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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Atazanavir + ritonavir + tenofovir + nucleoside
* Drug: Atazanavir + saquinavir + tenofovir + nucleoside
* Drug: Lopinavir/ritonavir + tenofovir + nucleoside


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: I<br>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 | Drug: Atazanavir + ritonavir + tenofovir + nucleoside<br>* Active Comparator, Capsules, tablets, Oral<br>* Other names: Reyataz;|
| Active Comparator: II<br>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 | Drug: Atazanavir + saquinavir + tenofovir + nucleoside<br>* Active Comparator, Capsules, tablets, Oral<br>* Other names: Reyataz;|
| Active Comparator: III<br>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 | Drug: Lopinavir/ritonavir + tenofovir + nucleoside<br>* Active Comparator, Capsules, tablets, Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in HIV Ribonucleic Acid (RNA) at Week 24 |  | Baseline, Week 24 | 
| Mean Change From Baseline in HIV RNA at Week 48 |  | Baseline, Week 48 | 
| Mean Change From Baseline in HIV RNA at Week 96 |  | Baseline, Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in HIV RNA at Week 2 |  | Baseline, 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. | Baseline, Week 24 | 
| 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. | Baseline, Week 48 | 
| 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. | Baseline, Week 96 | 
| Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 24 |  | 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. | Baseline, Week 24 | 
| Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 48 |  | 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. | Baseline, Week 48 | 
| Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 96 |  | 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. | Week 24 | 
| 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. | Week 48 | 
| 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. | Week 96 | 
| 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. | Week 24 | 
| 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. | Week 48 | 
| 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. | Week 96 | 
| Change From Baseline in CD4 Cell Count at Week 24 |  | Baseline, Week 24 | 
| Change From Baseline in CD4 Cell Count at Week 48 |  | Baseline, Week 48 | 
| Change From Baseline in CD4 Cell Count at Week 96 |  | Baseline, 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. | Baseline, Week 24 | 
| 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. | Baseline, Week 48 | 
| 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. | Baseline, Week 24 | 
| 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. | Baseline, Week 48 | 
| 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. | Baseline, Week 24 | 
| 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. | Week 48 | 
| 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. | Week 96 | 
| 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. | From Enrollment through Week 48 | 
| Most Common AEs and AEs of Interest Through Week 48 | Prespecified AEs of interest included jaundice, ocular icterus, and hyperbilirubinemia. | From Enrollment to Week 48 | 
| Fasting Glucose Mean Change From Baseline at Week 24 |  | Baseline, Week 24 | 
| Fasting Glucose Mean Change From Baseline at Week 48 |  | 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). | From Enrollment to Week 48 | 
| 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. | Baseline, Week 4 predose, 2-3 hours postdose, 6-12 hours postdose, Week 12, Week 24, Week 48 | 
| 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. | Baseline, Week 4 predose, 2-3 hours postdose, 6-12 hours postdose, Week 12, Week 24, Week 48 | 
| 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. | Baseline, Week 24, Week 48 | 
| 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. | Baseline, Week 24, Week 48 | 
| 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. | Baseline, Week 24, Week 48 | 
| 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. | Baseline, Week 24, Week 48 | 
| 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. | collected at the pre-dose time point after receiving atazanavir for at least four weeks | 
| HIV IC50 at Week 24 | IC50: inhibitory concentration of drug required to reduce viral replication by 50%. | Week 24 | 
| 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. | Baseline, Week 24 | 
| 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. | Baseline, Week 48 | 
| 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. | Baseline, Week 24 | 
| 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. | Baseline, Week 48 |