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

Phase 3

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

• Registration Number: ISRCTN30579828
• Lead Sponsor: St George's, University of London

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-03-04
• Last Update Posted: 8 July 2024
• Study Completion: 2026-08-31

Recruitment & Eligibility

• Status: Ongoing
• Sex: All
• Target Recruitment: 600

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

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 <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)

Late exclusion criteria: (after randomisation and day 1 visit)
10. DAIDS grade 4 abnormalities of platelets, neutrophil count or creatinine level on baseline bloods:
10.1. Platelets <25,000 x 10^6/l
10.2. Neutrophils <400 x10^6/l
10.3. Creatinine > 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)

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
All-cause mortality, measured using patient medical records and interviews, at 6 months after randomisation

Secondary Outcome Measures

Name	Time	Method
1. Time to all-cause mortality, measured using patient medical records and interviews, within the first 6 months2. All-cause mortality, measured using patient medical records and interviews, at 10 weeks3. Cryptococcal meningitis-free survival, measured using patient medical records, to 6 months4. 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 days6. Efficacy outcomes by baseline CrAg titre and semi-quantitative assay score at 10 weeks and 6 months7. Health service costs per life-year saved, measured using participant and health service provider interviews, over 6 months