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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT06414512
Other study ID # STUDY00017800
Secondary ID
Status Recruiting
Phase Phase 2
First received
Last updated
Start date April 9, 2024
Est. completion date September 1, 2024

Study information

Verified date May 2024
Source University of Minnesota
Contact David Boulware
Email coat.trial@gmail.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

Cryptococcal meningitis (CM) 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 Africa where the ongoing HIV/AIDS pandemic leads to higher prevalence of cryptococcosis. Combination of amphotericin and flucytosine (5-FC) is the mainstay of therapy for the initial management of CM. Indeed, it has even been shown that effective delivery of these therapies in Africa can lower mortality rates by 90%. This is a prospective open-label trial to compare the efficacy and safety of lower doses of 5FC during induction therapy to historical controls with standard 5FC dosing. Participants in the trial will receive 60mg/kg/day of 5-FC in 3 divided doses for 10 days. Single-dose liposomal amphotericin (10mg/kg) is preferred, if available. Amphotericin B 0.7-1.0 mg/kg/day may be used if needed. Historical controls drawn from the AMBITION trial will be used as a comparison group, selected weighted by inclusion/exclusion criteria, baseline characteristics and therapies received. Induction therapy for control group participants followed the 2018 WHO cryptococcal guidelines with 7 days of 5-FC 100mg/kg/day and 7 days of IV Amphotericin deoxycholate followed by 1200mg fluconazole/day for 7 days. The intervention group received single- dose liposomal amphotericin plus 5-FC and fluconazole 1200 mg/day. All participants will receive fluconazole 1200mg/day during consolidation therapy from day 1 to 14 then 800mg/day from day 15 to 10 weeks, and 200mg/day after 10 weeks. All participants will receive lumbar punctures at diagnosis, day 3, day 5-7, day 10-14, and additionally as required for control of intracranial pressure and documentation of CSF sterilization. Controls from Ambition will be matched for the same LP windows. Therapeutic LPs conducted during the first week have a ~70% relative survival benefit.


Recruitment information / eligibility

Status Recruiting
Enrollment 36
Est. completion date September 1, 2024
Est. primary completion date September 1, 2024
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - CSF cryptococcal antigen (CrAg) positive meningitis - Ability and willingness to provide informed consent - Willing to receive protocol-specified lumbar punctures Exclusion Criteria: - Age <18 years - Inability to take enteral (oral or nasogastric) medicine - Cannot or unlikely to attend regular clinic visits - Receiving chemotherapy or corticosteroids - Suspected Paradoxical immune reconstitution inflammatory syndrome (IRIS) - Pregnancy or breastfeeding - CrCl < 20 mL/minute - Absolute neutrophil count <500 x10 6 cells/L - Thrombocytopenia < 50,000 x 10 6 cells/L - Patients with prior 5-flucytosine exposure >3 days in the 12 months prior to enrollment - Any condition for which participation would not be in the best interest of the participant or that could limit protocol specified assessments.

Study Design


Intervention

Drug:
AMBITION trial control
Induction therapy for control group participants followed the 2018 WHO cryptococcal guidelines with 7 days of 5-FC 100mg/kg/day and 7 days of IV Amphotericin deoxycholate followed by 1200mg fluconazole/day for 7 days.
Flucytosine
Participants in the trial will receive 60mg/kg/day of 5-FC in 3 divided doses for 10 days. Single-dose liposomal amphotericin (10mg/kg) is preferred, if available. Amphotericin B 0.7-1.0 mg/kg/day may be used if needed.

Locations

Country Name City State
Uganda Infectious Disease Institute, Mulago Hospital Complex Kampala
Uganda Mbarara University of Science and Technology Mbarara

Sponsors (1)

Lead Sponsor Collaborator
University of Minnesota

Country where clinical trial is conducted

Uganda, 

Outcome

Type Measure Description Time frame Safety issue
Primary Rate of 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
Secondary CSF culture sterility cumulative incidence over 18 weeks 18 weeks
Secondary 18-week survival time 18 weeks
See also
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Completed NCT00976040 - Optimal Time to Start Antiretroviral Therapy in HIV-infected Adults With Cryptococcal Meningitis Phase 4
Completed NCT04031833 - Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial (EnACT) Phase 1/Phase 2
Completed NCT00830856 - Early Versus Delayed Antiretroviral Therapy (ART) in the Treatment of Cryptococcal Meningitis in Africa N/A
Completed NCT04532463 - Clinical Effectiveness and Safety of Amphotericin B With Flucytosine-Fluconazole Therapy for Cryptococcal Meningitis
Completed NCT02098525 - Clinical Outcomes of Cryptococcal Meningitis Among HIV-infected Patients in the Era of Antiretroviral Therapy N/A
Completed NCT01075152 - Cryptococcal Optimal ART Timing Trial Phase 4
Active, not recruiting NCT01715922 - Study Evaluating Efficiency and Tolerance of High-dose Fluconazole Associated With Flucytosine as Induction Therapy for Cryptococcal Meningitis Associated With HIV in Sub-saharan Africa Phase 2/Phase 3
Completed NCT00145249 - Amphotericin Alone or in Combination With Fluconazole for AIDS-Associated Meningitis Phase 2
Completed NCT01802385 - Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis Phase 3
Terminated NCT00324025 - Efficacy and Safety of Mycograb as Adjunctive Therapy for Cryptococcal Meningitis in Patients With AIDS Phase 2
Completed NCT02955862 - Vietnam Cryptococcal Retention in Care Study (CRICS) Federal Financial Report Phase 1
Recruiting NCT03945448 - Single Dose Liposomal Amphotericin for Asymptomatic Cryptococcal Antigenemia Phase 2/Phase 3
Active, not recruiting NCT02624453 - Pre-Antiretroviral Therapy (ART) Cryptococcal Antigen Screening in AIDS N/A
Recruiting NCT00867269 - Etiology, Pathogenesis, and Natural History of Idiopathic CD4+ Lymphocytopenia
Completed NCT01535469 - Operational Research for Cryptococcal Antigen Screening Phase 4
Active, not recruiting NCT04072640 - Three Induction Treatments on Cryptococcal Meningitis Early Phase 1
Not yet recruiting NCT05541107 - Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial 3 Phase 3
Not yet recruiting NCT02686853 - Efficacy of Intrathecal Administration of Liposomal Amphotericin B in Cryptococcal Meningitis Phase 4
Not yet recruiting NCT04140461 - AmB Dose for Cryptococcal Meningitis Phase 3