Study Evaluating Efficiency and Tolerance of High-dose Fluconazole Associated With Flucytosine as Induction Therapy for Cryptococcal Meningitis Associated With HIV in Sub-saharan Africa (Flucocrypto)

Prospective Pilot Study to Evaluate a Standardized Management of Cryptococcal Meningitis in Patients Infected With HIV in Sub-Saharan Africa Involving an Initial Combination Therapy With Fluconazole and Flucytosine in High Doses, Complemented by Repeat Lumbar Punctures

The aim of the trial is to demonstrate that in a sub-Saharan African setting, the association of:

1. Oral treatment : high dose of fluconazole (1600mg/d) associated with flucytosine (100 mg/kg/j) as induction therapy
2. lumbar punctures to control intracranial pressure

can decrease mortality rate below 35% at 10 weeks.

This is a non-randomized open label pilot study, with standardized management of cryptococcoses meningitis and follow-up in Burundi and Ivory Coast. A total of 41 patients will be enrolled.

Study Overview

• Status: Unknown
• Conditions: HIV; Cryptococcal Meningitis
• Intervention / Treatment: Drug: Fluconazole; Drug: Flucytosine; Procedure: lumbar punctures

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Burundi
  • Bujumbura, Burundi
    • CHU Kamenge
  • Bujumbura, Burundi
    • Hôpital Prince Régent Charles
  • Bururi, Burundi
    • Hôpital Général
  • Kayanza, Burundi
    • Hôpital Général
  • Muyinga, Burundi
    • Hôpital Général
• Côte D'Ivoire
  • Abidjan, Côte D'Ivoire
    • Service de Maladies Infectieuses & Tropicales - Hôpital Triechville
  • Abidjan, Côte D'Ivoire
    • Service de Neurologie - Hôpital Cocody

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:

• > 18 years
• HIV Infection
• First episode of cryptococcal meningitis on basis CSF India ink and/or CSF cryptococcal antigen.
• Glasgow > 9 after lumbar punctures
• Absence of peripheral focal deficit in the limbs
• informed consent signed

Exclusion Criteria:

• Hemoglobin <7.5 g / dl;
• neutrophils count <500/mm3;
• Platelets count <50 000/mm3;
• transaminases > 5 times upper limit of normal;
• Troubles with severe mental alertness Glasgow <9 after the initial lumbar puncture;
• focal neurological deficit in the limbs;
• Pregnancy or lactation on going;
• Ongoing systemic antifungal treatment;
• History of cryptococcal meningitis;
• Ongoing rifampicin and ritonavir treatment;
• Subject participating in another study with a risk of mutual interference on the interpretation of results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: oral treatment; Drug: Fluconazole and flucytosine Induction treatment for 2 weeks: Fluconazole (1600mg/j) + flucytosine (100 mg/kg/j) lumbar punctures to control intracranial pressure Consolidation treatment for 8 weeks: fluconazole (800 mg/j)	Drug: Fluconazole; Induction treatment for 2 weeks: Fluconazole (1600mg/j) Consolidation treatment for 8 weeks: fluconazole (800 mg/j); Drug: Flucytosine; Flucytosine (100 mg/kg/j) for 2 weeks; Procedure: lumbar punctures; lumbar punctures to control intracranial pressure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mortality rate	10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality rate		14 days and 24 weeks
Percentage of patients with negative cerebrospinal fluid (CSF) cultures		14 days and 10 weeks
Number of relapses of cryptococcal throughout the monitoring period		up to 24 weeks
Number of "Immune Reconstitution Inflammatory Syndrome" (IRIS) throughout the monitoring period	The IRIS diagnosis criteria will be those given in: Bicanic T, et al. Immune Reconstitution Inflammatory Syndrome in HIV-associated cryptococcal meningitis: a prospective study, J Acquir Immune Defic Syndr 2009; 51:130-134.	up to 24 weeks
Number and severity of adverse events		up to 24 weeks
Cerebrospinal fluid pressure evolution		up to 24 weeks
Percentage of patients with undetectable viral load		24 weeks
CD4 count		24 weeks
Concentration of flucytosine in cerebrospinal fluid		28 days or 10 weeks
Sensitivity of cryptococcal antigen by strip method LFA (lateral-flow immunoassay)	on urines, plasma, CSF and whole blood fingerstick	at study entry
CSF total volume discharged		up to 24 weeks
Number of lumbar punctures performed		up to 24 weeks
Concentration of fluconazole in plasma		28 days or 10 weeks
Concentration of fluconazole in cerebrospinal fluid		28 days or 10 weeks
Concentration of flucytosine in plasma		28 days or 10 weeks
MICs of fluconazole	MICs of fluconazole for cryptococcus strains, if CSF cultures ar positive at 28 days or 10 weeks or in case of relapse	28 days

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Collaborators: Institut Pasteur; Hôpital Necker-Enfants Malades; Hospital Avicenne; CHU Kamenge, BURUNDI; Institut de Médecine et Epidémiologie Appliquée (IMEA); Hôpital de Treichville; Hôpital Cocody
• Investigators: Study Chair: Olivier Bouchaud, PhD, Hopital Avicenne, Service des maladies infectieuses, Paris, france; Study Chair: Théodore Niyangobo, PhD, CHU Kamenge, Bujumbura, Burundi; Principal Investigator: Amélie Chabrol, MD, Hopital Avicenne, Service des maladies infectieuses, Paris, france; Principal Investigator: Kakou AKA, Professor, CHU Triechville

Publications and helpful links

Helpful Links

• Sponsor web page

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): September 1, 2015
• Study Completion (Anticipated): September 1, 2016

Study Registration Dates

• First Submitted: October 19, 2012
• First Submitted That Met QC Criteria: October 25, 2012
• First Posted (Estimate): October 29, 2012

Study Record Updates

• Last Update Posted (Estimate): July 12, 2016
• Last Update Submitted That Met QC Criteria: July 11, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: HIV Infections; Flucytosine; Burundi; Oral treatment; Cryptococcal meningitis; Ivory Coast; High dose of fluconazole
• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antimetabolites; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Fluconazole; Flucytosine
• Other Study ID Numbers: ANRS 12257 Flucocrypto