Encochleated Oral Amphotericin for HIV-related Cryptococcal Meningitis Trial: Phase 3 Trial

University Of Minnesota, Minneapolis MN

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Abstract

Fungal infections are a common cause of opportunistic infections (OIs) in immunocompromised persons. Among the most severe HIV/AIDS-related OIs are fungal meningitis. Cryptococcal meningitis is the most common cause of adult meningitis in Africa and accounts for ~15% of HIV/AIDS-related deaths globally. Intravenous (IV) amphotericin B with oral flucytosine (5FC) is recommended for cryptococcal meningitis; however, in many resource-limited settings amphotericin is rarely available in routine care. Barriers to availability include cold chain shipping, storage at 4⁰C, IV administration, and toxicity. Even in resource-rich settings like the United States, the necessity of IV therapy and intensive toxicity monitoring prolong hospitalization, increasing both healthcare costs and risks of nosocomial infections. However, an innovative orally-absorbed encochleated amphotericin B (cAMB) has been developed. Oral cAMB is amphotericin B wrapped in a soy-based lipoprotein (i.e. cochleate) that is absorbed and taken up by monocytes/macrophages for targeted intra-cellular delivery. cAMB achieves high intracellular concentrations where the phagocytosed yeast reside but low extracellular concentrations, resulting in minimal toxicity. We have completed Phase I and Phase II human trials in cryptococcal meningitis in Uganda where divided daily doses of 1.8g of oral cAMB were well tolerated with only mild GI side effects. With two standard IV amphotericin B loading doses followed by all oral cAMB therapy through 6 weeks in combination with 5FC, we achieved 97.5% (39/40) 30-day survival and 90% (36/40) 18-week survival. We propose to conduct a phase III multi-site randomized clinical trial as a pivotal FDA registrational trial to determine efficacy and safety of cAMB for initial therapy for HIV-related cryptococcal meningitis. Specific Aim 1. Determine if an encochleated oral formulation of amphotericin B (cAMB) with 5FC achieves non-inferior survival compared with IV amphotericin B with 5FC for HIV-related cryptococcal meningitis. Specific Aim 2. Determine the CSF yeast clearance rate of oral cAMB to quantify its mechanistic activity. Specific Aim 3. Determine if oral cAMB has a superior safety profile as compared to IV amphotericin B. Hypotheses: We hypothesize that 1) oral cAMB will have non-inferior 14-day and 18-week survival, meeting <10% non-inferiority margin, acceptable to FDA; 2) the CSF early fungicidal activity will be >0.30 log10 Cryptococcus colony forming units (CFU)/mL CSF/day over 2 weeks; 3) oral cAMB will have statistically lower incidence of Grade >3 acute kidney injury, anemia, hypokalemia, and hyponatremia. Impact: The results of this clinical trial have the potential to bring the first oral amphotericin B formulation to the global market, substantially expanding a gold-standard treatment currently unavailable for many with cryptococcosis in resource-limited settings around the world and enable outpatient amphotericin therapy.