Efficacy and Safety of Mycograb as Adjunctive Therapy for Cryptococcal Meningitis in Patients With AIDS

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Mycograb® as Adjunctive Therapy for Cryptococcal Meningitis in Patients With AIDS

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter efficacy and safety trial to evaluate Mycograb®. Subjects will be randomized to receive either Mycograb® (dosed 1 mg/kg) or placebo during the first week of induction therapy (amphotericin B plus 5-flucytosine) via a central line or peripheral venous line twice daily for 7 consecutive days. The total duration of the study will be approximately 24 months.

Study Overview

• Status: Terminated
• Conditions: Cryptococcal Meningitis
• Intervention / Treatment: Drug: placebo; Drug: Mycograb

Detailed Description

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 with CSF culture colony counts, India ink microscopy, and measurement of cryptococcal antigen (CrAg) will be performed at Baseline, Days 3, 7, and 14,. CSF will also be assayed for concentrations of Mycograb® on Days 3, 7, and 14. The primary efficacy parameter will be the proportion of subjects considered cured at day 14 (combined clinical AND mycological outcome).

A complimentary clinical trial will be run in parallel with this study in South America and South Africa. The protocol used will be essentially as described here except that there will be an additional (3rd) treatment arm (Amphotericin B [conventional at 0.7 mg/kg, i.v. once daily}with Mycograb®)..

An interim analysis will be performed after 30 patients (US and/or non-US) have completed Day 14, for the following reasons:

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®.

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 more prevalent.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama School of Medicine
  • Texas
    • San Antonio, Texas, United States, 78229
      • Department of Medicine/Infectious Disease, MC 7881, University of Texas Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

Male or non-pregnant female who is >18 years old, HIV-positive or unknown, with acute, either first or recurrent episode of cryptococcal meningitis Currently on no treatment, or receiving treatment (< 3 days) with either amphotericin B plus 5-flucytosine, or amphotericin B alone. Positive CSF culture for Cryptococcus neoforman. Physical signs and symptoms of meningitis, evidenced by one or more of the following: fever, headache, meningeal signs and neurologic findings.

Exclusion criteria:

Excluded for coma, or significant other medical conditions. Subject has other opportunistic fungal infections that requires other systemic antifungal therapies.

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Mycograb	Drug: Mycograb
Active Comparator: 2; biological	Drug: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
proportion of patients cured (combined clinical and microbiological response) versus placebo	Day 14

Secondary Outcome Measures

Outcome Measure	Time Frame
Assess the cerebrospinal fluid (CSF) penetration of Mycograb	Days 3, 7 and 14
Safety of Mycograb versus placebo. Safety assessment will include: physical examination, vital signs, laboratory parameters, adverse events, serious adverse events.	Week 10

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, MD, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): September 1, 2007
• Study Completion (Actual): September 1, 2007

Study Registration Dates

• First Submitted: May 8, 2006
• First Submitted That Met QC Criteria: May 8, 2006
• First Posted (Estimate): May 10, 2006

Study Record Updates

• Last Update Posted (Estimate): December 12, 2008
• Last Update Submitted That Met QC Criteria: December 11, 2008
• Last Verified: December 1, 2008

More Information

Terms related to this study

• Keywords: Cryptococcal meningitis
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections and Mycoses; Mycoses; Meningitis, Fungal; Central Nervous System Fungal Infections; Cryptococcosis; Meningitis; Meningitis, Cryptococcal; Anti-Infective Agents; Antifungal Agents; Efungumab
• Other Study ID Numbers: MYC123A2202; NTP/Mycograb/003A