Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
MRC (UK) ref: 76201; 1.0
Study information
Scientific title
A randomised controlled clinical trial to evaluate high dose fluconazole with or without flucytosine in the treatment of human immunodeficiency virus (HIV)-associated cryptococcal meningitis
Acronym
Study hypothesis
As of 27/02/2009 this record was updated to include the second phase Step 2 within this record. Ethics approval was extended to include this phase. All additions to this record regarding Step 2 can be found in the relevant field under the title Step 2. The titles for Step 2 are as follows:
Step 2 public title: High dose fluconazole with short course amphotericin B, with or without flucytosine in the treatment of human immunodeficiency virus (HIV)-associated cryptococcal meningitis
Step 2 scientific title: A randomised controlled clinical trial to evaluate high dose fluconazole with short course amphotericin B, with or without flucytosine in the treatment of human immunodeficiency virus (HIV)-associated cryptococcal meningitis
Please also note that the anticipated start and end dates for Step 2 are as follows:
Step 2 anticipated start date: 01/03/2009
Step 2 anticipated end date: 01/01/2010
At the time of registration, the initial trial dates reflected Step 1 of this trial, and therefore these have been amended to include the Step 2 dates as above; the initial end date (for Step 1) was 18/02/2009.
Step 1 hypothesis:
Addition of flucytosine to fluconazole will lead to more rapid sterilisation of cerebrospinal fluid (CSF) in cryptococcal meningitis.
Step 2 hypotheses:
1. In the presence of a short course of amphotericin B, the addition of flucytosine to fluconazole (1200 mg/d) will lead to more rapid sterilisation of cerebrospinal fluid (CSF) in cryptococcal meningitis
2. A short course of amphotericin B will avoid toxicity observed in longer courses of amphotericin B.
Ethics approval
1. Malawi National Health Sciences Research Committee approved on the 8th November 2007 (Step 2 amendment: 17th February 2009)
2. Wandsworth LREC (covering St Georges University of London UK) approved on the 8th January 2008 (Step 2 amendment: 13th February 2009)
3. Institutional review board (IRB) University of North Carolina at Chapel Hill approved on the 29th November 2007 (Step 2 amendment pending as of 26/02/2009)
Study design
Randomised open-labelled controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Cryptococcal meningitis/ HIV
Intervention
Step 1:
1. Fluconazole 1,200 mg/d for two weeks
2. Fluconazole 1,200 mg/d plus flucytosine 100 mg/kg/d for two weeks
After two weeks all patients receive fluconazole 800 mg/d.
Step 2:
1. Amphotericin B 1 mg/kg daily for 7 days plus fluconazole 1200 mg/d (started concurrently) for 2 weeks
2. Amphotericin B 1 mg/kg daily for 7 days, plus fluconazole 1200 mg/d, plus flycytosine 100 mg/kg/day (started concurrently) for 2 weeks
After two weeks all patients receive fluconazole 800 mg/d.
Intervention type
Drug
Phase
Not Applicable
Drug names
Fluconazole, flucytosine
Primary outcome measure
Early fungicidal activity (rate of clearance of infection) of alternative regimens over the first two weeks of therapy.
Secondary outcome measures
1. Clinical and laboratory side effects
2. Mortality at 2 and 10 weeks
Overall trial start date
18/02/2008
Overall trial end date
01/01/2010
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Patients greater than 18 years, either sex
2. A first episode of cryptococcal meningitis
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
80
Participant exclusion criteria
1. Alanine aminotransferase (ALT) greater than five times the upper limit of normal
2. Pregnancy or lactation
3. Previous serious reaction to study drugs
4. Taking systemic anti-fungals
5. Polymorphonuclear leukocytes (PMNs) less than 500 x 10^6/L
6. Platelets less than 50,000 x 10^6/L
7. Concomitant medication that is contraindicated with any study drugs
8. Already on antiretroviral therapy (ART)
STEP 2 additional criteria:
9. Initial creatinine greater than 2.5 mg/dl
Recruitment start date
18/02/2008
Recruitment end date
01/01/2010
Locations
Countries of recruitment
Malawi
Trial participating centre
Cranmer Terrace
London
SW17 ORE
United Kingdom
Sponsor information
Organisation
St George's University of London (UK)
Sponsor details
Cranmer Terrace
London
SW17 ORE
United Kingdom
Sponsor type
University/education
Website
Funders
Funder type
Research council
Funder name
Medical Research Council (UK) (grant ID: 76201)
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
Federal/National Government
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2009 results in http://www.ncbi.nlm.nih.gov/pubmed/20038244
Publication citations
-
Results
Nussbaum JC, Jackson A, Namarika D, Phulusa J, Kenala J, Kanyemba C, Jarvis JN, Jaffar S, Hosseinipour MC, Kamwendo D, van der Horst CM, Harrison TS, Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi., Clin. Infect. Dis., 2010, 50, 3, 338-344, doi: 10.1086/649861.