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

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ClinicalTrials.gov Identifier: NCT01384734
Recruitment Status : Completed
First Posted : June 29, 2011
Results First Posted : November 14, 2018
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
ViiV Healthcare

Brief 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.

Condition or disease Intervention/treatment Phase
Infection, Human Immunodeficiency Virus 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 Phase 2

Detailed 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)


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 254 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : July 26, 2011
Actual Primary Completion Date : February 18, 2013
Actual Study Completion Date : May 12, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Arm A: BMS-663068 (400mg) + Raltegravir + Tenofovir
Treatment Group 1
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

Drug: Raltegravir 400 mg
Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Drug: Tenofovir 300 mg
Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Experimental: Arm B: BMS-663068 (800 mg) + Raltegravir + Tenofovir
Treatment Group 2
Drug: BMS-663068 800 mg
Tablets, Oral, 800 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Drug: Raltegravir 400 mg
Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Drug: Tenofovir 300 mg
Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Experimental: Arm C: BMS-663068 (600 mg) + Raltegravir + Tenofovir
Treatment Group 3
Drug: BMS-663068 600 mg
Tablets, Oral, 600 mg, once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Drug: Raltegravir 400 mg
Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Drug: Tenofovir 300 mg
Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Experimental: Arm D: BMS-663068 (1200 mg) + Raltegravir + Tenofovir
Treatment Group 4
Drug: BMS-663068 1200 mg
Tablets, Oral, 1200 mg, once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Drug: Raltegravir 400 mg
Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Drug: Tenofovir 300 mg
Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Active Comparator: Arm E: Atazanavir + Ritonavir + Raltegravir + Tenofovir
Treatment Group 1 (reference arm)
Drug: Raltegravir 400 mg
Tablets, Oral, 400 mg, twice daily (BID), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Drug: Tenofovir 300 mg
Tablets, Oral, 300 mg, Once daily (QD), 24+ weeks until optimal dose is selected, or 96 weeks if optimal dose

Drug: Ritonavir 100 mg
Tablets, Oral, 100 mg, Once daily, 96 weeks

Drug: Atazanavir 300 mg
Capsules, Oral, 300 mg, Once daily, 96 weeks




Primary Outcome Measures :
  1. Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) < 50 Copies Per Milliliter (c/mL) at Week 24 [ Time Frame: 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.

  2. Number of Participants With Serious Adverse Events (SAE) and Discontinuation Due to AEs up to Week 24 [ Time Frame: 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.


Secondary Outcome Measures :
  1. Change From Monotherapy Baseline in log10 HIV RNA of the Monotherapy Period [ Time Frame: Baseline and up to Day 8 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).

  2. Maximum Decrease From Monotherapy Baseline in log10 Plasma HIV-1 RNA [ Time Frame: Baseline and up to Day 8 of the monotherapy period ]
    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.

  3. Percentage of Participants With Plasma HIV-1 RNA < 50 c/mL at Day 8 of the Monotherapy Period [ Time Frame: Up to 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.

  4. Number of Participants With SAE and Discontinuation Due to AEs During Monotherapy Period [ Time Frame: Up to Day 8 of the 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.

  5. Change From Monotherapy Baseline in Cluster of Differentiation (CD)4+ and CD8+ T-cell Counts During Monotherapy [ Time Frame: Baseline and Day 8 ]
    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.

  6. Change From Monotherapy Baseline in CD4+ and CD8+ T-cell Proportion During Monotherapy [ Time Frame: Baseline and Day 8 ]
    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.

  7. Percentage of Participants With Plasma HIV-1 RNA < 50 c/mL at Primary Study [ Time Frame: Weeks 48 and 96 ]
    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.

  8. Number of Participants With SAE and Discontinuation Due to AEs During Primary Study [ Time Frame: Weeks 48 and 96 ]
    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.

  9. Change From Baseline in CD4+ T-cell Count [ Time Frame: Baseline and Weeks 24, 48 and 96 ]
    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).

  10. Number of Participants With Newly-emergent Genotypic Substitutions at Week 24 [ Time Frame: Up to 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.

  11. Number of Participants With Newly-emergent Genotypic Substitutions at Week 48 [ Time Frame: Up to 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.

  12. Number of Participants With Newly-emergent Genotypic Substitutions at Week 96 [ Time Frame: Up to 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.

  13. Maximum Change From Baseline in Inhibitory Concentration at 50% (IC50) Fold Change Among Participants With VF at Week 24 [ Time Frame: Baseline and up to 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.

  14. Change From Baseline in IC50 Fold Change Among Participants With VF at Week 48 [ Time Frame: Baseline and up to 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.

  15. Change From Baseline in IC50 Fold Change Among Participants With VF at Week 96 [ Time Frame: Baseline and up to 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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

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): NCT01384734


  Show 56 Study Locations
Sponsors and Collaborators
ViiV Healthcare
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT01384734     History of Changes
Other Study ID Numbers: 205889
AI438-011 ( Other Identifier: Bristol-Myers Squibb )
First Posted: June 29, 2011    Key Record Dates
Results First Posted: November 14, 2018
Last Update Posted: November 14, 2018
Last Verified: August 2018

Additional relevant MeSH terms:
Infection
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
Ritonavir
Atazanavir Sulfate
Tenofovir
Raltegravir Potassium
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
HIV Integrase Inhibitors
Integrase Inhibitors