Nevirapine or Atazanavir/Ritonavir Given With Emtricitabine/Tenofovir in Human Immunodeficiency Virus (HIV)-1-infected Treatment Naive Adults

Study Overview
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Brief Summary
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Primary purpose of this study is to compare the efficacy and safety of two different nevirapine (Viramune) dosing regimens (once daily (QD) and twice daily (BID) application) and of atazanavir/ritonavir (Reyataz/Norvir), all on an emtricitabine/tenofovir disoproxil fumarate (DF) (Truvada) background. Patients will receive either nevirapine (NVP) 200 mg twice daily, or NVP 400 mg once daily , or ritonavir-boosted atazanavir (ATZ/r), all in combination with emtricitabine (FTC) and tenofovir DF (TDF). All patients receiving NVP will start at 200 mg once daily for 2 weeks, because it has been demonstrated that this lead-in dosing regimen reduces the frequency of NVP-induced rash. At Visit 3 (Week 2), patients increase the NVP dose to either 200 mg twice daily or to 400 mg once daily. Patients receiving ATZ/r will be treated with ATZ 300 mg once daily, boosted by 100 mg ritonavir (RTV) once daily. Background antiretroviral therapy for all patients consists of one tablet of Truvada. Treatment duration is 48 weeks (primary endpoint) with an extension to 144 weeks. Patients may also participate in the metabolic sub-study, comparing NVP and ATZ/r for signs and symptoms of lipodystrophy and serum lipid/glycaemic abnormalities.

Official Title
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Randomized, Open Label Study Evaluating the Lipid Profile Difference and Efficacy of a Combined Therapy Including Tenofovir, Emtricitabine + Atazanavir / r or NVP in Naive HIV - 1 Infected Patients.

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: nevirapine bid
* Drug: nevirapine qd
* Drug: atazanavir


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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 >= 18 years of age with positive serology confirmed by Western blot No previous antiretroviral treatment (of more than 7 days) Males with CD4+ counts of < 400 cells/mm3 and females with CD4+ counts of < 250 cells/mm3 NVP- and ATZ/r susceptibility based on HIV-1 genotypic resistance report Adequate renal function defined as a calculated creatinine clearance (CLCr) >= 50 ml/min according to the Cockcroft-Gault formula Karnofsky score >= 70 Acceptable medical history, as assessed by the investigator Exclusion criteria: Exclusion Criteria: Active drug abuse or chronic alcoholism at the investigator's discretion Hepatic cirrhosis stage Child-Pugh B or C Female patients of child-bearing potential who: have a positive serum pregnancy test at screening or during the study, 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 Division of Acquired Immunodeficiency Syndrome (DAIDS) > grade 2 (triglycerides > DAIDS grade 3; total cholesterol no restrictions) Active hepatitis B or C disease, defined as HBsAg-positive or Hepatitis C-Virus-Ribo Nucleic Acid (HCV-RNA)- positive with Aspartate Transaminase/Alanine Transaminase (AST/ALT) > 2.5x Upper Limit of Normal (ULN) (DAIDS grade 1) Hypersensitivity to any ingredients of the test products Have therapy with nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cisplatin, pentamidine, tacrolimus, cyclosporine) or potential competitors of renal excretion (e.g., cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, probenecid, high-dose non-steroidal anti-inflammatory drugs (i.e., ibuprofen)) within 3 months prior to study screening or are expected to receive these during the study Patients who are receiving other concomitant treatments which are not permitted 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 screening visit Patients who are receiving systemic treatment for malignant disease

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 bid<br>nevirapine (NVP) 200 mg BID in combination with emtricitabine (FTC) and tenofovir DF (TDF) | Drug: nevirapine bid<br>* nevirapine twice daily<br>|
| Experimental: NVP qd<br>nevirapine (NVP) 400 mg QD in combination with emtricitabine (FTC) and tenofovir DF (TDF) | Drug: nevirapine qd<br>* nevirapine once daily<br>|
| Active Comparator: ATZ/r<br>ritonavir-boosted atazanavir in combination with emtricitabine (FTC) and tenofovir DF (TDF) | Drug: atazanavir<br>* atazanavir once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response at Week 48 | Treatment response is defined as a viral load (VL) <50 copies/mL measured at two consecutive visits prior to Week 48 and without subsequent rebound or change of antiretroviral (ARV) therapy prior to Week 48. | From baseline to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response at Week 48 (TLOVR Algorithm) | Treatment response is defined as a VL <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, based on time to loss of virologic response (TLOVR) algorithm, as a sensitivity analysis for the primary analysis. | From baseline to Week 48 | 
| Proportion of Patients With VL < 50 Copies/ml | VL <50 copies/mL among observed patients on treatment at each visit, with the final visit at Week 144 or end of trial (EOT) for the patient | From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT | 
| Proportion of Patients With VL < 400 Copies/ml | VL <400 copies/mL among observed patients on treatment at each visit, with the final visit at Week 144 or end of trial (EOT) | From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT | 
| Change in CD4+ Count From Baseline | Change in CD4+ cell count from baseline among patients on treatment at each visit, with the final visit at Week 144 or EOT | From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT | 
| Change in Framingham Score From Baseline | Change in the estimated risk of cardiovascular disease using the Framingham algorithm from baseline to after 48, 96 and 144 weeks, last observation carried forward (LOCF). The score is based on age, gender, systolic blood pressure, total cholesterol, high density lipoprotein cholesterol and smoking status. Scores range from 0 to 21 with higher scores indicating a greater risk. | From baseline to Weeks 48, 96 and 144/EOT | 
| Change in Mental Health Summary (MHS) Score From Baseline | Quality of life (QoL) assessment by change in MHS score from baseline to after 48, 96 and 144 weeks (observed cases), from the Medical Outcomes Study HIV Health Survey (MOS-HIV), a 35-item self-administered questionnaire including 10 scales covering: health perceptions, pain, physical functioning, role functioning, social and cognitive functioning, mental health, energy/fatigue, health distress, and QoL. The MHS is a weighted average of the 10 scales and ranges from 0 to 100 with higher scores indicating better QoL. | From baseline to Weeks 48, 96 and 144/EOT | 
| Change in Physical Health Summary (PHS) Score From Baseline | QoL assessment by change in PHS score from baseline to after 48, 96 and 144 weeks (observed cases), from the MOS-HIV, a 35-item self-administered questionnaire including 10 scales covering: health perceptions, pain, physical functioning, role functioning, social and cognitive functioning, mental health, energy/fatigue, health distress, and QoL. The PHS is a weighted average of the 10 scales and ranges from 0 to 100 with higher scores indicating better QoL. | From baseline to Weeks 48, 96 and 144/EOT | 
| Number of Patients Hospitalized | Cost effectiveness assessment by number of patients hospitalized | From baseline to Week 24, Week 24 to 48, Week 48 to 96, and Week 96 to 144/EOT | 
| Non-scheduled Physician Visits | Cost effectiveness assessment by number of patients with non-scheduled physician visits | From baseline to Week 24, Week 24 to 48, Week 48 to 96, and Week 96 to 144/EOT | 
| Genotypic Resistance Associated With Virologic Failure | Number of treatment-emergent drug-associated substitutions in patients with virological failure up to Week 48. The total number of genotypic mutations in those patients who were virologic failures is given, not the number of patients with mutations. | From baseline to Week 48 | 
| Treatment-emergent AIDS-defining Illness | Treatment-emergent AIDS-defining illness (tr.-emerg. AIDS-def.illness) including worsening during treatment | From baseline to Week 144 | 
| Treatment-emergent AIDS-defining Illness Leading to Death | Patients with an AIDS-defining illness leading to death broken out by treatment. Statistical analysis shows time to death from AIDS-defining illness. | From baseline to Week 144 | 
| Lipodystrophy | Number of patients with AE lipodystrophy | From baseline to Week 144 | 
| Serum Lipid Abnormalities | Number of patients with AE elevated serum lipids (i.e. hypercholesterolaemia) | From baseline to Week 144 | 
| Glycaemic Abnormalities | Number of patients with AE elevated serum glucose | From baseline to Week 144 | 
| Treatment Response at Week 96 | Treatment response is defined as a viral load (VL) <50 copies/mL measured at two consecutive visits prior to Week 96 and without subsequent rebound or change of antiretroviral (ARV) therapy prior to Week 96. | From baseline to Week 96 | 
| Treatment Response at Week 144 | Treatment response is defined as a viral load (VL) <50 copies/mL measured at two consecutive visits prior to Week 144 and without subsequent rebound or change of antiretroviral (ARV) therapy prior to Week 144. | From baseline to Week 144 | 
| Proportion of Patients With Virological Rebound With VL >=50 Copies/mL After CVR (Confirmed Virological Response) at Week 24, 48, 96, 144 | The analyses of virologic rebound were performed on the original values at each visit(ORGV) rather than calculated results within time windows (CAL) | at Week 24, 48, 96, 144 | 
| Proportion of Patients With Virological Rebound With VL >=400 Copies/mL After CVR at Week 24, 48, 96, 144 | The analyses of virologic rebound were performed on the original values at each visit(ORGV) rather than calculated results within time windows (CAL) | at Week 24, 48, 96, 144 | 
| Proportion of Patients With Virologic Failure at Week 48, 96, 144 |  | at Week 48, 96, 144 | 
| Time to Treatment Response (First Confirmed VL<50 Copies/mL) | Time to treatment response was defined as the time from start of treatment until the first measurement of the first confirmed virological response | baseline to week 144 | 
| Time to Loss of Virologic Response (Rebound) | Time to loss of virologic response (TLOVR) was defined as the time from start of treatment to the first measurement showing VL ≥ 50 copies/mL in the first virologic rebound, after having a confirmed virological response. | Baseline to week 144 | 
| Time to Treatment Failure | Treatment failure is defined as the occurrence of the first of at least one of the following events: early discontinuation of trial drug, change in ARV therapy, failure to achieve an HIV RNA count < 50 copies/mL up to Visit 10 (week 48) or loss of virologic response | baseline to week 144 | 
| Change in the Calculated Glomerular Filtration Rate (GFR) at Week 48, 96 and 144 | Calculations based on the MDRD algorithm. | From baseline to Week 48, 96, 144 | 
| Proportion of Patients With >= DAIDS Grade 2 Laboratory Abnormalities |  | week 148 | 
| Proportion of Patients Reporting Rash of Any Severity | Proportion of Patients reporting rash of any severity | week 148 | 
| Proportion of Patients Reporting Hepatic Events of Any Severity | Proportion of Patients reporting hepatic events of any severity | week 148 | 
| Proportion of Patients Reporting CNS (Central Nervous System) Side Effects of Any Severity | Proportion of Patients reporting CNS (central nervous system) side effects of any severity | week 148 | 
| Change of Cholesterol Values From Baseline to Week 48, 96, 144 | Changes frombaseline in total cholesterol, LDL-cholesterol(LDL-c) and HDL | baseline to week 48, 96, 144 | 
| Changes of Apolipoprotein Values From Baseline to Week 48, 96, 144 | Changes frombaseline apolipoprotein A1 & B | baseline to week 48, 96, 144 | 
| Change of hsCRP From Baseline to Week 48, 96, 144 | Change of hsCRP from baseline to week 48, 96, 144 | baseline to week 48, 96, 144 | 
| Change of Total Triglycerides From Baseline to Week 48, 96, 144 | Change of total triglycerides from baseline to week 48, 96, 144 | baseline to week 48, 96, 144 | 
| Change of Total Cholesterol to HDL-cholesterol Ratio From Baseline to Week 48, 96, 144 | Change of Total cholesterol to HDL-cholesterol ratio from baseline to week 48, 96, 144 | baseline to week 48, 96, 144 |