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High dose fluconazole with or without flucytosine in the treatment of human immunodeficiency virus (HIV)-associated cryptococcal meningitiscryptococcal meningitis
ISRCTN ISRCTN02725351
DOI 10.1186/ISRCTN02725351
ClinicalTrials.gov identifier
EudraCT number
Public title High dose fluconazole with or without flucytosine in the treatment of human immunodeficiency virus (HIV)-associated cryptococcal meningitiscryptococcal meningitis
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 N/A
Serial number at source MRC (UK) ref: 76201; 1.0
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.
Lay summary
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
Countries of recruitment Malawi
Disease/condition/study domain Cryptococcal meningitis/ HIV
Participants - inclusion criteria 1. Patients greater than 18 years, either sex
2. A first episode of cryptococcal meningitis
Participants - 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
Anticipated start date 18/02/2008
Anticipated end date 01/01/2010
Status of trial Completed
Patient information material Not available in web format, please use the contact details below to request a patient information sheet
Target number of participants 80
Interventions 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.
Primary outcome measure(s) Early fungicidal activity (rate of clearance of infection) of alternative regimens over the first two weeks of therapy.
Secondary outcome measure(s) 1. Clinical and laboratory side effects
2. Mortality at 2 and 10 weeks
Sources of funding Medical Research Council (UK) (grant ID: 76201)
Trial website
Publications 2009 results in http://www.ncbi.nlm.nih.gov/pubmed/20038244
Contact name Prof  Thomas  Harrison
  Address Cranmer Terrace
  City/town London
  Zip/Postcode SW17 ORE
  Country United Kingdom
Sponsor St George's University of London (UK)
  Address Cranmer Terrace
  City/town London
  Zip/Postcode SW17 ORE
  Country United Kingdom
  Sponsor website: http://www.sgul.ac.uk
Date applied 11/02/2008
Last edited 05/01/2010
Date ISRCTN assigned 20/03/2008
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