Contact information
Type
Scientific
Primary contact
Dr Guy Thwaites
ORCID ID
Contact details
Oxford University Clinical Research Unit
The Hospital for Tropical Diseases
190 Ben Ham Tu
Ho Chi Minh City
5
Viet Nam
+84 (0)8 9237954
guy.thwaites@btinternet.com
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
061330
Study information
Scientific title
A randomised comparison of ciprofloxacin, levofloxacin and gatifloxacin for the treatment of adults with tuberculous meningitis
Acronym
BN study
Study hypothesis
Fluoroquinolones are bactericidal for Mycobacterium tuberculosis and are recommended by the World Health Organisation (WHO) for the treatment of multi-drug resistant pulmonary tuberculosis. Reports of their use in Tuberculous Meningitis (TBM) are restricted to case reports, and there are no controlled trials to clarify their role in management. In particular, data regarding Cerebrospinal Fluid (CSF) penetration and pharmacokinetics are scant, and it is uncertain which of the fluoroquinolones represents the best drug for treating TBM.
Ethics approval
Not provided at time of registration
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Not specified
Trial type
Treatment
Patient information sheet
Condition
Tuberculous meningitis
Intervention
Adults entering the study will be randomised to one of four treatment arms:
1. Conventional four drug Anti-Tuberculosis Chemotherapy (ATC) (comprising of isoniazid, rifampicin, pyrazinamide and ethambutol)
2. Conventional four drug ATC plus ciprofloxcin
3. Conventional four drug ATC plus levofloxacin
4. Conventional four drug ATC plus gatifloxacin.
The trial will be open-label. Sparse pharmacokinetic data will be generated from routine serial sampling of CSF/plasma performed upon each patient for the purposes of assessing response to treatment. Paired blood and CSF samples (for drug measurement and killing curves) will be taken at diagnosis, day two, day seven, day 30, and day 60. The precise timing of the Lumbar Puncture (LP), in relation to drug administration, will be randomised. Likewise, the timing of two further specimens of plasma (taken either side of the LP) will also be randomised.
Intervention type
Drug
Phase
Not Applicable
Drug names
Conventional four drug anti-tuberculosis chemotherapy (comprising of isoniazid, rifampicin, pyrazinamide and ethambutol), ciprofloxcin, levofloxacin and gatifloxacin.
Primary outcome measure
1. Clinical methods: the following will be used as markers of clinical response:
a. fever clearance, coma clearance, date of discharge, death at two months, disability or death at nine months
b. CSF pressure, lactate, white cell count, protein and glucose
2. Microbiological methods: we will attempt to demonstrate microbiological activity by two methods:
a. time to CSF sterility - serial lumbar punctures will allow us to assess the time taken to kill TBM in the CSF. 60% of adults with TBM isolated from the CSF before treatment have a sterile CSF after 48 hours of treatment, and 5% (often with resistant organisms) have TBM cultured from the CSF after 30 days of treatment (unpublished data from HTD). We aim to compare time to CSF sterility in the four treatment arms
b. time to negative CSF amplified TBM direct test (Mycobacterium Tuberculosis Direct [MTD] test: Gen-probe, California). Using the same principles described above, we will compare time to negative MTD in the four treatment arms
Secondary outcome measures
No secondary outcome measures
Overall trial start date
01/04/2003
Overall trial end date
01/02/2005
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Aged over 14 years
2. Clinical diagnosis of TBM
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
To be added
Participant exclusion criteria
1. Patients who are less than 15 years old
2. Patients who are pregnant or breast feeding
3. Patients in whom the physician believes fluoroquinolones are contraindicated e.g. previous adverse reaction
4. The consent of either the patient or their relatives is not obtained
Recruitment start date
01/04/2003
Recruitment end date
01/09/2004
Locations
Countries of recruitment
Viet Nam
Trial participating centre
Oxford University Clinical Research Unit
Ho Chi Minh City
5
Viet Nam
Sponsor information
Organisation
University of Oxford (UK)
Sponsor details
University Offices
Wellington Square
Oxford
OX1 2JD
United Kingdom
Sponsor type
University/education
Website
Funders
Funder type
Charity
Funder name
Wellcome Trust
Alternative name(s)
Wellcome
Funding Body Type
private sector organisation
Funding Body Subtype
international
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
Basic results (scientific)
Publication list
2011 results in http://www.ncbi.nlm.nih.gov/pubmed/21502621
Publication citations
-
Results
Thwaites GE, Bhavnani SM, Chau TT, Hammel JP, Török ME, Van Wart SA, Mai PP, Reynolds DK, Caws M, Dung NT, Hien TT, Kulawy R, Farrar J, Ambrose PG, Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis., Antimicrob. Agents Chemother., 2011, 55, 7, 3244-3253, doi: 10.1128/AAC.00064-11.