Optimizing the Dose of Flucytosine for the Treatment of Cryptococcal Meningitis

May 13, 2024 updated by: University of Minnesota

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

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

36

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

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
Rate of CSF Cryptococcus clearance (Early Fungicidal Activity, or EFA)
Time Frame: 2 weeks
quantified by the change of log 10 Cryptococcus CFU/mL CSF/day as measured by serial quantitative CSF fungal cultures over ~2 weeks
2 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
CSF culture sterility cumulative incidence over 18 weeks
Time Frame: 18 weeks
18 weeks
18-week survival time
Time Frame: 18 weeks
18 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Minnesota

Investigators

  • Principal Investigator: David B Meya, University of Minnesota
  • Principal Investigator: David R Boulware, University of Minnesota

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 9, 2024

Primary Completion (Estimated)

September 1, 2024

Study Completion (Estimated)

September 1, 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 (Actual)

May 16, 2024

Last Update Submitted That Met QC Criteria

May 13, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY00017800

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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