Nevirapine vs. Atazanavir Boosted With Ritonavir on a Background of Truvada in Human Immunodeficiency Virus (HIV) Infected Naive Patients (NEwArT)

Study Overview
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Brief Summary
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The aim of this clinical trial is to compare the efficacy and safety of ritonavir (RTV)-boosted atazanavir with nevirapine, each on a background of emtricitabine and tenofovir disoproxil fumarate (DF).

Official Title
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Comparison Atazanavir/Ritonavir (ATV/r) vs Nevirapine (NVP) Twice a Day (Bid) on Truvada Backbone

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: tenofovir DF 300 mg QD
* Drug: tenofovir DF 300 mg QD
* Drug: emtricitabine 200 mg QD
* Drug: emtricitabine 200 mg QD
* Drug: Nevirapine 200 mg BID
* Drug: Atazanavir 300 mg
* Drug: Ritonavir 100 mg


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed informed consent in accordance with Good Clinical Practice (GCP) and local regulatory requirements prior to trial participation HIV-1- infected males or females greater than or equal to 18 years of age with documented positive serology Enzyme-linked Immuno Sorbert Assay (ELISA) confirmed by Western blot No prior nucleoside reverse transcriptase inhibitor (NRTI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) use of more than 10 days AND No prior use of other classes of antiretrovirals (ARVs) of more than 2 weeks duration Males with CD4+ count less than 400 cells/mm cubed or females with CD4+ count less than 250 cells/mm cubed NVP and ATV/r susceptibility on screening HIV-1 genotypic resistance assay Adequate renal function defined as a calculated creatinine clearance greater than or equal to50 ml/min according to the Cockcroft-Gault formula Karnofsky score greater than or equal to 70 (see Appendix 10.7) Acceptable medical history, as assessed by the investigator Exclusion criteria: History of active drug or alcohol abuse within 2 years prior to study entry (at the investigators discretion) Hepatic cirrhosis with stage Child-Pugh B or C hepatic impairment Female patients of child-bearing potential who: have a positive serum pregnancy test at screening, are breast feeding, are planning to become pregnant, are not willing to use a barrier method of contraception, or are not willing to use methods of contraception other than ethinyl estradiol containing oral contraceptives Laboratory parameters greater than Division of Aids (National Institute of Health, USA) (DAIDS) grade 2 (triglycerides greater than DAIDS grade 3, total cholesterol no restrictions, see Appendix 10.1) Active hepatitis B or C disease, defined as HBsAg-positive or Hepatitis C Virus (HCV) RNA positive with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ALT/AST greater than2.5x Upper Limit of Normal (ULN) (greater than DAIDS grade 1) Known hypersensitivity to any ingredients in nevirapine or atazanavir Patients who are receiving concomitant treatments which are not permitted, as listed in Appendix 10.6 Use of other investigational medications within 30 days before study entry or during the trial Use of immunomodulatory drugs within 30 days before study entry or during the trial (e.g., interferon, cyclosporin, hydroxyurea, interleukin 2, chronic treatment with prednisone) Patients with Progressive Multifocal Leukoencephalopathy (PML), visceral Kaposi's Sarcoma (KS), and/or any lymphoma Any AIDS defining illness that is unresolved, symptomatic or not stable on treatment for at least 12 weeks at the screening visit Patients who are receiving systemic chemotherapy

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 |
| --- | --- |
| Active Comparator: NVP 200mg bis indie (BID)<br>after receiving nevirapine (NVP) 200 mg quaue die (QD) for 2 weeks, pt titrated to NVP 200 mg bis in die (BID) combined with emtricitabine 200 mg QD/ tenofovir DF 300 mg QD (fixed dose combination Truvada) for 48 weeks | Drug: tenofovir DF 300 mg QD<br>* 300 mg QD<br>Drug: emtricitabine 200 mg QD<br>* 200 mg QD<br>Drug: Nevirapine 200 mg BID<br>* 200 mg BID<br>|
| Active Comparator: Atazanavir 300 mg QD/ritonavir 100 mg QD<br>patients to receive atazanavir 300 mg QD boosted with ritonavir 100 mg QD combined with emtricitabine 200 mg QD/ tenofovir DF 300 mg QD (fixed dose combination Truvada) for 48 weeks | Drug: tenofovir DF 300 mg QD<br>* 300 mg QD<br>Drug: emtricitabine 200 mg QD<br>* 200 mg QD<br>Drug: Atazanavir 300 mg<br>* 300 mg QD<br>Drug: Ritonavir 100 mg<br>* 100 mg QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Virologic Response (VR) | VR is defined as HIV viral load of <50 copies/ml measured at two consecutive visits PRIOR TO Week 48 and without subsequent rebound or change of ARV therapy prior to Week 48. | baseline to week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Virologic Response According to the Time to Loss of Virologic Response (TLOVR) Algorithm | HIV viral load <50 copies/ml measured at two consecutive visits UP TO Week 48 and without subsequent rebound or change of ARV therapy up to Week 48. | baseline to week 48 | 
| Number of Participants With HIV Viral Load < 50 Copies/ml at Week 48 | HIV viral load <50 copies/ml measured at Week 48 among observed cases on-treatment. | baseline to week 48 | 
| Number of Participants With Virologic Success (FDA Definition) | HIV viral load <50 copies/ml measured in the Week 48 window whereby patients withdrawing early and patients without a Week 48 assessment are considered failures. Includes all participants in full analysis set (FAS). | baseline to week 48 | 
| Time to Virologic Response (First Confirmed Viral Load < 50 Copies/ml), All Participants | Time to response whereby patients withdrawing early were censored after their withdrawal | baseline to week 48 | 
| Time to Virologic Response (First Confirmed Viral Load < 50 Copies/ml), Only Participants With Confirmed Viral Load < 50 Copies/ml |  | baseline to week 48 | 
| Number of Participants With Loss of Virologic Response Following Confirmed Virologic Response | HIV viral load > 50 copies/ml on two consecutive measurements separated by at least 2 weeks, after confirmed virologic response (2 consecutive HIV viral load values < 50 copies/ml) | baseline to week 24 and week 48 | 
| Number of Participants With HIV Viral Load < 50 Copies/ml at Week 2 of Treatment | Results within time windows, patients on-treatment | baseline to week 2 | 
| Number of Participants With HIV Viral Load < 50 Copies/ml at Week 4 of Treatment | Results within time windows, patients on-treatment | baseline to week 4 | 
| Number of Participants With HIV Viral Load < 50 Copies/ml at Week 6 of Treatment | Results within time windows, patients on-treatment | baseline to week 6 | 
| Number of Participants With HIV Viral Load < 50 Copies/ml at Week 8 of Treatment | Results within time windows, patients on-treatment | baseline to week 8 | 
| Number of Participants With HIV Viral Load < 50 Copies/ml at Week 12 of Treatment | Results within time windows, patients on-treatment | baseline to week 12 | 
| Number of Participants With HIV Viral Load < 50 Copies/ml at Week 24 of Treatment | Results within time windows, patients on-treatment | baseline to week 24 | 
| Number of Participants With HIV Viral Load < 50 Copies/ml at Week 36 of Treatment | Results within time windows, patients on-treatment | baseline to week 36 | 
| Number of Participants With HIV Viral Load < 50 Copies/ml at Week 48 of Treatment | Results within time windows, patients on-treatment | baseline to week 48 | 
| Number of Participants With HIV Viral Load < 400 Copies/ml at Week 2 of Treatment | Results within time windows, patients on-treatment | baseline to week 2 | 
| Number of Participants With HIV Viral Load < 400 Copies/ml at Week 4 of Treatment | Results within time windows, patients on-treatment | baseline to week 4 | 
| Number of Participants With HIV Viral Load < 400 Copies/ml at Week 6 of Treatment | Results within time windows, patients on-treatment | baseline to week 6 | 
| Number of Participants With HIV Viral Load < 400 Copies/ml at Week 8 of Treatment | Results within time windows, patients on-treatment | baseline to week 8 | 
| Number of Participants With HIV Viral Load < 400 Copies/ml at Week 12 of Treatment | Results within time windows, patients on-treatment | baseline to week 12 | 
| Number of Participants With HIV Viral Load < 400 Copies/ml at Week 24 of Treatment | Results within time windows, patients on-treatment | baseline to week 24 | 
| Number of Participants With HIV Viral Load < 400 Copies/ml at Week 36 of Treatment | Results within time windows, patients on-treatment | baseline to week 36 | 
| Number of Participants With HIV Viral Load < 400 Copies/ml at Week 48 of Treatment | Results within time windows, patients on-treatment | baseline to week 48 | 
| Number of Patients With Virologic Rebound to >400 Copies/ml | HIV viral load >400 copies/ml on two consecutive measurements separated by at least 2 weeks, after confirmed virologic response (2 consecutive HIV viral load values < 50 copies/ml) | baseline to week 48 | 
| AIDS Progression and Death: Number of Patients With a Treatment-emergent AIDS Defining Illness or an AIDS-defining Illness Leading to Death | AIDS defining illnesses include: Aspergillosis, Bartonellosis, Candidiasis, Cervical cancer, Chagas disease, Coccidiodomycosis, Cryptococcosis, Cytomegalovirus retinus, encephalopathy, Herpes Simplex Virus, Histoplasmosis, Isosporiasis, Kaposi's sarcoma, Leishmaniasis, Microsporidiosis, Mycobacterium avium complex, mycobacterium (non-tuberculous), Nocardiosis, Pneumocystis carinii pneumonia, Pneumonia, Progressive Multifocal Leukoencephalopathy, Rhodococcus equi, Salmonella, Toxoplasmosis, Wasting. Number of cases (no time-to analysis was performed due to small numbers). | baseline to week 48 | 
| Change in CD4+ Cell Count From Baseline to Week 2. | Patients on-treatment, data within time windows | baseline to week 2 | 
| Change in CD4+ Cell Count From Baseline to Week 4. | Patients on-treatment, data within time windows | baseline to week 4 | 
| Change in CD4+ Cell Count From Baseline to Week 6. | Patients on-treatment, data within time windows | baseline to week 6 | 
| Change in CD4+ Cell Count From Baseline to Week 8. | Patients on-treatment, data within time windows | baseline to week 8 | 
| Change in CD4+ Cell Count From Baseline to Week 12. | Patients on-treatment, data within time windows | baseline to week 12 | 
| Change in CD4+ Cell Count From Baseline to Week 24. | Patients on-treatment, data within time windows | baseline to week 24 | 
| Change in CD4+ Cell Count From Baseline to Week 36. | Patients on-treatment, data within time windows | baseline to week 36 | 
| Change in CD4+ Cell Count From Baseline to Week 48. | Patients on-treatment, data within time windows | baseline to week 48 | 
| Change in Fasting Plasma Total Cholesterol Level |  | baseline to week 48 | 
| Change in Fasting Plasma Triglycerides Level |  | baseline to week 48 | 
| Change in Fasting High Density Lipoprotein (HDL) Cholesterol Level |  | baseline to week 48 | 
| Change in Fasting Low Density Lipoprotein (LDL)Cholesterol Level |  | baseline to week 48 | 
| Change in Fasting Total Cholesterol to High Density Lipoprotein (HDL) Ratio |  | baseline to week 48 | 
| Change in Framingham Score | Framingham prediction of 10-year risk of Coronary Heart Disease (CHD) outcomes (myocardial infarction [MI] or CHD death) based on the patient's gender, age, systolic blood pressure, total cholesterol, HDL-c and smoking status. The scale for the estimated risk ranges from 0 to 30%. | baseline to week 48 | 
| Change in Revised Framingham Score According to the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group |  | baseline to week 48 | 
| Change in Glomerular Filtration Rate (GFR) From Baseline to Week 48 | using 4-variable Modification of Diet in Renal Disease (MDRD) formula | baseline to week 48 | 
| Percentage Adherence by Pill Count | Number of pills not returned / number of treatment days in percent (%) | baseline to week 48 | 
| Number of Participants With Genotypic Resistance at the Time of Virologic Failure. | Genotypic resistance was measured by the following: Plasma samples for HIV-1 resistance were analyzed using a standard clinical assay that generates a virtual phenotypic interpretation of HIV-1 sequence data and predicts susceptibility or resistance of the isolate to approved ARVs. This analysis has not been performed. | baseline to week 48 | 
| Incidence of Patients With AIDS Progression at Each Visit | Cumulative incidence of patients with AIDS progression are shown | baseline to week 52 | 
| Proportion of Patients Reporting CNS Side Effects of Any Severity |  | baseline to week 52 | 
| Proportion of Patients Reporting Hepatic Events of Any Severity |  | baseline to week 52 | 
| Proportion of Patients Reporting Rash of Any Severity |  | baseline to week 52 | 
| Proportion of Patients With DAIDS Grade >= 2 Laboratory Abnormalities |  | baseline to week 52 |