Clinical trial NCT06414512: Optimizing the Dose of Flucytosine for the Treatment of Cryptococcal Meningitis
Official title: Optimizing the Dose of Flucytosine for the Treatment of Cryptococcal Meningitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cryptococcal Meningitis
Lead sponsor: University of Minnesota
Sponsor class: OTHER
First posted: 2024-05-16
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Rate of CSF Cryptococcus clearance (Early Fungicidal Activity, or EFA)
timeFrame: 2 weeks
Secondary outcomes:
measure: CSF culture sterility cumulative incidence over 18 weeks
timeFrame: 18 weeks
measure: 18-week survival time
timeFrame: 18 weeks
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Infectious Disease Institute, Mulago Hospital Complex
city: Mbarara
country: Uganda
facility: Mbarara University of Science and Technology
Study officials:
affiliation: University of Minnesota
name: David B Meya
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: David R Boulware
role: PRINCIPAL_INVESTIGATOR
References: