Pappas 2009.

Methods	Study type: unblinded RCT Setting: 8 hospitals in the USA and 5 hospitals in Thailand
Participants	Inclusion criteria: ≥ 13 years of age; positive CSF culture Exclusion criteria: pregnant or breastfeeding; prior cryptococcal meningitis; concomitant CNS illness that would interfere with assessment of response; creatinine clearance < 50 mL/min; ALT > 5 x ULN; coma; anticipated survival < 14 days; previous antifungal therapy > 3 days; untreated active tuberculosis Number randomized: 143 (8 excluded for negative CSF culture, withdrawal of consent before treatment, poor renal function, prior episode of cryptococcosis, or receipt of substantial antifungal therapy or rifampicin before study enrolment) Age: mean 37 years (AmBd); 36 years (AmBd and fluconazole 400 mg); 36 years (AmBd and fluconazole 800 mg) Gender: 65% male (AmBd); 65% male (AmBd and fluconazole 400 mg); 64% male (AmBd and fluconazole 800 mg) CD4 T‐cell count: median 18 cells/μL (AmBd); 17 cells/μL (AmBd and fluconazole 400 mg/day); 15 cells/μL (AmBd and fluconazole 800 mg/day) Baseline ART: 8% of participants on ART at baseline Baseline GCS/AMS: excluded if in coma
Interventions	Intervention AmBd 0.7 mg/kg/day for 2 weeks AmBd 0.7 mg/kg/day and fluconazole 400 mg/day for 2 weeks AmBd 0.7 mg/kg/day and fluconazole 800 mg/day for 2 weeks Consolidation: fluconazole 400 mg/day for 8 weeks in intervention 1 and intervention 2; fluconazole 800 mg/day for 8 weeks in intervention 3 Postdiagnosis ART: participants on baseline ART continued; investigators discouraged initiation of ART before 42 days; at day 42, 17% (AmBd), 4% (AmBd and fluconazole 400 mg/day), and 22% (AmBd and fluconazole 800 mg/day) had initiated ART. Lumbar puncture schedule: encouraged aggressive management of raised intracranial pressure with LP; scheduled on days 14 and, if still positive, repeated on days 42 or 70 Laboratory monitoring: monitoring schedule not specified
Outcomes	Primary outcomes Composite of survival, neurological stability, and negative CSF culture at 2 weeks Severe or life‐threatening treatment‐related toxicities by day 100 Secondary outcomes: none Outcome assessment schedule: participants evaluated regularly while hospitalized, then followed through 100 days.
Notes	Date of study: 2005 to 2007 Funding: National Institutes of Health (USA); fluconazole donated by Pfizer Declaration of conflict of interest by authors: Authors declared research support from several pharmaceutical companies including manufacturer of study drug.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	1:1:1 randomization via adaptive randomization system stratified by country and CSF opening pressures (≤ 250 mm versus > 250 mm)
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	Unblinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinded data review committee adjudicated study data related to clinical and safety outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcomes reported for all participants.
Selective reporting (reporting bias)	Low risk	Authors reported on all primary clinical and safety outcomes.
Other bias	Unclear risk	Several authors received research support from pharmaceutical companies, including manufacturer of study drug.