NORA was a randomized double-blind Phase II toxicity trial conducted at two clinical centres in Uganda [Joint Clinical Research Center (JCRC), Kampala and the Medical Research Council/Uganda Virus Research Institute (MRC/UVRI) Uganda Research Unit on AIDS, Entebbe], as a nested substudy within the DART trial [same International Standard Randomised Controlled Trial

Number (ISRCTN) 13968779] [7]. Six hundred previously untreated symptomatic HIV-infected adults initiating ART with CD4 counts <200 cells/μL were randomly allocated 1:1 to receive zidovudine/lamivudine [coformulated as Combivir® (GlaxoSmithKline, Research Triangle Park, NC, USA)] plus 300 mg abacavir and nevirapine placebo twice daily or abacavir placebo and 200 mg nevirapine twice daily for 24 weeks (double-dummy design), after which participants continued on open-label. Active and placebo nevirapine was dose-escalated from Nutlin-3 purchase the lead-in 100 mg to 200 mg daily at 2 weeks as standard. Randomization was stratified by clinical

centre, baseline CD4 count (0–99 or 100–199 cells/μL) and selleck compound allocation to clinically driven monitoring (CDM) or laboratory plus clinical monitoring (LCM) in the main trial randomisation. The primary endpoint was any serious adverse event (SAE) judged definitely/probably or uncertain whether related to blinded nevirapine/abacavir to 24 weeks; secondary endpoints were adverse events of any grade leading to permanent discontinuation of blinded nevirapine/abacavir, and any grade 4 events, defined according to minor modifications of the AIDS Clinical Trials Group criteria [8]. The sample size of 600 participants provided 80% power to detect differences in the primary toxicity endpoint between 15 and 8% at 24 weeks. Individual informed consent was obtained from every participant for both NORA and DART. Both NORA and DART received ethics approval in Uganda (UVRI Science and Ethics Committee) and the United

Kingdom (Imperial College, London). During the blinded phase, participants experiencing suspected adverse reactions to abacavir or nevirapine were to be unblinded; others needing to substitute blinded nevirapine/abacavir (e.g. to start anti-tuberculosis medication) changed Loperamide to tenofovir DF without unblinding. After 24 weeks (the primary/secondary outcome analysis time-point), participants changed to open-label NORA according to allocation, continued zidovudine/lamivudine and remained in follow-up in DART. All participants attended the study clinic every 4 weeks when nurses administered standard symptom and adherence checklists and dispensed 28-day ART prescriptions. Participants could be referred to a study doctor at any time and were asked to return to the clinic if they felt unwell between visits.