Condition category
Infections and Infestations
Date applied
11/02/2008
Date assigned
20/03/2008
Last edited
05/01/2010
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Prof Thomas Harrison

ORCID ID

Contact details

Cranmer Terrace
London
SW17 ORE
United Kingdom

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 measures

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

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

http://www.sgul.ac.uk

Funders

Funder type

Research council

Funder name

Medical Research Council (UK) (grant ID: 76201)

Alternative name(s)

MRC

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

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

Results - basic reporting

Publication summary

2009 results in http://www.ncbi.nlm.nih.gov/pubmed/20038244

Publication citations

  1. 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.

Additional files

Editorial Notes