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.

Conditions

• Hiv
• Cryptococcal Meningitis

Intervention / Treatment

• Drug: Standard of care
• Drug: Oteseconazole - antifungal therapy 1
• Drug: Turletricin injection - antifungal therapy 2
• Drug: Turletricin Injection - antifungal therapy 3
• Drug: Oteseconazole with Flucytosine - antifungal therapy 4

Primary Outcome Measures

• 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

Countries

Uganda

Locations and Investigators

• Infectious Diseases Institute, Kampala, Uganda (Recruiting)
  • David Meya, PhD
• Mbarara University of Science and Technology, Mbarara, Uganda (Recruiting)
  • Conrad Muzoora, MBChB MMed

Study Officials

• David R Boulware, MD, MPH (Principal Investigator) — University of Minnesota
• David B Meya, MBChB, MMed, PhD (Principal Investigator) — Uganda