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
Protocol serial number	MRC (UK) ref: 76201; 1.0
Sponsor	St George's University of London (UK)
Funder	Medical Research Council (UK) (grant ID: 76201)

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

Primary study design	Interventional
Study design	Randomised open-labelled controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
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
Study objectives	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(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) studied	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 / device / biological / vaccine name(s)	Fluconazole, flucytosine
Primary outcome measure(s)	Early fungicidal activity (rate of clearance of infection) of alternative regimens over the first two weeks of therapy.
Key secondary outcome measure(s)	1. Clinical and laboratory side effects 2. Mortality at 2 and 10 weeks
Completion date	01/01/2010

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	80
Key inclusion criteria	1. Patients greater than 18 years, either sex 2. A first episode of cryptococcal meningitis
Key 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
Date of first enrolment	18/02/2008
Date of final enrolment	01/01/2010

Locations

Countries of recruitment

United Kingdom
Malawi

Study participating centre

Cranmer Terrace

London
SW17 ORE
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not 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
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes