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NCT Number: NCT06666322

Platform Trial For Cryptococcal Meningitis (PLATFORM-CM)

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.

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Key information

Conditions

HIV Acquired Immunodeficiency Syndrome Bacterial Infections and Mycoses Blood-Borne Infections Central Nervous System Diseases Central Nervous System Fungal Infections Central Nervous System Infections Communicable Diseases Cryptococcal Meningitis Cryptococcosis Genital Diseases HIV Infections Immune System Diseases Immunologic Deficiency Syndromes Infections Lentivirus Infections Meningitis Meningitis, Cryptococcal Meningitis, Fungal Mycoses Nervous System Diseases Neuroinflammatory Diseases RNA Virus Infections Retroviridae Infections Sexually Transmitted Diseases Sexually Transmitted Diseases, Viral Slow Virus Diseases Urogenital Diseases Virus Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Infectious Diseases Institute, Kampala, Uganda

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • CSF cryptococcal antigen (CrAg) positive meningitis
  • Living with HIV
  • 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 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
  • 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

Treatment and study plan

Standard of care

Drug

2022 WHO First Line Induction Therapy:

  • Liposomal Amphotericin B 10mg/kg IV given once
  • Flucytosine 100mg/kg/day for 14 days in divided doses
  • 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.

Primary outcomes

  1. Rate of cerebrospinal fluid (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. All-cause mortality

    Time frame: 2 weeks

    measured at 2-weeks

Secondary outcomes

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

    Time frame: 18 weeks

    • Death by 18-weeks
    • Serious Adverse Event through 18 weeks (e.g. all-cause re- hospitalization, permanent neurologic deficit, etc.), lost to follow up before 10-weeks.
    • Grade 4 lab adverse event by 10 weeks, early discontinuation of study drug, or lost to follow up after 10 weeks.
    • Grade 3 lab adverse event by 10 weeks OR study drug interruption or dose reduction
    • Survival through 18-weeks

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

    Time frame: 18 weeks

    number of participants

  3. CSF culture sterility (cumulative incidence over 18 weeks)

    Time frame: 18 weeks

  4. 18-week survival time

    Time frame: 18 weeks

  5. Use of rescue/additional IV amphotericin beyond scheduled use

    Time frame: 18 weeks

  6. Modified Rankin score on functional status at 18 weeks

    Time frame: 18 weeks

  7. Incidence of laboratory abnormalities by Grade 1-5

    Time frame: 10 weeks

  8. Incidence of serious adverse events

    Time frame: 18 weeks

  9. Incidence of study drug discontinuation or interruption >1 day due to toxicity, by adverse event grade.

    Time frame: 10 weeks

Study contacts

Contact information is provided by the study sponsor or research team.

David Boulware, MD, MPH

CONTACT

[email protected]

612-624-9996

Sponsors and collaborators

Lead sponsor

David Boulware

Other

Collaborators

  • Infectious Diseases Institute, Uganda
  • University of Minnesota

Registry information

Official study title

Platform Trial For Cryptococcal Meningitis

Acronym: PLATFORM-CM

Important dates

Study start
2025
Primary completion
2032
Study completion
2032
First posted
Oct 30, 2024
Registry last updated
Jul 27, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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