Optimizing the Dose of Flucytosine for the Treatment of Cryptococcal Meningitis

NCT06414512 | Completed Phase 2 Results

• 2 other identifiers: STUDY00017800R01NS0863121
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 2

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

Outcome Measures

Primary Outcomes (1)

• Early Fungicidal Activity

  Rate of clearance of Cryptococcus from CSF.

  2 weeks

Secondary Outcomes (2)

• CSF Culture Sterility

  18 weeks

• Mortality

  16 weeks

Study Arms (2)

control

ACTIVE COMPARATOR

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

Low Dose Flucytosine

EXPERIMENTAL

HIV-infected persons in Uganda with cryptococcal meningitis

Drug: Flucytosine

Interventions

AMBITION trial control 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.

control

Flucytosine 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.

Low Dose Flucytosine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Minnesota: lead
• Infectious Diseases Institute, Makerere University: collaborator
• Mbarara University of Science and Technology: collaborator
• Meningitis Foundation: collaborator

Study Sites (2)

Infectious Disease Institute, Mulago Hospital Complex

Kampala, 22418, Uganda

Location

Mbarara University of Science and Technology

Mbarara, 1410, Uganda

Location

Related Publications (1)

• 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.

  PMID: 40795226 DERIVED

MeSH Terms

Conditions

Meningitis, Cryptococcal

Interventions

Flucytosine

Condition Hierarchy (Ancestors)

Meningitis, Fungal; Central Nervous System Fungal Infections; Mycoses; Bacterial Infections and Mycoses; Infections; Cryptococcosis; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

Cytosine; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: David Boulware
• Organization: University of Minnesota

idim@umn.edu

612-624-9996

Study Officials

• David B Meya

  University of Minnesota

  PRINCIPAL INVESTIGATOR

• David R Boulware

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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. 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.

Study Record Dates

• First Submitted: May 7, 2024
• First Posted: May 16, 2024
• Study Start: April 9, 2024
• Primary Completion: October 2, 2024
• Study Completion: October 2, 2024
• Last Updated: August 27, 2025
• Results First Posted: August 27, 2025

Record last verified: 2025-08

Locations

UG (2)