A randomised comparison of ciprofloxacin, levofloxacin and gatifloxacin for the treatment of adults with tuberculous meningitis

ISRCTN	ISRCTN07062956
DOI	https://doi.org/10.1186/ISRCTN07062956
Protocol serial number	061330
Sponsor	University of Oxford (UK)
Funder	Wellcome Trust

Submission date: 22/07/2005
Registration date: 22/07/2005
Last edited: 06/02/2015

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

Dr Guy Thwaites
Scientific

Oxford University Clinical Research Unit
The Hospital for Tropical Diseases
190 Ben Ham Tu
Ho Chi Minh City
5
Viet Nam

Phone	+84 (0)8 9237954
Email	guy.thwaites@btinternet.com

Study information

Primary study design	Interventional
Study design	Randomised controlled trial
Secondary study design	Randomised controlled trial
Scientific title	A randomised comparison of ciprofloxacin, levofloxacin and gatifloxacin for the treatment of adults with tuberculous meningitis
Study acronym	BN study
Study objectives	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(s)	Not provided at time of registration
Health condition(s) or problem(s) studied	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 / device / biological / vaccine name(s)	Conventional four drug anti-tuberculosis chemotherapy (comprising of isoniazid, rifampicin, pyrazinamide and ethambutol), ciprofloxcin, levofloxacin and gatifloxacin.
Primary outcome measure(s)	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
Key secondary outcome measure(s)	No secondary outcome measures
Completion date	01/02/2005

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	All
Key inclusion criteria	1. Aged over 14 years 2. Clinical diagnosis of TBM
Key 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
Date of first enrolment	01/04/2003
Date of final enrolment	01/09/2004

Locations

Countries of recruitment

Viet Nam

Study participating centre

Oxford University Clinical Research Unit

Ho Chi Minh City
5
Viet Nam

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	01/07/2011		Yes	No