Clinical trial NCT06666322: Platform Trial For Cryptococcal Meningitis
Official title: Platform Trial For Cryptococcal Meningitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Hiv
Cryptococcal Meningitis
Lead sponsor: University of Minnesota
Sponsor class: OTHER
First posted: 2024-10-30
Enrollment: 2000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Cryptococcal meningitis 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 low and middle income countries where the ongoing HIV/AIDS pandemic increases the risk of cryptococcosis among persons living with HIV infection. The combination of amphotericin and flucytosine (5-FC) has been the mainstay of therapy for the initial management of cryptococcal meningitis for 4 decades. Indeed, the effective delivery of these first line therapy in Africa can lower mortality to 25%. However, several challenges exist. First, even while 5-FC is included on the WHO list of essential medicines, the availability of 5-FC worldwide is limited. Second, liposomal amphotericin (Ambisome ®) is currently available from a single source supplier, creating risk. Third, current therapies have substantial toxicity. Lastly, with widespread agricultural fungicide use of azoles, the median fluconazole minimum inhibitory concentration (MIC50 ) for Cryptococcus has doubled since 2013. Globally, new or improved antifungals are needed for cryptococcal meningitis, particularly those which have less toxicity, greater efficacy, a prolonged half-life, and minimal drug-drug interactions. As multiple new antifungal medicines are on the horizon, this platform trial utilizes a master protocol to investigate, multiple regimens using standardized eligibility criteria, standardized study schedule of events, and standardized contemporary endpoints.


Eligibility criteria: Inclusion Criteria:

* CSF cryptococcal antigen (CrAg) positive meningitis
* HIV positive
* Ability and willingness to provide informed consent
* Willing to receive protocol-specified lumbar punctures
* Age \>= 18 years
* Female participants of childbearing potential who are participating in sexual activity that could lead to pregnancy must agree to use reliable forms of contraception (duration will be indicated in each Trial Appendix).

Exclusion Criteria:

* Received \>= 3 doses of antifungal therapy for meningitis treatment or \> 6mg/kg of liposomal amphotericin B cumulatively within prior 30 days
* Inability to take enteral (oral or nasogastric) medicine
* Cannot or unlikely to attend regular clinic visits
* Receiving chemotherapy or corticosteroids
* Receiving hemodialysis or known liver cirrhosis
* Suspected Paradoxical immune reconstitution inflammatory syndrome (IRIS)
* Pregnancy or breastfeeding
* Previous administration of investigational study drug
* Any condition for which participation would not be in the best interest of the participant or that could limit protocol specified assessments
* Trial Appendix study-drug specific eligibility criteria

Primary outcomes:
measure: Rate of cerebrospinal fluid (CSF) Cryptococcus clearance (Early Fungicidal Activity, or EFA)
timeFrame: 2 weeks
measure: All-cause mortality
timeFrame: 2 weeks
Secondary outcomes:
measure: Desirability of Outcome Response (DOOR) as ordinal ranked maximum score tested by Win Ratio.
timeFrame: 18 weeks
measure: Survival time through 18 weeks without Cryptococcus culture-positive relapse of meningitis
timeFrame: 18 weeks
measure: CSF culture sterility (cumulative incidence over 18 weeks)
timeFrame: 18 weeks
measure: 18-week survival time
timeFrame: 18 weeks
measure: Use of rescue/additional IV amphotericin beyond scheduled use
timeFrame: 18 weeks
measure: Modified Rankin score on functional status at 18 weeks
timeFrame: 18 weeks
measure: Incidence of laboratory abnormalities by Grade 1-5
timeFrame: 10 weeks
measure: Incidence of serious adverse events
timeFrame: 18 weeks
measure: Incidence of study drug discontinuation or interruption >1 day due to toxicity, by adverse event grade.
timeFrame: 10 weeks
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Infectious Diseases Institute
city: Mbarara
country: Uganda
facility: Mbarara University of Science and Technology
Study officials:
affiliation: University of Minnesota
name: David R Boulware, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Uganda
name: David B Meya, MBChB, MMed, PhD
role: PRINCIPAL_INVESTIGATOR
References: