Platform Trial For Cryptococcal Meningitis

NCT ID: NCT06666322

Last Updated: 2026-01-07

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 2000 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-05-28
• Study Completion Date: 2032-04-21

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Control group

randomized to standard of care

Group Type: ACTIVE_COMPARATOR

Standard of care

Intervention Type: 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

Experimental group 1

randomized to experimental antifungal therapy #1

Group Type: EXPERIMENTAL

Oteseconazole - antifungal therapy 1

Intervention Type: 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 2

randomized to experimental antifungal therapy #2

Group Type: EXPERIMENTAL

Sfu-AM2-19 Injection - antifungal therapy 2

Intervention Type: 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 3

randomized to experimental antifungal therapy #3

Group Type: EXPERIMENTAL

Antifungal therapy 3

Intervention Type: DRUG

To be determined

Experimental group 4

randomized to experimental antifungal therapy #4

Group Type: EXPERIMENTAL

Antifungal therapy 4

Intervention Type: DRUG

To be determined

Interventions

Standard of care

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

Intervention Type: DRUG

Oteseconazole - antifungal therapy 1

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.

Intervention Type: DRUG

Sfu-AM2-19 Injection - antifungal therapy 2

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

Intervention Type: DRUG

Antifungal therapy 3

To be determined

Intervention Type: DRUG

Antifungal therapy 4

To be determined

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David R Boulware, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

David B Meya, MBChB, MMed, PhD

Role: PRINCIPAL_INVESTIGATOR

Uganda

Locations

Infectious Diseases Institute

Kampala, , Uganda

Site Status: RECRUITING

Mbarara University of Science and Technology

Mbarara, , Uganda

Site Status: RECRUITING

Countries

Uganda

Central Contacts

David Boulware, MD, MPH

Role: CONTACT

coat.trial@gmail.com

612-624-9996

Facility Contacts

David Meya, PhD

Role: primary

david.meya@gmail.com

Conrad Muzoora

Role: primary

conradmuzoora@gmail.com

256772547175

Other Identifiers

IDIM-2024-32879

Identifier Type: -

Identifier Source: org_study_id