Cryptococcal Meningitis, Hiv
Conditions
Keywords
cryptococcus
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 antifungal regimens using standardized eligibility criteria, standardized study schedule of events, and standardized contemporary endpoints.
Interventions
DRUGStandard 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
DRUGOteseconazole - 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.
DRUGTurletricin 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
DRUGTurletricin Injection - antifungal therapy 3
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
DRUGOteseconazole with Flucytosine - antifungal therapy 4
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.
Sponsors
David Boulware
Infectious Diseases Institute, Uganda
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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-weeks |
| Survival 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 | — |
Countries
Uganda
Contacts
CONTACTDavid Boulware, MD, MPH
PRINCIPAL_INVESTIGATORDavid R Boulware, MD, MPH
University of Minnesota
PRINCIPAL_INVESTIGATORDavid B Meya, MBChB, MMed, PhD
Uganda
Outcome results
None listed