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Atazanavir (BMS-232632) in Combination With Ritonavir or Saquinavir, and Lopinavir/Ritonavir, Each With Tenofovir and a Nucleoside in Subjects With HIV

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Atazanavir + ritonavir + tenofovir + nucleoside
Atazanavir + saquinavir + tenofovir + nucleoside
Lopinavir/ritonavir + tenofovir + nucleoside
Sponsored by
Bristol-Myers Squibb
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Virologic failure to 2 or more highly active antiretroviral therapy (HAART) regimens that, in total, have included at least one drug from all approved classes protease inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors (PI, NNRTI, NRTI): Currently on a failing HAART regimen with 2 qualifying plasma viral load measurements (hospital/clinic value within 4 weeks of screening with viral load equivalent to =>1,000 c/mL on the Roche Amplicor[TM] and central lab measurements of =>1,000 c/mL (Roche Amplicor[TM]) within 4 weeks of randomization Cluster of Differentiation 4 (CD4) cell count =>50 cells/mm3 obtained within 4 weeks prior to randomization =>16 years of age (or minimum age as determined by local regulations or as legal requirements dictate); History of prior virologic response to at least one HAART regimen, defined as a 1.0 log10 decline or a decline in viral load to <400 c/mL by Roche Amplicor or <500 c/mL by Chiron Quantiplex branched DNA (bDNA) assay Both females of child bearing potential and males must utilize effective barrier contraception to reduce transmission of sexually transmitted disease, including human immunodeficiency virus (HIV). Other contraception in addition to barrier methods is permitted; interaction between atazanavir and oral contraceptives has not been studied. Subjects must be able to provide written informed consent; Subjects should be available for follow-up for a period of at least 48 weeks Baseline laboratory values measured within 2 weeks prior to initiating study drugs as follows: serum creatine <1.5 times the upper limit of normal (ULN) total serum lipase <1.4 times the ULN liver enzymes alanine aminotransferase (AST), aspartate aminotransferase (ALT) <3 times the ULN total serum bilirubin <1.5 times the ULN Exclusion Criteria: Prior use (=>3 days) of atazanavir, TVF or LPV/RTV; if history of SQV, then must be phenotypically sensitive the current failing antiretroviral regimen must have been administered for at least eight weeks at he initiation of screening and must not include both a PI and NNRTI Presence of a newly diagnosed HIV-related opportunistic infection or any medical requiring acute therapy at the time of enrollment Proven or suspected acute hepatitis in the 30 days prior to study entry. Subjects with chronic hepatitis are eligible provided that their liver function enzymes (ALT/AST) are <3 x ULN Previous therapy with agents with significant systemic myelosuppressive, neurotoxic, pancreatoxic, hepatoxic or cytotoxic potential within 3 months of study start or the expected need for such therapy at the time of enrollment of therapy with methadone or ribavirin/interferons or treatment with neurotoxic drugs or drugs that affect Cytochrome P450 3A4 (CYP3A4). Active alcohol or substance use sufficient, in the Investigator's opinion, to prevent adequate compliance with study therapy or to increase the risk of developing pancreatitis or chemical hepatitis Intractable diarrhea (=> 6 loose stools/day for at least 7 days consecutive days) within 30 days prior to study entry Pregnancy or breast-feeding History of hemophilia Presence of cardiomyopathy Any one of the following: Heart rate-corrected QT (QTc) interval >450 msec on the screening electrocardiogram (EKG) Heart rate <40 beats per minute (bpm) Pause length >3 seconds seen on EKG Clinical symptoms potentially related to heart block Third degree heart block History of acute or chronic pancreatitis If choosing 2'-3' dideoxyinosine (ddI) or 2',3'-didehydro-3'-deoxythymidine (d4T) as the NRTI: History or signs and symptoms of bilateral peripheral neuropathy => Grade 2 at the time of screening Inability to tolerate oral medications Any other clinical conditions or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for study or unable to comply with the dosing requirements.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

I

II

III

Arm Description

ATV 300 mg + RTV 100 mg + TDF 300 mg + nucleoside of choice ATV , RTV, and TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study

ATV 400 mg + SQV 1200 mg + TDF 300 mg + nucleoside of choice ATV, SQV, and TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study

LPV/RTV 400/100 mg + TDF 300 mg + nucleoside of choice LPV/RTV twice daily, TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study

Outcomes

Primary Outcome Measures

Mean Change From Baseline in HIV Ribonucleic Acid (RNA) at Week 24
Mean Change From Baseline in HIV RNA at Week 48
Mean Change From Baseline in HIV RNA at Week 96

Secondary Outcome Measures

Mean Change From Baseline in HIV RNA at Week 2
Participants Achieving Virologic Half Log Suppression (Limit of Quantification [LOQ] = 400 c/mL) at Week 24 (Overall and by Protease Inhibitor [PI] Sensitivity)
Number of participants with a >=0.5 log10 decrease in HIV RNA from baseline or HIV RNA < 400 c/mL at Week 24, by their baseline phenotypic sensitivity to their randomized PI.
Participants Achieving Virologic Half Log Suppression (LOQ = 400 c/mL) at Week 48, (Overall and by PI Sensitivity)
Number of participants with a >=0.5 log10 decrease in HIV RNA from baseline or HIV RNA < 400 c/mL at Week 48, by their baseline phenotypic sensitivity to their randomized PI.
Participants Achieving Virologic Half Log Suppression (LOQ = 400 c/mL) at Week 96
Number of participants with a >=0.5 log10 decrease in HIV RNA from baseline or HIV RNA < 400 c/mL at Week 96.
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 24
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 24, by PI Sensitivity
Number of participants with a >=0.5 log10 decrease in HIV RNA from baseline or HIV RNA < 50 c/mL at Week 24, by their baseline phenotypic sensitivity to their randomized PI.
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 48
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 48, by PI Sensitivity
Number of participants with a >=0.5 log10 decrease in HIV RNA from baseline or HIV RNA < 50 c/mL at Week 48, by their baseline phenotypic sensitivity to their randomized PI.
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 96
Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 24
Treatment Response = confirmed suppression to LOQ (400 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 48
Treatment Response = confirmed suppression to LOQ (400 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 96
Treatment Response = confirmed suppression to LOQ (400 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 24
Treatment Response = confirmed suppression to LOQ (50 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 48
Treatment Response = confirmed suppression to LOQ (50 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 96
Treatment Response = confirmed suppression to LOQ (50 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Change From Baseline in CD4 Cell Count at Week 24
Change From Baseline in CD4 Cell Count at Week 48
Change From Baseline in CD4 Cell Count at Week 96
Correlation of ATV Minimum Plasma Concentration (Cmin), Inhibitory Quotient (IQ), and Number of Protease Inhibitor (PI) Mutations at Baseline With HIV RNA Change From Baseline at Week 24
Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with HIV RNA change from baseline at Week 24 were explored.
Correlation of ATV Minimum Plasma Concentration (Cmin), Inhibitory Quotient (IQ), and Number of Protease Inhibitor (PI) Mutations at Baseline With HIV RNA Change From Baseline at Week 48
Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with HIV RNA change from baseline at Week 48 were explored.
Correlation of ATV Minimum Plasma Concentration (Cmin) Inhibitory Quotient (IQ), and Number of PI Mutations at Baseline and CD4 Cell Count Change From Baseline at Week 24
Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with CD4 cell count change from baseline at Week 24 were explored.
Correlation of ATV Minimum Plasma Concentration (Cmin) Inhibitory Quotient (IQ), and Number of PI Mutations at Baseline and CD4 Cell Count Change From Baseline at Week 48
Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with CD4 cell count change from baseline at Week 48 were explored.
Lipid Mean Percent Change From Baseline at Week 24
Mean percent change in total cholesterol, high density lipoprotein (HDL) cholesterol, fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides.
Lipid Mean Percent Change From Baseline at Week 48
Mean percent change in total cholesterol, high density lipoprotein (HDL) cholesterol, fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides.
Lipid Mean Percent Change From Baseline at Week 96, Observed Values
Mean percent change in total cholesterol, high density lipoprotein (HDL) cholesterol, fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides.
Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) Through Week 48
AE=any new untoward medical occurrence/worsening of a pre-existing medical condition regardless of causal relationship. SAE=any untoward medical occurrence at any dose that: results in death; is life-threatening; requires/prolongs inpatient hospitalization; results in persistent/significant disability; is cancer; is congenital anomaly/birth defect; results in drug dependency/abuse; is an important medical event.
Most Common AEs and AEs of Interest Through Week 48
Prespecified AEs of interest included jaundice, ocular icterus, and hyperbilirubinemia.
Fasting Glucose Mean Change From Baseline at Week 24
Fasting Glucose Mean Change From Baseline at Week 48
Grade 3/4 Laboratory Abnormalities Through Week 48
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Grades:1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death. Abnormal values: absolute neutrophil count: ≥500 to <750/mm3 (grade 3), <500/mm3 (grade 4); platelets: 20,000-49,999/mm3 (grade 3), <20,000/mm3 or diffuse petechiae (grade 4); alanine transaminase (ALT): 5.1-10 x upper limit of normal (ULN; grade 3), >10 x ULN (grade 4); aspartate transaminase (AST): 5.1-10 x ULN (grade 3), >10 x ULN (grade 4); bilirubin: 2.6-5 x ULN (grade 3), >5 x ULN (grade 4).
Fridericia-corrected QT (QTcF) Interval and Change From Baseline by Analysis Time Point
The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QT interval was corrected for heart rate using Fridericia's (QTcF) formula.
PR Interval and Change From Baseline by Analysis Time Point
The PR interval is measured from the beginning of the P wave to the beginning of the QRS complex, and reflects the time the electrical impulse takes to travel from the sinus node through the atrioventricular (AV) node and entering the ventricles. The PR interval is therefore a good estimate of AV node function.
Adherence to Regimen Though Week 48 Based on MACS the Multicenter AIDS Cohort Study (MACS) Adherence Questionnaire
The MACS adherence questionnaire asks patients how many medication doses they missed during the previous day, 2 days, 3 days and 4 days. Drug-specific questions included adherence with dose and frequency. Adherence was defined as taking all doses and numbers of pills as prescribed for each medication. This strict adherence cut-off was based on the guidelines stating that anything less than excellent adherence may result in a virus breakthrough and development of resistance.
Mean Score of European Quality of Life-5 Dimensions (EQ-5D) Health Index Score at Baseline, Mid-Study (Week 24), and Final (Week 48)
The EQ-5D is a 5-item questionnaire to assess health-related quality of life in 5 health dimensions (mobility, self-care, usual activity, pain/discomfort, anxiety/depression) are scored on a 3-level scale: no problems (1), some problems (2), extreme problems (3). Using a standard algorithm, responses are summarized into a single score, the EQ-5D Health Index Score (HIS), which ranges between 1 (representing perfect health) and 0 (representing the worst imaginable health state or death). The smallest coefficient of change is 0.03.
Mean Score of European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) at Baseline, Mid-Study (Week 24), and Final (Week 48)
The EQ-5D has a Visual Analog Scale (VAS), which is a feeling thermometer-like scale with a range between 0 and 100. Patients are required to draw a line from a box on the VAS scale to an actual mark on the thermometer-like scale that corresponds with a number that reflects their self-assessed health status at the time they are completing the questionnaire. Higher VAS scores indicate better overall health. There is no minimum clinically important difference reported in the literature for VAS.
Number of Participants Utilizing Resources for Managing Lipid Elevation
Participants' overall resource utilization for managing lipid elevation that includes the management of side effects of lipid lowering medications, such as those due to drug interactions.
Mean ATV, RTV and SQV Minimum Concentration (Cmin) Values
The minimum or "trough" concentration (Cmin) of a drug observed after its administration and just prior to the administration of a subsequent dose.
HIV IC50 at Week 24
IC50: inhibitory concentration of drug required to reduce viral replication by 50%.
Inhibitory Quotient at Week 24
Inhibitory quotient is a measure of drug exposure and susceptibility in an individual. The IQ is typically calculated as the ratio of Cmin to HIV IC50.
Inhibitory Quotient at Week 48
Inhibitory quotient is a measure of drug exposure and susceptibility in an individual. The IQ is typically calculated as the ratio of Cmin to HIV IC50.
HIV RNA Level - Treated Subjects With Evaluable Cmins at Week 24
Week 24 HIV RNA level and change from baseline were summarized for treated subjects with evaluable Cmins.
HIV RNA Level - Treated Subjects With Evaluable Cmins at Week 48
Week 24 HIV RNA level and change from baseline were summarized for treated subjects with evaluable Cmins.

Full Information

First Posted
May 6, 2002
Last Updated
November 29, 2010
Sponsor
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT00035932
Brief Title
Atazanavir (BMS-232632) in Combination With Ritonavir or Saquinavir, and Lopinavir/Ritonavir, Each With Tenofovir and a Nucleoside in Subjects With HIV
Official Title
Phase III Open Label Atazanavir (BMS-232632) in Combination With Ritonavir or Saquinavir, and Lopinavir/Ritonavir, Each With Tenofovir and a Nucleoside in Subjects With HIV
Study Type
Interventional

2. Study Status

Record Verification Date
November 2010
Overall Recruitment Status
Completed
Study Start Date
November 2001 (undefined)
Primary Completion Date
July 2003 (Actual)
Study Completion Date
March 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to learn how well atazanavir (ATV) works in combination with ritonavir (RTV) or saquinavir (SQV) with tenofovir (TDF) and a nucleoside to reduce the viral load of treatment experienced subjects with human immunodeficiency virus (HIV). There is a comparison arm with lopinavir (LPV)/RTV and TDF and a nucleoside.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
571 (Actual)

8. Arms, Groups, and Interventions

Arm Title
I
Arm Type
Active Comparator
Arm Description
ATV 300 mg + RTV 100 mg + TDF 300 mg + nucleoside of choice ATV , RTV, and TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study
Arm Title
II
Arm Type
Active Comparator
Arm Description
ATV 400 mg + SQV 1200 mg + TDF 300 mg + nucleoside of choice ATV, SQV, and TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study
Arm Title
III
Arm Type
Active Comparator
Arm Description
LPV/RTV 400/100 mg + TDF 300 mg + nucleoside of choice LPV/RTV twice daily, TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study
Intervention Type
Drug
Intervention Name(s)
Atazanavir + ritonavir + tenofovir + nucleoside
Other Intervention Name(s)
BMS-232632, Reyataz
Intervention Description
Active Comparator, Capsules, tablets, Oral
Intervention Type
Drug
Intervention Name(s)
Atazanavir + saquinavir + tenofovir + nucleoside
Other Intervention Name(s)
BMS-232632, Reyataz
Intervention Description
Active Comparator, Capsules, tablets, Oral
Intervention Type
Drug
Intervention Name(s)
Lopinavir/ritonavir + tenofovir + nucleoside
Intervention Description
Active Comparator, Capsules, tablets, Oral
Primary Outcome Measure Information:
Title
Mean Change From Baseline in HIV Ribonucleic Acid (RNA) at Week 24
Time Frame
Baseline, Week 24
Title
Mean Change From Baseline in HIV RNA at Week 48
Time Frame
Baseline, Week 48
Title
Mean Change From Baseline in HIV RNA at Week 96
Time Frame
Baseline, Week 96
Secondary Outcome Measure Information:
Title
Mean Change From Baseline in HIV RNA at Week 2
Time Frame
Baseline, Week 2
Title
Participants Achieving Virologic Half Log Suppression (Limit of Quantification [LOQ] = 400 c/mL) at Week 24 (Overall and by Protease Inhibitor [PI] Sensitivity)
Description
Number of participants with a >=0.5 log10 decrease in HIV RNA from baseline or HIV RNA < 400 c/mL at Week 24, by their baseline phenotypic sensitivity to their randomized PI.
Time Frame
Baseline, Week 24
Title
Participants Achieving Virologic Half Log Suppression (LOQ = 400 c/mL) at Week 48, (Overall and by PI Sensitivity)
Description
Number of participants with a >=0.5 log10 decrease in HIV RNA from baseline or HIV RNA < 400 c/mL at Week 48, by their baseline phenotypic sensitivity to their randomized PI.
Time Frame
Baseline, Week 48
Title
Participants Achieving Virologic Half Log Suppression (LOQ = 400 c/mL) at Week 96
Description
Number of participants with a >=0.5 log10 decrease in HIV RNA from baseline or HIV RNA < 400 c/mL at Week 96.
Time Frame
Baseline, Week 96
Title
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 24
Time Frame
Week 24
Title
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 24, by PI Sensitivity
Description
Number of participants with a >=0.5 log10 decrease in HIV RNA from baseline or HIV RNA < 50 c/mL at Week 24, by their baseline phenotypic sensitivity to their randomized PI.
Time Frame
Baseline, Week 24
Title
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 48
Time Frame
Week 48
Title
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 48, by PI Sensitivity
Description
Number of participants with a >=0.5 log10 decrease in HIV RNA from baseline or HIV RNA < 50 c/mL at Week 48, by their baseline phenotypic sensitivity to their randomized PI.
Time Frame
Baseline, Week 48
Title
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 96
Time Frame
Week 96
Title
Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 24
Description
Treatment Response = confirmed suppression to LOQ (400 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Time Frame
Week 24
Title
Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 48
Description
Treatment Response = confirmed suppression to LOQ (400 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Time Frame
Week 48
Title
Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 96
Description
Treatment Response = confirmed suppression to LOQ (400 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Time Frame
Week 96
Title
Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 24
Description
Treatment Response = confirmed suppression to LOQ (50 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Time Frame
Week 24
Title
Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 48
Description
Treatment Response = confirmed suppression to LOQ (50 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Time Frame
Week 48
Title
Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 96
Description
Treatment Response = confirmed suppression to LOQ (50 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Time Frame
Week 96
Title
Change From Baseline in CD4 Cell Count at Week 24
Time Frame
Baseline, Week 24
Title
Change From Baseline in CD4 Cell Count at Week 48
Time Frame
Baseline, Week 48
Title
Change From Baseline in CD4 Cell Count at Week 96
Time Frame
Baseline, Week 96
Title
Correlation of ATV Minimum Plasma Concentration (Cmin), Inhibitory Quotient (IQ), and Number of Protease Inhibitor (PI) Mutations at Baseline With HIV RNA Change From Baseline at Week 24
Description
Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with HIV RNA change from baseline at Week 24 were explored.
Time Frame
Baseline, Week 24
Title
Correlation of ATV Minimum Plasma Concentration (Cmin), Inhibitory Quotient (IQ), and Number of Protease Inhibitor (PI) Mutations at Baseline With HIV RNA Change From Baseline at Week 48
Description
Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with HIV RNA change from baseline at Week 48 were explored.
Time Frame
Baseline, Week 48
Title
Correlation of ATV Minimum Plasma Concentration (Cmin) Inhibitory Quotient (IQ), and Number of PI Mutations at Baseline and CD4 Cell Count Change From Baseline at Week 24
Description
Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with CD4 cell count change from baseline at Week 24 were explored.
Time Frame
Baseline, Week 24
Title
Correlation of ATV Minimum Plasma Concentration (Cmin) Inhibitory Quotient (IQ), and Number of PI Mutations at Baseline and CD4 Cell Count Change From Baseline at Week 48
Description
Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with CD4 cell count change from baseline at Week 48 were explored.
Time Frame
Baseline, Week 48
Title
Lipid Mean Percent Change From Baseline at Week 24
Description
Mean percent change in total cholesterol, high density lipoprotein (HDL) cholesterol, fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides.
Time Frame
Baseline, Week 24
Title
Lipid Mean Percent Change From Baseline at Week 48
Description
Mean percent change in total cholesterol, high density lipoprotein (HDL) cholesterol, fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides.
Time Frame
Week 48
Title
Lipid Mean Percent Change From Baseline at Week 96, Observed Values
Description
Mean percent change in total cholesterol, high density lipoprotein (HDL) cholesterol, fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides.
Time Frame
Week 96
Title
Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) Through Week 48
Description
AE=any new untoward medical occurrence/worsening of a pre-existing medical condition regardless of causal relationship. SAE=any untoward medical occurrence at any dose that: results in death; is life-threatening; requires/prolongs inpatient hospitalization; results in persistent/significant disability; is cancer; is congenital anomaly/birth defect; results in drug dependency/abuse; is an important medical event.
Time Frame
From Enrollment through Week 48
Title
Most Common AEs and AEs of Interest Through Week 48
Description
Prespecified AEs of interest included jaundice, ocular icterus, and hyperbilirubinemia.
Time Frame
From Enrollment to Week 48
Title
Fasting Glucose Mean Change From Baseline at Week 24
Time Frame
Baseline, Week 24
Title
Fasting Glucose Mean Change From Baseline at Week 48
Time Frame
Week 48
Title
Grade 3/4 Laboratory Abnormalities Through Week 48
Description
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Grades:1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death. Abnormal values: absolute neutrophil count: ≥500 to <750/mm3 (grade 3), <500/mm3 (grade 4); platelets: 20,000-49,999/mm3 (grade 3), <20,000/mm3 or diffuse petechiae (grade 4); alanine transaminase (ALT): 5.1-10 x upper limit of normal (ULN; grade 3), >10 x ULN (grade 4); aspartate transaminase (AST): 5.1-10 x ULN (grade 3), >10 x ULN (grade 4); bilirubin: 2.6-5 x ULN (grade 3), >5 x ULN (grade 4).
Time Frame
From Enrollment to Week 48
Title
Fridericia-corrected QT (QTcF) Interval and Change From Baseline by Analysis Time Point
Description
The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QT interval was corrected for heart rate using Fridericia's (QTcF) formula.
Time Frame
Baseline, Week 4 predose, 2-3 hours postdose, 6-12 hours postdose, Week 12, Week 24, Week 48
Title
PR Interval and Change From Baseline by Analysis Time Point
Description
The PR interval is measured from the beginning of the P wave to the beginning of the QRS complex, and reflects the time the electrical impulse takes to travel from the sinus node through the atrioventricular (AV) node and entering the ventricles. The PR interval is therefore a good estimate of AV node function.
Time Frame
Baseline, Week 4 predose, 2-3 hours postdose, 6-12 hours postdose, Week 12, Week 24, Week 48
Title
Adherence to Regimen Though Week 48 Based on MACS the Multicenter AIDS Cohort Study (MACS) Adherence Questionnaire
Description
The MACS adherence questionnaire asks patients how many medication doses they missed during the previous day, 2 days, 3 days and 4 days. Drug-specific questions included adherence with dose and frequency. Adherence was defined as taking all doses and numbers of pills as prescribed for each medication. This strict adherence cut-off was based on the guidelines stating that anything less than excellent adherence may result in a virus breakthrough and development of resistance.
Time Frame
Baseline, Week 24, Week 48
Title
Mean Score of European Quality of Life-5 Dimensions (EQ-5D) Health Index Score at Baseline, Mid-Study (Week 24), and Final (Week 48)
Description
The EQ-5D is a 5-item questionnaire to assess health-related quality of life in 5 health dimensions (mobility, self-care, usual activity, pain/discomfort, anxiety/depression) are scored on a 3-level scale: no problems (1), some problems (2), extreme problems (3). Using a standard algorithm, responses are summarized into a single score, the EQ-5D Health Index Score (HIS), which ranges between 1 (representing perfect health) and 0 (representing the worst imaginable health state or death). The smallest coefficient of change is 0.03.
Time Frame
Baseline, Week 24, Week 48
Title
Mean Score of European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) at Baseline, Mid-Study (Week 24), and Final (Week 48)
Description
The EQ-5D has a Visual Analog Scale (VAS), which is a feeling thermometer-like scale with a range between 0 and 100. Patients are required to draw a line from a box on the VAS scale to an actual mark on the thermometer-like scale that corresponds with a number that reflects their self-assessed health status at the time they are completing the questionnaire. Higher VAS scores indicate better overall health. There is no minimum clinically important difference reported in the literature for VAS.
Time Frame
Baseline, Week 24, Week 48
Title
Number of Participants Utilizing Resources for Managing Lipid Elevation
Description
Participants' overall resource utilization for managing lipid elevation that includes the management of side effects of lipid lowering medications, such as those due to drug interactions.
Time Frame
Baseline, Week 24, Week 48
Title
Mean ATV, RTV and SQV Minimum Concentration (Cmin) Values
Description
The minimum or "trough" concentration (Cmin) of a drug observed after its administration and just prior to the administration of a subsequent dose.
Time Frame
collected at the pre-dose time point after receiving atazanavir for at least four weeks
Title
HIV IC50 at Week 24
Description
IC50: inhibitory concentration of drug required to reduce viral replication by 50%.
Time Frame
Week 24
Title
Inhibitory Quotient at Week 24
Description
Inhibitory quotient is a measure of drug exposure and susceptibility in an individual. The IQ is typically calculated as the ratio of Cmin to HIV IC50.
Time Frame
Baseline, Week 24
Title
Inhibitory Quotient at Week 48
Description
Inhibitory quotient is a measure of drug exposure and susceptibility in an individual. The IQ is typically calculated as the ratio of Cmin to HIV IC50.
Time Frame
Baseline, Week 48
Title
HIV RNA Level - Treated Subjects With Evaluable Cmins at Week 24
Description
Week 24 HIV RNA level and change from baseline were summarized for treated subjects with evaluable Cmins.
Time Frame
Baseline, Week 24
Title
HIV RNA Level - Treated Subjects With Evaluable Cmins at Week 48
Description
Week 24 HIV RNA level and change from baseline were summarized for treated subjects with evaluable Cmins.
Time Frame
Baseline, Week 48

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Virologic failure to 2 or more highly active antiretroviral therapy (HAART) regimens that, in total, have included at least one drug from all approved classes protease inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors (PI, NNRTI, NRTI): Currently on a failing HAART regimen with 2 qualifying plasma viral load measurements (hospital/clinic value within 4 weeks of screening with viral load equivalent to =>1,000 c/mL on the Roche Amplicor[TM] and central lab measurements of =>1,000 c/mL (Roche Amplicor[TM]) within 4 weeks of randomization Cluster of Differentiation 4 (CD4) cell count =>50 cells/mm3 obtained within 4 weeks prior to randomization =>16 years of age (or minimum age as determined by local regulations or as legal requirements dictate); History of prior virologic response to at least one HAART regimen, defined as a 1.0 log10 decline or a decline in viral load to <400 c/mL by Roche Amplicor or <500 c/mL by Chiron Quantiplex branched DNA (bDNA) assay Both females of child bearing potential and males must utilize effective barrier contraception to reduce transmission of sexually transmitted disease, including human immunodeficiency virus (HIV). Other contraception in addition to barrier methods is permitted; interaction between atazanavir and oral contraceptives has not been studied. Subjects must be able to provide written informed consent; Subjects should be available for follow-up for a period of at least 48 weeks Baseline laboratory values measured within 2 weeks prior to initiating study drugs as follows: serum creatine <1.5 times the upper limit of normal (ULN) total serum lipase <1.4 times the ULN liver enzymes alanine aminotransferase (AST), aspartate aminotransferase (ALT) <3 times the ULN total serum bilirubin <1.5 times the ULN Exclusion Criteria: Prior use (=>3 days) of atazanavir, TVF or LPV/RTV; if history of SQV, then must be phenotypically sensitive the current failing antiretroviral regimen must have been administered for at least eight weeks at he initiation of screening and must not include both a PI and NNRTI Presence of a newly diagnosed HIV-related opportunistic infection or any medical requiring acute therapy at the time of enrollment Proven or suspected acute hepatitis in the 30 days prior to study entry. Subjects with chronic hepatitis are eligible provided that their liver function enzymes (ALT/AST) are <3 x ULN Previous therapy with agents with significant systemic myelosuppressive, neurotoxic, pancreatoxic, hepatoxic or cytotoxic potential within 3 months of study start or the expected need for such therapy at the time of enrollment of therapy with methadone or ribavirin/interferons or treatment with neurotoxic drugs or drugs that affect Cytochrome P450 3A4 (CYP3A4). Active alcohol or substance use sufficient, in the Investigator's opinion, to prevent adequate compliance with study therapy or to increase the risk of developing pancreatitis or chemical hepatitis Intractable diarrhea (=> 6 loose stools/day for at least 7 days consecutive days) within 30 days prior to study entry Pregnancy or breast-feeding History of hemophilia Presence of cardiomyopathy Any one of the following: Heart rate-corrected QT (QTc) interval >450 msec on the screening electrocardiogram (EKG) Heart rate <40 beats per minute (bpm) Pause length >3 seconds seen on EKG Clinical symptoms potentially related to heart block Third degree heart block History of acute or chronic pancreatitis If choosing 2'-3' dideoxyinosine (ddI) or 2',3'-didehydro-3'-deoxythymidine (d4T) as the NRTI: History or signs and symptoms of bilateral peripheral neuropathy => Grade 2 at the time of screening Inability to tolerate oral medications Any other clinical conditions or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for study or unable to comply with the dosing requirements.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
City
San Francisco
State/Province
California
ZIP/Postal Code
94121
Country
United States
City
Torrance
State/Province
California
ZIP/Postal Code
90502
Country
United States
City
Boulder
State/Province
Colorado
ZIP/Postal Code
80304
Country
United States
City
Altamonte Springs
State/Province
Florida
Country
United States
City
Ft Lauderdale
State/Province
Florida
ZIP/Postal Code
33306
Country
United States
City
Ft Lauderdale
State/Province
Florida
ZIP/Postal Code
33308
Country
United States
City
Miami Beach
State/Province
Florida
ZIP/Postal Code
33160
Country
United States
City
Orlando
State/Province
Florida
ZIP/Postal Code
32801
Country
United States
City
Decatur
State/Province
Georgia
Country
United States
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96816
Country
United States
City
Boise
State/Province
Indiana
Country
United States
City
Wichita
State/Province
Kansas
ZIP/Postal Code
67214
Country
United States
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
City
New Orleans
State/Province
Louisiana
Country
United States
City
Brookline
State/Province
Massachusetts
Country
United States
City
Fall River
State/Province
Massachusetts
ZIP/Postal Code
02720
Country
United States
City
East Orange
State/Province
New Jersey
Country
United States
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07103
Country
United States
City
Buffalo
State/Province
New York
ZIP/Postal Code
14215
Country
United States
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10019
Country
United States
City
Rochester
State/Province
New York
ZIP/Postal Code
14620
Country
United States
City
Huntersville
State/Province
North Carolina
ZIP/Postal Code
28078
Country
United States
City
Winston Salem
State/Province
North Carolina
ZIP/Postal Code
29203
Country
United States
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
City
Akron
State/Province
Ohio
Country
United States
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
City
Dallas
State/Province
Texas
Country
United States
City
Houston
State/Province
Texas
ZIP/Postal Code
77006
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Atazanavir (BMS-232632) in Combination With Ritonavir or Saquinavir, and Lopinavir/Ritonavir, Each With Tenofovir and a Nucleoside in Subjects With HIV

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