Clinical trial NCT01011413: Safety and Efficacy of Reduced Versus Standard Dose Efavirenz (EFV) Plus Two Nucleotides in Antiretroviral-naïve Adults.
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: HIV
Antiretroviral Therapy (ART)
Efavirenz (EFV)
Dose reduction
Lead sponsor: Kirby Institute
Sponsor class: OTHER_GOV
First posted: 2009-11-11
Enrollment: 636
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Plasma HIV-1 RNA <200 Copies/mL 48 Weeks After Randomisation
timeFrame: 48 weeks
Secondary outcomes:
measure: Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL and <50 Copies/mL at 48 and 96 Weeks After Randomisation
timeFrame: Baseline and 2 years
measure: Mean Change From Baseline in CD4+ T-cell Count
timeFrame: Baseline and 2 years
measure: Clinical Endpoints: Opportunistic Disease or Death, and Serious Non-AIDS-defining Events and Non-AIDS-related Mortality
timeFrame: up to 2 years
measure: Change From Baseline in Metabolic Endpoints
timeFrame: Baseline and 2 years
measure: Adherence: Median Scores of Self-reported Adherence to Randomised Study Medications
timeFrame: 2 years
measure: Change From Baseline in Fasted Insulin Levels
timeFrame: Baseline and 2 years
measure: Change in Selected Serum Biochemical Parameters
timeFrame: Baseline and 2 years
measure: Change From Baseline in Estimate Creatinine Clearance
timeFrame: Baseline and 2 years
measure: Steady-state Efavirenz Concentrations
timeFrame: Week 4
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: St Vincent's Hospital
state: New South Wales
Study officials:
affiliation: Kirby Institute
name: David Cooper, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: ENCORE1 Study Group. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014 Apr 26;383(9927):1474-1482. doi: 10.1016/S0140-6736(13)62187-X. Epub 2014 Feb 10.
citation: ENCORE1 Study Group; Carey D, Puls R, Amin J, Losso M, Phanupak P, Foulkes S, Mohapi L, Crabtree-Ramirez B, Jessen H, Kumar S, Winston A, Lee MP, Belloso W, Cooper DA, Emery S. Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis. 2015 Jul;15(7):793-802. doi: 10.1016/S1473-3099(15)70060-5. Epub 2015 Apr 12.
citation: Winston A, Amin J, Clarke A, Else L, Amara A, Owen A, Barber T, Jessen H, Avihingsanon A, Chetchotisakd P, Khoo S, Cooper DA, Emery S, Puls R; ENCORE Cerebrospinal Fluid (CSF) Substudy Team; ENCORE Cerebrospinal Fluid CSF Substudy Team. Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomized controlled trial. Clin Infect Dis. 2015 Apr 1;60(7):1026-32. doi: 10.1093/cid/ciu976. Epub 2014 Dec 11.