>* Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>|
| Active Comparator: Arm E: Atazanavir + Ritonavir + Raltegravir + Tenofovir<br>Treatment Group 1 (reference arm) | Drug: Raltegravir 400 mg<br>* Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>Drug: Tenofovir 300 mg<br>* Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose<br>Drug: Ritonavir 100 mg<br>* Tablets, Oral, 100 mg, Once daily, 96 weeks<br>Drug: Atazanavir 300 mg<br>* Capsules, Oral, 300 mg, Once daily, 96 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 |