Phase IIB Pilot of Atazanavir + Raltegravir

Study Overview
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Brief Summary
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The purpose of this study is to determine if the combination of atazanavir and raltegravir taken together is safe and effective in the treatment of human immunodeficiency virus (HIV).

Official Title
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A Multicenter, Randomized, Open-Label, Active-Controlled Pilot Study to Evaluate the Safety and Antiretroviral Activity of Unboosted Atazanavir BID Plus Raltegravir BID and Boosted Atazanavir QD in Combination With Tenofovir/Emtricitabine QD in Treatment Naive HIV-Infected Subjects

Conditions
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HIV

Intervention / Treatment
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* Drug: Atazanavir
* Drug: Raltegravir
* Drug: Atazanavir
* Drug: Ritonavir
* Drug: Tenofovir/Emtricitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Human Immunodeficiency Virus (HIV)-1 positive status HIV ribonucleic acid (RNA) level >=5000 copies/mL Antiretroviral treatment-naive Absolute Cluster of Differentiation 4 (CD4) cell count meeting 1 of the following criteria: <350 cells/mm^3 Screening CD4 >=350 and <=500 cells/mm^3 ONLY if at least 1 of the following conditions apply: Screening HIV RNA level >100,000 copies/mL, or CD4 decline >50-100 cells/mm^3/year, or Age >=55 years Any CD4 cell count, if participant has a history of an acquired immune deficiency syndrome-defining illness Medically stable Exclusion Criteria: Screening HIV genotype showing resistance to any component of the study regimen (Atazanavir, Raltegravir, Tenofovir/Emtricitabine) Hepatitis B or hepatitis C coinfection History of or current cardiac disease Electrocardiogram findings: PR Interval >260 msec (severe 1st degree atrioventricular block) QRS Interval >120 msec

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atazanavir + Raltegravir<br>Atazanavir 300 mg twice daily + Raltegravir 400 mg twice daily | Drug: Atazanavir<br>* Capsules, Oral, 300 mg, twice daily, 96 weeks<br>* Other names: BMS-232632;Drug: Raltegravir<br>* Tablet, Oral, 400 mg, twice daily, 96 weeks<br>|
| Active Comparator: Atazanavir + Ritonavir + Tenofovir /Emtricitabine<br>Atazanavir, 300 mg once daily, + Ritonavir, 100 mg once daily, + Tenofovir 300 mg/Emtricitabine, 200 mg once daily | Drug: Atazanavir<br>* Capsules, Oral, 300 mg, once daily, 96 weeks<br>* Other names: BMS-232632;Drug: Ritonavir<br>* Capsules, Oral, 100 mg, once daily, 96 weeks<br>Drug: Tenofovir/Emtricitabine<br>* Tablet, Oral, 300-mg Tenofovir/200-mg Emtricitabine, once daily, 96 weeks<br>* Other names: Truvada;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) Level <50 Copies/mL at Week 24 | The number of HIV 1-infected treatment-naive participants with an HIV RNA level <50 copies/mL after 24 weeks of treatment. Confirmed virologic response noncompleter=failure (NC=F); noncompleter=missing (NC=M); virologic response-observed cases (VR-OC). | At Week 24 from Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Nonresponders at Week 8 | Participants were classified as nonresponders if they had an HIV RNA level ≥400 copies/mL and a decrease from baseline <2 log10 copies/mL. | At Week 8 from Baseline | 
| Number of Participants With HIV RNA Levels <50 Copies/mL at Weeks 48 and 96 | Participant HIV RNA level was determined at Weeks 48 and 96 using the Roche Amplicor® Ultrasensitive Assay Version 1. VR-OC=Virologic response-observed cases. | At Weeks 48 and 96 from Baseline | 
| Number of Participants With HIV RNA Levels <400 Copies/mL at Week 24 | NC=F: noncompleter=failure; NC=M: noncompleter=missing; VR-OC: virologic response-observed | At Week 24 from Baseline | 
| Number of Participants With HIV RNA Levels <400 Copies/mL at Week 48 |  | At Week 48 from Baseline | 
| Number of Participants With HIV RNA Levels <400 Copies/mL at Week 96 |  | At Week 96 from Baseline | 
| Mean Change From Baseline in Absolute Cluster of Differentiation 4 Cell Count |  | From Baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Death as Outcome, AEs Leading to Discontinuation, SAEs Leading to Discontinuation | AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in drug dependency or drug abuse, or is an important medical event. | Week 1 to Week 96, continuously | 
| Baseline and Mean Change From Baseline in Total Cholesterol Levels | The mean change from baseline in participant fasting lipids was determined using fasting serum samples. | From Baseline to Week 24 and Week 48 | 
| Mean Change From Baseline in Total Bilirubin Level |  | From Baseline to Week 24 and Week 48 | 
| Mean Change From Baseline in Electrocardiogram Findings | The incidence of QRS wave widening and QT and PR prolongation on participant electrocardiogram findings were evaluated at study Week 24. | From Baseline to Week 24 | 
| Atazanavir Maximum Observed Plasma Concentration (Cmax) in 1 Dosing Interval | Serial blood samples were collected over a 12-hour period after the morning dose at Week 2. | At Week 2 from Baseline | 
| Raltegravir Cmax in 1 Dosing Interval | Serial blood samples were collected over a 12-hour period after the morning dose at Week 2. | At Week 2 from Baseline | 
| Atazanavir Time of Maximum Observed Plasma Concentration (Tmax) | Serial blood samples were collected over a 12-hour period after the morning dose at Week 2. | At Week 2 from Baseline | 
| Raltegravir Tmax | Serial blood samples were collected over a 12-hour period after the morning dose at Week 2. | At Week 2 from Baseline | 
| Atazanavir Trough Plasma Concentration (Cmin) 12 Hours Postdose |  | At Week 2 from Baseline | 
| Raltegravir Cmin 12 Hours Postdose |  | At Week 2 from Baseline | 
| Atazanavir Cmin Prior to the Morning Dose |  | At Week 2 from Baseline | 
| Raltegravir Cmin Prior to the Morning Dose |  | At Week 2 from Baseline | 
| Atazanavir Area Under the Concentration Curve From Time 0 to 12 Hours (AUC [0-12h]) in 1 Dosing Interval |  | At Week 2 from Baseline | 
| Raltegravir AUC (0-12h) in 1 Dosing Interval |  | At Week 2 from Baseline | 
| Atazanavir Area Under the Concentration Curve From Time 0 to 24 Hours (AUC [0-24h]) in 1 Dosing Interval | AUC (0-24h) was estimated by multiplying AUC (0-12h) by 2. | At Week 2 from Baseline | 
| Atazanavir Individual Inhibitory Quotient (IQ) | Individual IQ was defined at Cmin at Week 2 divided by the protein binding adjusted EC90 (ie, the drug concentration observed to inhibit virion production by 90% in a cell-based assay) values for Atazanavir that were derived from individual participant clinical isolates. | At Week 2 from Baseline | 
| Atazanavir Terminal Elimination Half Life |  | At Week 2 from Baseline | 
| Raltegravir Terminal Elimination Half Life |  | At Week 2 from Baseline | 
| Number of Participants With Hematology Laboratory Test Results With Worst Toxicity of Grades 1 to 4 Among All Treated Participants | ULN=upper limit of normal. Hematocrit(%) Grade (Gr) 1: ≥28.5-<31; Gr 2: ≥24-<28.5; Gr 3: ≥19.5-<24; Gr 4: <19.5. Hemoglobin (g/dL) Gr 1: 9.5-11; Gr 2: 8-9.4; Gr 3: 6.5-7.9; Gr 4: <6.5. Platelets (/mm^3) Gr 1: 75,000-99,000; Gr 2: 50,000-74,999; Gr 3: 20,000-49,999; Gr 4: <20,000. White Blood Cells (/mm^3) Gr 1: >2500-4000; Gr 2: >1000-<2500; Gr 3: >800-<1000; Gr 4: <800. . Prothrombin time (seconds) Gr 1: 1.01-1.25*ULN; Gr 2: 1.26-1.5*ULN; Gr 3: 1.51-3*ULN; Gr 4: >3*ULN. | While on treatment from Baseline through Week 96 | 
| Number of Participants With Blood Chemistry Laboratory Test Results With Worst Toxicity of Grades 1 to 4 | Blood urea nitrogen Gr 1:1.25-2.5*ULN;Gr 2:2.6-5.0*ULN; Gr 3:5.1-10*ULN; Gr 4:>10*ULN. Creatinine (mg/dL) Gr 1: 1.1-1.5 *ULN; Gr 2: 1.6-3*ULN: Gr 3: 3.1-6*ULN; Gr 4: >6*ULN. Hypercarbia (meq/L)Gr 1: 33-36; Gr 2:37-40; Gr 3: 41-45; Gr 4:>45. Hypocarbia (meq/L)Gr 1:19-21; Gr 2: 15-18; Gr 3: 10-14; Gr 4:<10. Hypercalcemia (mg/dL)Gr 1:10.6-11.5;Gr 2:11.6-12.5; Gr 3:12.6-13.5;Gr 4: >13.5. Hypocalcemia (mg/dL)Gr 1: 8.4-7.8;Gr 2:7.7-7; Gr 3:6.9-6.1; Gr 4: <6.1.Hyperchloremia(meq/L)Gr 1:113-116; Gr 2:117-120; Gr 3:121-125; Gr 4: >125.Hypochloremia(meq/L)Gr 1: 90-93; Gr 2: 85-89; Gr 3:80-84; Gr 4:<80. | While on treatment from Baseline through Week 96 | 
| Number of Participants With Blood Chemistry Laboratory Test Results With Worst Toxicity of Grades 1 to 4 (Continued) | Hyperkalemia(meq/L) Gr 1: 5.6-6; Gr 2: 6.1-6.5; Gr 3: 6.6-7; Gr4: >7. Hypokalemia(meq/L) Gr 1: 3-3.4; Gr 2: 2.5-2.9; Gr 3: 2-2.4; Gr 4:<2. Hypernatremia (meq/L) Gr 1: 148-150; Gr 2: 151-157; Gr 3: 148-165; Gr 4: >165. Hyponatremia (meq/L) Gr 1: 130-132; Gr 2: 123-129; Gr 3: 116-122; Gr 4: >115.Hyperglycemia(mg/dL)Gr 1: 116-160; Gr 2: 161-250; Gr 3: 251-500; Gr 4: >500. Hypoglycemia(mg/dL)Gr 1: 55-64; Gr 2: 40-54; Gr 3:30-39;Gr 4:<30.Creatine kinase (IU/L) Gr 1: >ULN-1.5*ULN; Gr 2: 1.5-3*ULN; Gr 3: >3-6*ULN; Gr 4: >6.0*ULN. Albumin (g/dL) Gr 1: <LLN-30; Gr 2: <30-20; Gr 3&4: <20. | While on treatment from Baseline through Week 96 | 
| Number of Participants With Enzyme and Urine Laboratory Test Results With Worst Toxicity of Grades 1 to 4 | AST/SGOT=Aspartate aminotransferase/serum glutamate oxaloacetate transaminase; ALT/SGPT=Alanine transaminase/serum glutamic pyruvic transaminase. Bilirubin (mg/dL)Gr 1: 1.1-1.5*ULN;Gr 2:1.6-2.5*ULN;Gr3:2.6-5*ULN;Gr4:>5*ULN.AST/SGOT(U/L)Gr 1:1.25-2.5*ULN;Gr 2: 2.6-5*ULN;Gr 3:5.1-10*ULN;Gr4:>10*ULN.ALT/SGPT (U/L)Gr 1:1.25-2.5*ULN;Gr 2:1.4-2.09*ULN;Gr 3:5.1-10*ULN;Gr4:>10*ULN. Lipase(U/L)Gr 1:1.1-1.39*ULN;Gr 2:>1.5-2*ULN;Gr 3:2.5-5;Gr 4:5*ULN.Proteinuria(g/24 hr loss)Gr 1:1+or <1;Gr 2:2-3+or>1-2; Gr 3:4+or>2-3.5;Gr4:>3.5.Creatine kinase(IU/L)Gr1:2-3*ULN;Gr 2:3.1-5*ULN;Gr 3:5.1-10*ULN;Gr4:>10*ULN. | While on treatment from Baseline through Week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Combination Therapy