Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial

Abstract

Background: Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed.

Methods: In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus-associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA).

Results: We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10 Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin.Grade 3-4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04).

Conclusions: This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin.

Clinical trials registration: NCT04031833.

Keywords: AIDS-related opportunistic infection; HIV; amphotericin B; cryptococcal meningitis; randomized controlled trial.

Graphical Abstract

Figure 1.

Oral LNC amphotericin B randomized trial design. Cohort 1 was a pilot assessing tolerability and toxicity of oral lipid nanocrystal (LNC) amphotericin B (ampho) in an ill population with advanced human immunodeficiency virus disease and cryptococcal meningitis. After Cohort 1, investigators reduced the LNC amphotericin B dose from 333 mg per unit dose to 300 mg per unit dose with induction therapy at a 1.8 g daily total dose and consolidation therapy from week 2 to week 6 at a 1.2 g daily total dose. Cohort 3 was a safety pilot assessing an initial all-oral regimen with scheduled IV amphotericin B given from day 6 to day 14. Cohort 2 and cohort 4 assessed efficacy of a 6-week oral LNC amphotericin B regimen with or without 2 IV amphotericin B loading doses, respectively. Randomized controls were pooled across all 4 cohorts, receiving IV liposomal amphotericin B 3 mg/kg (n = 22) or IV amphotericin B deoxycholate 1 mg/kg (n = 19). Flucytosine was administered at 100 mg/kg/d in 4 divided doses. This 4-stage trial was designed to maximize participant safety using a new experimental therapy for a 100% fatal infection. *Randomization was stratified by first vs second episode of cryptococcosis, resulting in cohort 2 enrolling 1 more participant randomized to control (n = 57 in total). Abbreviations: 5FC, flucytosine; Ampho, amphotericin B; IV, intravenous; LNC, lipid nanocrystal.

Figure 2.

CONSORT (Consolidated Standards of Reporting Trials) diagram. Randomization occurred in a 2.5:1 ratio in 4 sequential cohorts, stratified by first (n = 139) vs second (n = 2) episode of cryptococcal meningitis. The randomized IV amphotericin B controls were pooled across the 4 cohorts with n = 41 in total as 1 pooled overall control group for comparison. Abbreviations: CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; IV, intravenous; LNC, lipid nanocrystal; MAT2203, lipid nanocrystal amphotericin B (Matinas Biopharma).

Figure 3.

Survival through 18 weeks with oral LNC amphotericin B (MAT2203; Matinas Biopharma) vs IV amphotericin B with (A) and without (B) 2 IV amphotericin loading doses. The standard-of-care control arm received liposomal amphotericin B (n = 22) at 3 mg/kg/d or amphotericin B deoxycholate (n = 19) 1 mg/kg/d for 7 days with flucytosine followed by fluconazole 1200 mg/d through day 14. Oral LNC amphotericin B regimens were given with oral flucytosine 100 mg/kg daily for 2 weeks. After 2 weeks, all participants received fluconazole 800 mg/d to week 10, then secondary prophylaxis with fluconazole 200 mg/d. Absolute risk difference calculated with Wald 95% confidence intervals. Abbreviations: CI, confidence interval; IV, intravenous; LNC, lipid nanocrystal.