Platform Trial For Cryptococcal Meningitis

NCT06666322 | Recruiting Phase 2 FDA Drug

• 1 other identifier: IDIM-2024-32879
• Study Type: interventional
• Target: 2,000
• Locations: 1 country
• Sites: 2

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.

Conditions

Hiv; Cryptococcal Meningitis

Outcome Measures

Primary Outcomes (2)

• 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.

  2 weeks

• All-cause mortality

  measured at 2-weeks

  2 weeks

Secondary Outcomes (9)

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

  18 weeks

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

  18 weeks

• 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

Study Arms (5)

Control group

ACTIVE COMPARATOR

randomized to standard of care

Drug: Standard of care

Experimental group 1

EXPERIMENTAL

randomized to experimental antifungal therapy #1

Drug: Oteseconazole - antifungal therapy 1

Experimental group 2

EXPERIMENTAL

randomized to experimental antifungal therapy #2

Drug: Sfu-AM2-19 Injection - antifungal therapy 2

Experimental group 3

EXPERIMENTAL

randomized to experimental antifungal therapy #3

Drug: Antifungal therapy 3

Experimental group 4

EXPERIMENTAL

randomized to experimental antifungal therapy #4

Drug: Antifungal therapy 4

Interventions

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

Control group

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.

Experimental group 1

Sfu-AM2-19 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

Experimental group 2

Antifungal therapy 3 DRUG

To be determined

Experimental group 3

Antifungal therapy 4 DRUG

To be determined

Experimental group 4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Minnesota: lead

Study Sites (2)

Infectious Diseases Institute

Kampala, Uganda

RECRUITING

Mbarara University of Science and Technology

Mbarara, Uganda

RECRUITING

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome; Meningitis, Cryptococcal

Interventions

Standard of Care

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• David R Boulware, MD, MPH

  University of Minnesota

  PRINCIPAL INVESTIGATOR

• David B Meya, MBChB, MMed, PhD

  Uganda

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David Boulware, MD, MPH

CONTACT

612-624-9996; coat.trial@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2024
• First Posted: October 30, 2024
• Study Start: May 28, 2025
• Primary Completion (Estimated): April 21, 2032
• Study Completion (Estimated): April 21, 2032
• Last Updated: January 7, 2026

Record last verified: 2026-01

Locations

UG (2)