Optimizing the Dose of Flucytosine for the Treatment of Cryptococcal Meningitis

Cryptococcal meningitis (CM) is a fungal infection that causes a severe syndrome of meningitis that is 100% fatal without antifungal therapy. Even with antifungal therapy, mortality rates remain high, especially in Africa where the ongoing HIV/AIDS pandemic leads to higher prevalence of cryptococcosis. Combination of amphotericin and flucytosine (5-FC) is the mainstay of therapy for the initial management of CM. Indeed, it has even been shown that effective delivery of these therapies in Africa can lower mortality rates by 90%.

This is a prospective open-label trial to compare the efficacy and safety of lower doses of 5FC during induction therapy to historical controls with standard 5FC dosing. Participants in the trial will receive 60mg/kg/day of 5-FC in 3 divided doses for 10 days. Single-dose liposomal amphotericin (10mg/kg) is preferred, if available. Amphotericin B 0.7-1.0 mg/kg/day may be used if needed. Historical controls drawn from the AMBITION trial will be used as a comparison group, selected weighted by inclusion/exclusion criteria, baseline characteristics and therapies received. Induction therapy for control group participants followed the 2018 WHO cryptococcal guidelines with 7 days of 5-FC 100mg/kg/day and 7 days of IV Amphotericin deoxycholate followed by 1200mg fluconazole/day for 7 days. The intervention group received single- dose liposomal amphotericin plus 5-FC and fluconazole 1200 mg/day.

All participants will receive fluconazole 1200mg/day during consolidation therapy from day 1 to 14 then 800mg/day from day 15 to 10 weeks, and 200mg/day after 10 weeks. All participants will receive lumbar punctures at diagnosis, day 3, day 5-7, day 10-14, and additionally as required for control of intracranial pressure and documentation of CSF sterilization. Controls from Ambition will be matched for the same LP windows. Therapeutic LPs conducted during the first week have a ~70% relative survival benefit.

Study Overview

• Status: Completed
• Conditions: Cryptococcal Meningitis
• Intervention / Treatment: Drug: AMBITION trial control; Drug: Flucytosine

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda, 22418
    • Infectious Disease Institute, Mulago Hospital Complex
  • Mbarara, Uganda, 1410
    • Mbarara University of Science and Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• CSF cryptococcal antigen (CrAg) positive meningitis
• Ability and willingness to provide informed consent
• Willing to receive protocol-specified lumbar punctures

Exclusion Criteria:

• Age <18 years
• Inability to take enteral (oral or nasogastric) medicine
• Cannot or unlikely to attend regular clinic visits
• Receiving chemotherapy or corticosteroids
• Suspected Paradoxical immune reconstitution inflammatory syndrome (IRIS)
• Pregnancy or breastfeeding
• CrCl < 20 mL/minute
• Absolute neutrophil count <500 x10 6 cells/L
• Thrombocytopenia < 50,000 x 10 6 cells/L
• Patients with prior 5-flucytosine exposure >3 days in the 12 months prior to enrollment
• Any condition for which participation would not be in the best interest of the participant or that could limit protocol specified assessments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: control; Historical controls drawn from the AMBITION trial will be used as a comparison group, selected weighted by inclusion/exclusion criteria, baseline characteristics and therapies received.	Drug: AMBITION trial control; Induction therapy for control group participants followed the 2018 WHO cryptococcal guidelines with 7 days of 5-FC 100mg/kg/day and 7 days of IV Amphotericin deoxycholate followed by 1200mg fluconazole/day for 7 days.
Experimental: Low Dose Flucytosine; HIV-infected persons in Uganda with cryptococcal meningitis	Drug: Flucytosine; Participants in the trial will receive 60mg/kg/day of 5-FC in 3 divided doses for 10 days. Single-dose liposomal amphotericin (10mg/kg) is preferred, if available. Amphotericin B 0.7-1.0 mg/kg/day may be used if needed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early Fungicidal Activity	Rate of clearance of Cryptococcus from CSF.	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CSF Culture Sterility	Cryptococcus is cleared or not from the cerebrospinal fluid	18 weeks
Mortality	The proportion of participants who died after 16 weeks follow up	16 weeks

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: Mbarara University of Science and Technology; Infectious Diseases Institute, Makerere University; Meningitis Foundation
• Investigators: Principal Investigator: David B Meya, University of Minnesota; Principal Investigator: David R Boulware, University of Minnesota

Publications and helpful links

General Publications

• Rutakingirwa MK, Skipper CP, Dai B, Wele A, Namombwe S, Mugabi T, Ndyetukira JF, Sadiq A, Kabahubya M, Chemusto L, Ahimbisibwe C, Nabbale S, Kandole TK, Muyise RCB, Kagimu E, Luggya T, Mulungi J, Jjunju S, Nicol MR, Stott KE, Kwizera R, Meya DB, Boulware DR, McHale TC; FLOOR trial team. Evaluating the Use of Lower Dose Flucytosine for the Treatment of Cryptococcal Meningitis: A Clinical Trial. Clin Infect Dis. 2025 Aug 7:ciaf432. doi: 10.1093/cid/ciaf432. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2024
• Primary Completion (Actual): October 2, 2024
• Study Completion (Actual): October 2, 2024

Study Registration Dates

• First Submitted: May 7, 2024
• First Submitted That Met QC Criteria: May 13, 2024
• First Posted (Actual): May 16, 2024

Study Record Updates

• Last Update Posted (Estimated): August 27, 2025
• Last Update Submitted That Met QC Criteria: August 25, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Bacterial Infections and Mycoses; Central Nervous System Infections; Meningitis, Fungal; Central Nervous System Fungal Infections; Mycoses; Cryptococcosis; Meningitis; Meningitis, Cryptococcal; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Pyrimidinones; Cytosine; Flucytosine
• Other Study ID Numbers: STUDY00017800; R01NS0863121 (Other Identifier: National Institutes of Health)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No