Health Trials

Platform Trial For Cryptococcal Meningitis (PLATFORM-CM)

ConditionsHivCryptococcal Meningitis
Trial statusRecruiting
Trial phasePhase 2, Phase 3
Trial typeInterventional
Biological sexAll
Age18+
SponsorDavid Boulware

About this trial

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 antifungal regimens using standardized eligibility criteria, standardized study schedule of events, and standardized contemporary endpoints.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

CSF cryptococcal antigen (CrAg) positive meningitis

Living with HIV

Ability and willingness to provide informed consent

Willing to receive protocol-specified lumbar punctures

Disqualifiers

Received 3 or more doses of antifungal therapy for meningitis within last 30 days

Inability to take enteral (oral or nasogastric) medicine

Cannot or unlikely to attend regular clinic visits

Receiving chemotherapy or corticosteroids

Trial design

Design model

Parallel

Treatments tested in this trial

  • Standard of care

    Drug

    2022 WHO First Line Induction Therapy: 1. Liposomal Amphotericin B 10mg/kg IV given once 2. Flucytosine 100mg/kg/day for 14 days in divided doses 3. Fluconazole 1200mg/day for 14 days Consolidation Therapy: Fluconazole 800mg/day from 2 to 10 weeks Secondary Prophylaxis: Fluconazole 200mg/day through 1 year minimum

  • Oteseconazole - antifungal therapy 1

    Drug

    Oteseconazole, is an azole metalloenzyme inhibitor targeting the fungal sterol, 14α demethylase (CYP51) * Loading doses of oral Oteseconazole 600 mg twice daily for 10 days, then 600 mg oteseconazole weekly on weeks 3, 4, 5, and 6. * Liposomal Amphotericin B 10 mg/kg IV once. * No fluconazole or 5FC to be given.

  • Turletricin injection - antifungal therapy 2

    Drug

    SF001 2.0 mg/kg IV administered on day 1, followed by 1.5 mg/kg on day 8 with Fluconazole 1200mg/day and flucytosine 100mg/day in divided doses x 14 days

  • Turletricin Injection - antifungal therapy 3

    Drug

    SF001 3.0 mg/kg IV administered on day 1, 8, and 15 with fluconazole 1200mg/day and flucytosine 100mg/day in divided doses x 14 days

  • Oteseconazole with Flucytosine - antifungal therapy 4

    Drug

    Oteseconazole, is an azole metalloenzyme inhibitor targeting the fungal sterol, 14α demethylase (CYP51) ● Loading doses of oral Oteseconazole 600 mg twice daily for 12 days, then 600 mg oteseconazole weekly on weeks 3 to 12. ● Liposomal Amphotericin B 10 mg/kg IV once. ● Flucytosine 100mg/kg given for 7 days.

Treatment groups

2,000 Participants
are divided into 5 treatment groups
Group A: Control groupActive comparator 1 intervention
Group B: Experimental group 1Experimental treatment 1 intervention
Group C: Experimental group 2Experimental treatment 1 intervention
Group D: Experimental group 3Experimental treatment 1 intervention
Group E: Experimental group 4Experimental treatment 1 intervention

Trial outcomes

Primary outcomes

1

Rate of cerebrospinal fluid (CSF) Cryptococcus clearance (Early Fungicidal Activity, or EFA)

quantified by the change of log 10 Cryptococcus CFU/mL CSF/day as measured by serial quantitative CSF fungal cultures over \~2 weeks.

Time frame
2 weeks
2

All-cause mortality

measured at 2-weeks

Time frame
2 weeks

Secondary outcomes

1

Desirability of Outcome Response (DOOR) as ordinal ranked maximum score tested by Win Ratio.

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-weeks

Time frame
18 weeks
2

Survival time through 18 weeks without Cryptococcus culture-positive relapse of meningitis

number of participants

Time frame
18 weeks
3

CSF culture sterility (cumulative incidence over 18 weeks)

Time frame
18 weeks
4

18-week survival time

Time frame
18 weeks

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

David Boulware

Lead sponsor

University of Minnesota

Sponsor institution

Infectious Diseases Institute, Uganda

Collaborator

University of Minnesota

Collaborator

Source ClinicalTrials.gov
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