Optimizing the Dose of Flucytosine for the Treatment of Cryptococcal Meningitis

NCT ID: NCT06414512

Last Updated: 2025-08-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-04-09
• Study Completion Date: 2024-10-02

Brief Summary

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.

Conditions

Cryptococcal Meningitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

AMBITION trial control

Intervention Type: DRUG

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.

Low Dose Flucytosine

HIV-infected persons in Uganda with cryptococcal meningitis

Group Type: EXPERIMENTAL

Flucytosine

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Infectious Diseases Institute, Makerere University

UNKNOWN

Sponsor Role: collaborator

Mbarara University of Science and Technology

OTHER

Sponsor Role: collaborator

Meningitis Foundation

UNKNOWN

Sponsor Role: collaborator

University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David B Meya

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

David R Boulware

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

Locations

Infectious Disease Institute, Mulago Hospital Complex

Kampala, , Uganda

Mbarara University of Science and Technology

Mbarara, , Uganda

Countries

Uganda

References

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.

Reference Type: DERIVED

PMID: 40795226 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

R01NS0863121

Identifier Type: OTHER

Identifier Source: secondary_id

STUDY00017800

Identifier Type: -

Identifier Source: org_study_id