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Combination anti-fungal therapy in cryptococcal meningitis
ISRCTN ISRCTN95123928
DOI 10.1186/ISRCTN95123928
ClinicalTrials.gov identifier
EudraCT number
Public title Combination anti-fungal therapy in cryptococcal meningitis
Scientific title A randomised controlled trial of combination anti-fungal therapy in cryptococcal meningitis
Acronym BK Study
Serial number at source 061330
Study hypothesis Cryptococcal meningitis is the second leading cause of death in Human Immunodeficiency Virus (HIV) patients worldwide after Tuberculosis (TB). The Hospital for Tropical Diseases has seen a dramatic increase in the number of cases of cryptococcal meningitis as the HIV epidemic has accelerated in Viet Nam. The mortality rate is high, even with treatment according to international guidelines. Optimum treatment for cryptococcal meningitis is not determined. Combination treatment with amphotericin and flucytosine has shown no clinical benefit when compared with amphotericin alone, yet this combination of potentially toxic drugs has become the standard of care, recommended in US and European guidelines.

The azole drugs, with their ease of administration and good safety profile, have not been investigated in combination with amphotericin in the treatment of cryptococcal meningitis. The trial will determine whether amphotericin combined with high dose fluconazole is superior to amphotericin alone or amphotericin combined with flucytosine, using clinical endpoints.

As of 18/03/2009 the anticipated trial dates of this record have been updated; the intial trial dates at the time of registration were:
Initial anticipated start date: 01/04/2004
Initial anticipated end date: 01/01/2006
Lay summary Not provided at time of registration
Ethics approval The ethical review board of the Hospital for Tropical Diseases, Ho Chi Minh City, and Liverpool School of Tropical Medicine, UK gave approval prior to participant recruitment.
Study design Open label randomised controlled trial
Countries of recruitment Viet Nam
Disease/condition/study domain Cryptococcal meningitis
Participants - inclusion criteria 1. Patients aged 15 years and older
2. HIV positive
3. Cryptococcal meningitis defined by a clinical syndrome consistent with cryptococcal meningitis and one or more of: positive Cerebrospinal Fluid (CSF) culture, positive cryptococcal antigen in CSF, positive CSF india ink test
Participants - exclusion criteria 1. Pregnancy
2. Renal or liver failure
3. Active TB
4. Aged less than 15 years old
Anticipated start date 22/04/2004
Anticipated end date 01/12/2009
Status of trial Completed
Patient information material
Target number of participants 300 (237 as of March 2009)
Interventions Treatment Group 1:
Induction Treatment: Amphotericin 1 mg/kg/day for 4 weeks
Consolidation Treatment: Fluconazole 400 mg/day for 6 weeks
Secondary Prophylaxis: Fluconazole 200 mg/day

Treatment Group 2:
Induction Treatment: Amphotericin 1 mg/kg/day plus flucytosine 100 mg/kg/day for 2 weeks
Consolidation Treatment: Fluconazole 400 mg/day for 8 weeks
Secondary Prophylaxis: Fluconazole 200 mg/day

Treatment Group 3:
Induction Treatment: Amphotericin 1 mg/kg/day plus Fluconazole 800 mg/day for 2 weeks
Consolidation Treatment: Fluconazole 400 mg/day for 8 weeks
Secondary Prophylaxis: Fluconazole 200 mg/day
Primary outcome measure(s) Mortality at 2 and 10 weeks
Secondary outcome measure(s) Amended as of 19/03/2009:
1. Rates of disability at 10 weeks
2. Rates of clearance of yeasts from CSF at 6 months
3. Changes in immune parameters at 6 months
4. Combined death and disability at 6 months
5. Death at 6 months

Initial information at the time of registration:
1. Duration of ventilation
2. Duration of supplemental oxygen
3. Duration of hospitalisation
4. Viral load in clinical specimens
5. Cytokine levels
6. Adverse effects
Sources of funding The Wellcome Trust (UK) (grant ref: 061330)
Trial website
Publications 1. 2013 results in http://www.ncbi.nlm.nih.gov/pubmed/23550668
Contact name Dr  Jeremy  Farrar
  Address Hospital for Tropical Diseases
The Hospital for Tropical Diseases
Oxford University Clinical Research
190 Ben Ham Tu
  City/town Ho Chi Minh City
  Zip/Postcode 5
  Country Viet Nam
  Tel +84 88362225
  Fax +84 89238904
  Email jfarrar@oucru.org
Sponsor University of Oxford (UK)
  Address University Offices
Wellington Square
  City/town Oxford
  Zip/Postcode OX1 2JD
  Country United Kingdom
  Tel +44 (0)1865 270143
  Fax +44 (0)1865 280467
  Email research.services@admin.ox.ac.uk
  Sponsor website: http://www.ox.ac.uk
Date applied 22/07/2005
Last edited 05/04/2013
Date ISRCTN assigned 22/07/2005
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