Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial (EnACT)

Study Overview
=================
Brief Summary
-----------------
This study is designed as two sequential trials. The first is a phase I open label trial to evaluate the safety and tolerability of MAT2203. The maximal tolerated and non-toxic daily dose,will then be moved forward into a multi-day safety trial. The Phase II trial will investigate toxicity and early fungicidal activity (EFA) of MAT2203 with flucytosine.

Detailed Description
-----------------
Cryptococcal meningitis has emerged as one of the most frequent and deadly opportunistic infections in HIV patients. Historically, amphotericin B (AMB) has been considered the gold standard in antifungal treatments due to its broad spectrum of activity and lack of emergence of resistance. However, the use of AMB is limited by side effects, including nephrotoxicity, anemia, and infusion-related reactions. MAT2203 or encochleated oral amphotericin B (cAMB) is a lipid nano-crystal formulation designed for targeted oral delivery of the antifungal drug AMB for treatment of fungal and parasitic infections.

Official Title
-----------------
Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial

Conditions
-----------------
Cryptococcal Meningitis

Intervention / Treatment
-----------------
* Drug: MAT2203
* Drug: Amphotericin B


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Phase 1: Age >18 years Calculated creatinine clearance >70 mL/min/1.73 m2 (measured within 3 months) Written informed consent Phase 2: Cryptococcal meningitis diagnosed by CSF cryptococcal antigen (CRAG) Ability and willingness to provide informed consent Willing to receive protocol-specified lumbar punctures Exclusion Criteria: Phase 1: Symptomatic Current illness Known significant, untreated health problem Inability to take enteral medicine Pregnant or breast feeding Receiving amphotericin B therapy in past 90 days Phase 2: Presenting Glasgow Coma Scale (GCS) < 15 Received 3 or more doses of IV amphotericin therapy within last 30 days Inability to take enteral (oral or nasogastric) medicine Cannot or unlikely to attend regular clinic visits Pregnancy or breastfeeding Receiving chemotherapy or corticosteroids Suspected Paradoxical immune reconstitution inflammatory syndrome (IRIS) Recent initiation of HIV therapy or ART class switch (within 2 weeks)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase I: Persons in Uganda without meningitis or active infections Phase II: HIV-infected persons in Uganda with cryptococcal meningitis
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a single ascending dose study<br>Phase IA will consist of a single ascending dose study in 9 participants to test three doses to determine the max tolerated dose. | Drug: MAT2203<br>* Encochleated amphotericin B<br>* Other names: oral amphotericin B;|
| Experimental: Phase 1b multiple day dosing<br>9 subjects will receive the Phase Ia 100% tolerated MAT2203 dose for 7 days. | Drug: MAT2203<br>* Encochleated amphotericin B<br>* Other names: oral amphotericin B;|
| Experimental: Phase 2 safety and tolerability<br>Safety, tolerability, and microbiologic efficacy of MAT2203 among HIV-infected patients with cryptococcal meningitis compared with standard IV AMB. | Drug: MAT2203<br>* Encochleated amphotericin B<br>* Other names: oral amphotericin B;Drug: Amphotericin B<br>* Intravenous amphotericin B<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Highest dose tolerated without inducing vomiting | Proportion of cAMB daily dose received and tolerated without vomiting within 30 minutes. | 7 days | 
| Evidence of fungicidal activity | CSF early fungicidal activity (EFA) during 2-week induction therapy | 2 weeks |