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

Phase 2

• Conditions: Cryptococcal Meningitis; HIV
• Interventions: Drug: Fluconazole; Drug: Flucytosine; Procedure: lumbar punctures

• Registration Number: NCT01715922
• Lead Sponsor: ANRS, Emerging Infectious Diseases

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2012-05
• Study First Submitted: 2012-10-19
• Study First Submitted QC: 2012-10-25
• Study First Posted: 2012-10-29
• Primary Completion: 2015-09
• Status Verified: 2016-07
• Last Update Submitted: 2016-07-11
• Last Update Posted: 2016-07-12
• Study Completion: 2016-09

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 41

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
oral treatment	Flucytosine	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)
oral treatment	lumbar punctures	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)
oral treatment	Fluconazole	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)

Primary Outcome Measures

Name	Time	Method
Mortality rate	10 weeks

Secondary Outcome Measures

Name	Time	Method
Mortality rate	14 days and 24 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
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
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
Percentage of patients with negative cerebrospinal fluid (CSF) cultures	14 days and 10 weeks
Number of lumbar punctures performed	up to 24 weeks
Concentration of fluconazole in cerebrospinal fluid	28 days or 10 weeks
Number of relapses of cryptococcal throughout the monitoring period	up to 24 weeks
Concentration of fluconazole in plasma	28 days or 10 weeks
Percentage of patients with undetectable viral load	24 weeks

Trial Locations

Locations (5)

Hôpital général; 🇧🇮 Muyinga, Burundi

Service de Maladies Infectieuses & Tropicales - Hôpital Triechville; 🇨🇮 Abidjan, Côte D'Ivoire

CHU Kamenge; 🇧🇮 Bujumbura, Burundi

Hôpital Prince Régent Charles; 🇧🇮 Bujumbura, Burundi

Service de Neurologie - Hôpital Cocody; 🇨🇮 Abidjan, Côte D'Ivoire