Effect trial: Treatment of cryptococcal antigen-positive patients identified through screening using fluconazole plus flucytosine vs fluconazole alone

Fluconazole plus flucytosine vs fluconazole alone for cryptococcal antigen-positive patients identified through screening: a phase III randomised controlled trial

Status

Active, not recruiting

Phases

Phase 3

Study type

Interventional

Source

ISRCTN

Registry ID

ISRCTN30579828

Enrollment

600

Registered

2021-03-04

Start date

2022-05-08

Completion date

Unknown

Last updated

2026-05-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Asymptomatic cryptococcal antigen (CrAg)-positive individuals with advanced HIV infection Infections and Infestations Cerebral cryptococcosis, Human immunodeficiency virus [HIV] disease

Interventions

Individual randomisation using SAS PROC PLAN via a permuted-block randomisation method stratified by site. Block sizes will vary. 1. Fluconazole 1200 mg/day plus flucytosine 25 mg/kg four times daily

Eligibility

Sex/Gender

All

Age

18 Years to 120 Years

Inclusion criteria

Inclusion criteria: 1. Consecutive patients aged >18 years 2. HIV-seropositive 3. CD4 count of <100 cells/µl 4. Serum/plasma Cryptococcal antigen (CrAg) test positive within the last 14 days 5. Cerebrospinal fluid (CSF) CrAg test negative or lumbar puncture not done (declined) 6. Willing to participate in the study

Exclusion criteria

Exclusion criteria: Current exclusion criteria: Initial exclusion criteria: 1. Prior episode of cryptococcal meningitis 2. Pregnancy (confirmed by urine or serum pregnancy test) or breastfeeding 3. Previous serious reaction to flucytosine or fluconazole 4. Already taking high-dose fluconazole treatment (800-1200 mg/day) for =1 week 5. Contraindicated concomitant medications including cisapride and the class of antihistamines including terfenadine 6. HIV-seronegative 7. Clinical symptoms/ signs of symptomatic meningitis at any time since CrAg screening, i.e. a progressively severe headache OR a headache and marked nuchal rigidity OR a headache and vomiting OR seizures OR a Glasgow Coma Scale (GCS) score of 3.5x upper limit of normal (with standardised ULN of 114 µmol/l, this includes any creatinine level =400 µmol/l) 11. Microbiological evidence of CM on CSF if full CSF results not present at randomisation (e.g. screening CSF CrAg negative but culture on same sample later returns positive for CM) _____ Previous exclusion criteria: 1. Prior episode of Cryptococcal meningitis 2. Pregnancy (confirmed by urine or serum pregnancy test) or breastfeeding 3. Previous serious reaction to flucytosine or fluconazole 4. Already taking high-dose fluconazole treatment (800-1200 mg/day) for =1 week 5. Contraindicated concomitant medications including cisapride and the class of antihistamines including terfenadine 6. HIV-seronegative 7. Clinical symptoms/ signs of symptomatic meningitis at any time since CrAg screening, i.e. a progressively severe headache OR a headache and marked nuchal rigidity OR a headache and vomiting OR seizures OR a Glasgow Coma Scale (GCS) score of <15 8. Jaundice 9. CSF positive for Cryptococcal meningitis (i.e. positive microscopy with India Ink, culture, or CrAg test) at any time between the CrAg test and screening for eligibility, while the patient remained without clinical symptoms/ signs of meningitis as described in 7 (late withdrawal criterion)

Design outcomes

Secondary

Measure	Time frame
Current secondary outcome measures as of 24/07/2025: 1. Time to all-cause mortality within first 6 months measured using patient medical records and interviews, at 6months. 2. All-cause mortality at 10 weeks measured using patient medical records and interviews, at 10 weeks 3. Time to all-cause mortality within first 10 weeks measured using patient medical records and interviews, at 10 weeks 4. Cryptococcal meningitis-free survival to 6-months measured using patient medical records, to 6 months 5. Incidence rate of symptomatic laboratory-confirmed cryptococcal meningitis, measured using patient medical records, measured to 6 months 6. Crypto-related mortality at 6-months measured using patient medical records, to 6 months 7. Tolerability and safety: proportions of patients developing clinical and laboratory-defined grade III/IV adverse events measured using patient medical records and interviews at 6 months 8. Efficacy outcomes by baseline CrAg titre and semi-quantitative assay score at 10 weeks and 6 months 9. Rate of disability at 6 months measured using patient medical records and interviews at 6 months 10. Health service costs per life-year saved, measured using participant and health service provider interviews, at 6 months _____ Previous secondary outcome measures: 1. Time to all-cause mortality, measured using patient medical records and interviews, within the first 6 months 2. All-cause mortality, measured using patient medical records and interviews, at 10 weeks 3. Cryptococcal meningitis-free survival, measured using patient medical records, to 6 months 4. Incidence rate of symptomatic laboratory-confirmed cryptococcal meningitis, measured using patient medical records, over 6 months 5. Tolerability and safety: proportions of patients developing clinical and laboratory-defined grade III/IV adverse events measured using patient medical records and interviews up to 21 days 6. Efficacy outcomes by baseline CrAg titre and semi-quantitative assay scor	—

Measure

Time frame

Current secondary outcome measures as of 24/07/2025: 1. Time to all-cause mortality within first 6 months measured using patient medical records and interviews, at 6months. 2. All-cause mortality at 10 weeks measured using patient medical records and interviews, at 10 weeks 3. Time to all-cause mortality within first 10 weeks measured using patient medical records and interviews, at 10 weeks 4. Cryptococcal meningitis-free survival to 6-months measured using patient medical records, to 6 months 5. Incidence rate of symptomatic laboratory-confirmed cryptococcal meningitis, measured using patient medical records, measured to 6 months 6. Crypto-related mortality at 6-months measured using patient medical records, to 6 months 7. Tolerability and safety: proportions of patients developing clinical and laboratory-defined grade III/IV adverse events measured using patient medical records and interviews at 6 months 8. Efficacy outcomes by baseline CrAg titre and semi-quantitative assay score at 10 weeks and 6 months 9. Rate of disability at 6 months measured using patient medical records and interviews at 6 months 10. Health service costs per life-year saved, measured using participant and health service provider interviews, at 6 months _____ Previous secondary outcome measures: 1. Time to all-cause mortality, measured using patient medical records and interviews, within the first 6 months 2. All-cause mortality, measured using patient medical records and interviews, at 10 weeks 3. Cryptococcal meningitis-free survival, measured using patient medical records, to 6 months 4. Incidence rate of symptomatic laboratory-confirmed cryptococcal meningitis, measured using patient medical records, over 6 months 5. Tolerability and safety: proportions of patients developing clinical and laboratory-defined grade III/IV adverse events measured using patient medical records and interviews up to 21 days 6. Efficacy outcomes by baseline CrAg titre and semi-quantitative assay scor

—

Primary

Measure	Time frame
All-cause mortality, measured using patient medical records and interviews, at 6 months after randomisation	—

Countries

South Africa, Tanzania

Outcome results

None listed

Source: ISRCTN (via WHO ICTRP) · Data processed: May 7, 2026