Flucocrypto: 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

Sponsor

ANRS, Emerging Infectious Diseases (Other)

Overall Status

Unknown status

CT.gov ID

NCT01715922

Collaborator

CHU Kamenge, BURUNDI (Other), Hospital Avicenne (Other), Institut Pasteur (Industry), Hôpital Necker-Enfants Malades (Other), Institut de Médecine et Epidémiologie Appliquée (IMEA) (Other), Hôpital de Treichville (Other), Hôpital Cocody (Other)

Enrollment

Locations

Arm

Duration (Months)

5.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Oral treatment : high dose of fluconazole (1600mg/d) associated with flucytosine (100 mg/kg/j) as induction therapy
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.

Condition or Disease	Intervention/Treatment	Phase
Cryptococcal Meningitis HIV	Drug: Fluconazole Drug: Flucytosine Procedure: lumbar punctures	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

41 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

May 1, 2012

Actual Primary Completion Date :

Sep 1, 2015

Anticipated Study Completion Date :

Sep 1, 2016

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Mortality rate [10 weeks]

Secondary Outcome Measures

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 [up to 24 weeks]
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.
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) [at study entry]
on urines, plasma, CSF and whole blood fingerstick
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 [28 days]
MICs of fluconazole for cryptococcus strains, if CSF cultures ar positive at 28 days or 10 weeks or in case of relapse

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country
1	CHU Kamenge	Bujumbura	Burundi
2	Hôpital Prince Régent Charles	Bujumbura	Burundi
3	Hôpital général	Bururi	Burundi
4	Hôpital général	Kayanza	Burundi
5	Hôpital général	Muyinga	Burundi
6	Service de Maladies Infectieuses & Tropicales - Hôpital Triechville	Abidjan	Côte D'Ivoire
7	Service de Neurologie - Hôpital Cocody	Abidjan	Côte D'Ivoire

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