Individuals with advanced HIV disease, without symptoms of meningitis, who are blood-cryptococcal antigen-positive (CrAg) and cerebrospinal fluid (CSF) CrAg-negative or who decline lumbar puncture (LP) Infections and Infestations
Conditions
Interventions
All participants will receive flucytosine (sustained-release, Viatris, 6 g twice per day, orally, in fasting conditions) plus fluconazole (1200 mg/day, orally) for 14 days. All participants will then
Sponsors
Wits Health Consortium (Pty) Ltd
Eligibility
Sex/Gender
All
Age
18 Years to 100 Years
Inclusion criteria
Inclusion criteria: 1. Consecutive patients aged >=18 years 2. HIV-seropositive 3. CD4 count of <200 cells/µl 4. Serum/plasma CrAg test positive within the last 21 days 5. CSF CrAg test negative or LP not done (declined) 6. Willing to participate in the study
Exclusion criteria
Exclusion criteria: 1. Prior episode of CM or cryptococcal antigenaemia 2. Pregnancy (confirmed by urine or serum pregnancy test) or breastfeeding 3. Women of childbearing potential who do not agree to use contraception during the study period. 4. Male participants (or their female partners of childbearing potential) who do not agree to use effective contraception during the study period. 5. Already taking high-dose fluconazole treatment (800-1200 mg/day) for =10 days 6. Known dihydropyridine dehydrogenase (DPD) deficiency 7. Previous serious reaction to flucytosine or fluconazole 8. Contraindicated concomitant medications including: cisapride and the class of antihistamines including terfenadine 9. HIV-seronegative 10. 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 3x upper limit of normal) on baseline blood testing 20. Participants should be excluded in case of any severe medical or psychiatric condition that may increase the risk associated with trial participation or may interfere with the interpretation of trial results. 21. Late exclusion criteria: Microbiological evidence of CM on CSF if full CSF results are not available at randomisation (e.g. screening CSF CrAg negative but culture on the same sample later returns positive for CM)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area under the plasma concentration versus time curve for 5FC, and possibly 5FU, from dose administration until 24 h, AUC(0-24h)) Pharmacokinetics: Plasma level concentrations of 5FC and metabolite 5FU Population PK parameters for SR 5FC: Depending on the final structural and stochastic population PK model, but e.g. for a two-compartment model the following primary PK parameters: apparent oral clearance (CL/F); absorption rate constant (ka); intercompartmental clearance (Q/F); central and peripheral volume of distribution (Vc/F and Vp/F, respectively). Identifiable between-subject variabilities and between-occasion variabilities on any of the primary PK parameters. Exposure and target attainment: 1. Area-under-curve plasma concentration versus time for 5FC and 5FU, from the start of treatment to t, where t is the time of the last quantifiable concentration (AUC(0-t)) 2. Area under the plasma concentration versus time curve for 5FC and 5FU, with extrapolation to infinity (AUC(0 8)) 3. Maximum observed plasma concentration (Cmax) and Cmax at steady-state (Cmax,ss) 4. Time to maximum observed plasma concentration (tmax) 5. Minimum observed plasma concentration (Cmin) and Cmin at steady-state (Cmin,ss) 6. Average for 5FC and 5FU concentration during a dosing interval (AUC(0- t) / t)(Cav) 7. Fluctuation ([(Cmax-Cmin)/Cav]) 8. Apparent initial and terminal elimination half-life (t½) 9. Time within a predefined therapeutic window for individually predicted 5FC plasma concentrations (therapeutic monitoring boundaries of =20 mg/L and =100 mg/L) and time above the published MIC90 value of 8 mg/L Note: if quantifiable, all parameters will be estimated for both 5FC and 5FU | — |
Secondary
| Measure | Time frame |
|---|---|
| Tolerability and safety: Proportions of participants developing clinical and laboratory-defined grade III/IV/V adverse events and treatment discontinuation due to AEs, measured using clinical assessments, laboratory tests, interviews and patient medical records up to day 30 Additional exploratory outcomes: 1. All-cause mortality at 2 and 4 weeks, measured using patient medical records and interviews 2. Development of symptomatic cryptococcal meningitis within the first 4 weeks, measured using patient medical records and interviews 3. Change in blood fungal antigen concentration measured using CrAg titre/CrAg semi-quantitative (SQ) assay score from baseline to 2 weeks post-treatment initiation 4. Acceptability and palatability of SR 5FC (taste, texture, flavour), measured using a participant questionnaire (visual analogue scale) on days 2, 8 and 15 | — |
Countries
South Africa
Contacts
Public ContactJack Adams
Outcome results
None listed