Safety and Efficacy of Reduced Versus Standard Dose Efavirenz (EFV) Plus Two Nucleotides in Antiretroviral-naïve Adults.

Study Overview
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Brief Summary
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Clinical data suggests that the standard dose of the anti-HIV medication, efavirenz (EFV), could be reduced without compromising its effectiveness. Lower drug doses could have fewer side effects and would make EFV more affordable. The purpose of this study is to compare the safety and effectiveness, over 96 weeks, of standard (600mg) versus reduced dose (400mg) EFV in controlling HIV as part of initial combination antiretroviral therapy.

Detailed Description
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In this international, multicenter trial, 630 HIV infected patients who have not received any previous treatment for their HIV-infection will be enrolled. Participants will be randomized equally (1:1) to receive Truvada (tenofovir and emtricitabine) with either the standard or reduced dose of EFV. Neither the study doctor nor the participant will know which treatment the participant is receiving. Physical examinations, laboratory analyses and questionnaires will be performed at the 11 study visits at screening, baseline (Week 0), Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96. The primary aim of this study is to compare between treatment groups the proportion of patients with undetectable HIV viral load (HIV RNA < 200 copies/mL) after 48 weeks. Information on immune function, drug adherence, resistance to antiretrovirals, quality of life, mental state and HIV-related conditions will also be collected. Blood samples will be collected for future testing. Interim analyses will be performed when the first 125 participants in each treatment group reach week 24 and when all participants reach week 24. These interim analyses will provide an early check that the reduced dose of EFV suppresses HIV infection as effectively as the standard dose of EFV. A follow-up analysis will be performed when all participants reach week 96.

Official Title
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A Randomised, Double-blind, Placebo-controlled, Trial to Compare the Safety and Efficacy of Reduced Dose Versus Standard Dose EFV Plus Two Nucleotides (N(t)RTI) in Antiretroviral-naïve HIV-infected Adults Over 96 Weeks

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Efavirenz 600mg
* Drug: Efavirenz 400mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 positive by licensed diagnostic test aged >16 years of age (or minimum age as determined by local regulations or as legal requirements dictate) 50 < cluster of differentiation (CD)4 <500 cells/µL No prior AIDS-defining illness, using the Center for Diseases Control 1993 Case Definition (except pulmonary tuberculosis) HIV RNA ≥1000 copies/mL no prior exposure to antiretroviral therapy (ART) (including short course ART for preventing MTCT) calculated creatinine clearance (CLCr) more than or equal to 50 mL/min (Cockcroft-Gault formula) provision of written informed consent. Exclusion Criteria: the following laboratory values: absolute neutrophil count (ANC) <500 cells/μL hemoglobin <7.0 g/dL platelet count <50,000 cells/μL alanine aminotransferase and/or aspartate aminotransferase >5 x upper limit of normal pregnant women or nursing mothers active opportunistic or malignant disease not under adequate control use of immunomodulators within 30 days prior to screening use of any prohibited medications current alcohol or illicit substance use that might adversely affect study participation

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 600 milligram (mg) Efavirenz<br>Eligible patients will be centrally randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd) | Drug: Efavirenz 600mg<br>* 3 x EFV 200 milligram (mg) tablets once daily<br>* Other names: Matrix EFV 200mg tablets;|
| Experimental: 400mg Efavirenz<br>Eligible patients will be centrally randomised to receive TDF (300mg qd)/FTC (200mg qd) + EFV (400mg qd; 2 x 200mg + 1 x 200mg placebo qd). | Drug: Efavirenz 400mg<br>* 2 x EFV 200 milligram (mg) tablets plus 1x matched EFV placebo tablet once daily<br>* Other names: Matrix EFV 200mg matched placebo tablets.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Plasma HIV-1 RNA <200 Copies/mL 48 Weeks After Randomisation | Percentage of participants in each of the treatment arms with centrally quantified plasma HIV-1 RNA viral load <200 copies/mL 48 weeks after randomisation. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation | Percentage of participants in each of the two treatment arms with plasma HIV-1 RNA <400 copies/mL and <50 copies/mL at 48 and 96 weeks after randomisation | Baseline and 2 years | 
| Mean Change From Baseline in CD4+ T-cell Count | Mean change from baseline to week 96 in CD4+ T-cell count/mm3 between the two treatment arms | Baseline and 2 years | 
| Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality | Number of participants in each randomised arm diagnosed with a serious non-AIDS defining event, who die from an AIDS-defining event, who die from a non-AIDS-defining event | up to 2 years | 
| Change From Baseline in Metabolic Endpoints | Change from baseline to week 96 in fasted total cholesterol, high density cholesterol and low density cholesterol, and glucose between randomised treatment arms | Baseline and 2 years | 
| Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications | AIDS Clinical Trials Group (ACTG) 7-day adherence questionnaire scores. Maximum value is all pills taken every day; minimum value is no pills taken per day. Higher scores indicate a better outcome. | 2 years | 
| Change From Baseline in Fasted Insulin Levels | Change from baseline to week 96 in fasted insulin levels | Baseline and 2 years | 
| Change in Selected Serum Biochemical Parameters | Change from baseline to week 96 in alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels between randomised treatment arms | Baseline and 2 years | 
| Change From Baseline in Estimate Creatinine Clearance | Change from baseline to week 96 in estimate creatinine clearance between randomised treatment arms | Baseline and 2 years | 
| Steady-state Efavirenz Concentrations | Steady-state efavirenz mid-dosing interval plasma concentrations | Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Antiretroviral Therapy (ART), Efavirenz (EFV), Dose reduction