Platform Trial For Cryptococcal Meningitis
- Conditions
- HivCryptococcal Meningitis
- Interventions
- Drug: Standard of careDrug: Sfu-AM2-19 Injection - antifungal therapy 2Drug: Antifungal therapy 3Drug: Antifungal therapy 4
- Registration Number
- NCT06666322
- Lead Sponsor
- University of Minnesota
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 2000
- 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).
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control group Standard of care randomized to standard of care Experimental group 1 Oteseconazole - antifungal therapy 1 randomized to experimental antifungal therapy #1 Experimental group 2 Sfu-AM2-19 Injection - antifungal therapy 2 randomized to experimental antifungal therapy #2 Experimental group 3 Antifungal therapy 3 randomized to experimental antifungal therapy #3 Experimental group 4 Antifungal therapy 4 randomized to experimental antifungal therapy #4
- Primary Outcome Measures
Name Time Method Rate of cerebrospinal fluid (CSF) Cryptococcus clearance (Early Fungicidal Activity, or EFA) 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.
All-cause mortality 2 weeks measured at 2-weeks
- Secondary Outcome Measures
Name Time Method Desirability of Outcome Response (DOOR) as ordinal ranked maximum score tested by Win Ratio. 18 weeks 1. Death by 18-weeks
2. Serious Adverse Event through 18 weeks (e.g. all-cause re- hospitalization, permanent neurologic deficit, etc.), lost to follow up before 10-weeks.
3. Grade 4 lab adverse event by 10 weeks, early discontinuation of study drug, or lost to follow up after 10 weeks.
4. Grade 3 lab adverse event by 10 weeks OR study drug interruption or dose reduction
5. Survival through 18-weeksSurvival time through 18 weeks without Cryptococcus culture-positive relapse of meningitis 18 weeks number of participants
CSF culture sterility (cumulative incidence over 18 weeks) 18 weeks 18-week survival time 18 weeks Use of rescue/additional IV amphotericin beyond scheduled use 18 weeks Modified Rankin score on functional status at 18 weeks 18 weeks Incidence of laboratory abnormalities by Grade 1-5 10 weeks Incidence of serious adverse events 18 weeks Incidence of study drug discontinuation or interruption >1 day due to toxicity, by adverse event grade. 10 weeks