High dose fluconazole with or without flucytosine in the treatment of human immunodeficiency virus (HIV)-associated cryptococcal meningitiscryptococcal meningitis

ISRCTN ISRCTN02725351
DOI https://doi.org/10.1186/ISRCTN02725351
Secondary identifying numbers MRC (UK) ref: 76201; 1.0
Submission date
11/02/2008
Registration date
20/03/2008
Last edited
05/01/2010
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Infections and Infestations
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Thomas Harrison
Scientific

Cranmer Terrace
London
SW17 ORE
United Kingdom

Study information

Study designRandomised open-labelled controlled trial
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Hospital
Study typeTreatment
Participant information sheet Not available in web format, please use the contact details below to request a patient information sheet
Scientific titleA randomised controlled clinical trial to evaluate high dose fluconazole with or without flucytosine in the treatment of human immunodeficiency virus (HIV)-associated cryptococcal meningitis
Study objectivesAs 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(s)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)
Health condition(s) or problem(s) studiedCryptococcal meningitis/ HIV
InterventionStep 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 typeDrug
Pharmaceutical study type(s)
PhaseNot Applicable
Drug / device / biological / vaccine name(s)Fluconazole, flucytosine
Primary outcome measureEarly fungicidal activity (rate of clearance of infection) of alternative regimens over the first two weeks of therapy.
Secondary outcome measures1. Clinical and laboratory side effects
2. Mortality at 2 and 10 weeks
Overall study start date18/02/2008
Completion date01/01/2010

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
SexAll
Target number of participants80
Key inclusion criteria1. Patients greater than 18 years, either sex
2. A first episode of cryptococcal meningitis
Key exclusion criteria1. 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
Date of first enrolment18/02/2008
Date of final enrolment01/01/2010

Locations

Countries of recruitment

  • Malawi
  • United Kingdom

Study participating centre

Cranmer Terrace
London
SW17 ORE
United Kingdom

Sponsor information

Funders

Funder type

Research council

Medical Research Council (UK) (grant ID: 76201)
Government organisation / National government
Alternative name(s)
Medical Research Council (United Kingdom), UK Medical Research Council, MRC
Location
United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing plan

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Results article results 01/02/2010 Yes No
BMC - Part of Springer Nature Springer Nature