This multicenter, randomized, double-blind, parallel-group clinical trial is designed to evaluate Mycograb® versus placebo as adjunctive therapy to antifungal induction therapy (amphotericin B plus 5-flucytosine) in subjects who have acute cryptococcal meningitis associated with AIDS. After pre-study screening and baseline assessments and meeting all inclusion criteria, on Day 1 subjects will be randomized to 1 of 2 treatment arms:
- Amphotericin B (conventional at 0.7 mg/kg, i.v. once daily) plus 5-flucytosine (100 mg/kg orally daily, divided QID), with placebo.
- Amphotericin B (conventional at 0.7 mg/kg, i.v. once daily) plus 5-flucytosine (100 mg/kg orally daily, divided QID), with Mycograb®.
Study medication will be administered via a central line or peripheral venous line twice daily for 7 consecutive days (Days 1-7). A lumbar puncture (LP) with CSF culture colony counts, India ink microscopy, and measurement of cryptococcal antigen (CrAg) will be performed at Baseline, Days 3, 7, and 14, and Week 10. CSF will also be assayed for concentrations of Mycograb® on Days 3, 7, and 14. The primary efficacy parameter will be fungicidal activity, measured by the rate of reduction in CSF cryptococcal colony-forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of treatment (20).
A complimentary clinical trial will be run in parallel with this study in South America and South Africa, where there is a much higher incidence of cryptococcosis. The protocol used will be essentially as described here except that, because of the greater number of patients, there will be an additional third treatment arm of Mycograb® plus amphotericin B.
An interim analysis will be performed after 30 patients (US and/or non-US) have completed Day 14, for the following reasons:
- To evaluate whether the primary endpoint chosen for this study is the most appropriate.
- To assess whether the dosing level of 1 mg/kg Mycograb® twice daily is adequate, or if the dose should be increased to 2 mg/kg twice daily
- To evaluate the safety of Mycograb® by reviewing the adverse events classified by the investigator as possibly related to the study drug
- To adjust the proposed sample size if necessary.
A Safety Monitoring Committee and an independent expert will assess the safety profile of Mycograb®. The decision as to whether or not it would be beneficial to increase the dose will be based on the drug`s safety profile, the CSF levels and a preliminary assessment of efficacy.
A total of 40 completed patients are planned for the US. It is estimated that enrollment will require 54 screened and 48 enrolled to achieve 40 completed patients. The total duration of the trial will be approximately 24 months. If the recruitment rate is low in the US, the number from the US may be reduced, having been replaced by patients outside the US where cryptococcosis is commoner.
Purpose
