Condition category
Infections and Infestations
Date applied
05/10/2009
Date assigned
06/10/2009
Last edited
14/01/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Infection with bacteria called M. tuberculosis causes tuberculosis and is generally treated with a course of four or five types of antibiotic drugs. In cases of tuberculous meningitis (TBM), the bacteria has gotten into a patient's brain and spinal cord, causing life-threatening inflammation. It is estimated that almost one third of patients with TBM die, despite treatment. HIV patients have a worse prognosis - about two thirds of patients with both TBM and HIV die. Without treatment all patients with TBM die. The investigators of this study believe that the usual course of antibiotic drugs often does not work as well for TBM as for tuberculosis of the lungs, because the drugs are not able to effectively penetrate to the patient's brain to treat the infection there. This study examines the effect of increased dosages and addition of drugs to the standard course of antibiotics for patients with TBM, in order to optimise the killing of bacteria in the brain.

Who can participate?
The study aims to recruit 750 patients with TBM to the study, including patients with HIV. Patients need to be over 18 years of age, have a clinical diagnosis of TBM, and give informed consent to participate.

What does the study involve?
Patients are randomly allocated to one of two treatment groups. The intensified treatment group receives the normal course of anti-tuberculosis treatment, plus levofloxacin and increased dosages of rifampicin. The standard treatment group receives the normal course of anti-tuberculosis treatment, plus placebo (dummy) pills that look the same as levofloxacin and rifampicin, but do not contain the actual drug. By giving one group placebo pills, neither the patient nor the doctor can know which group a patient belongs to. This is the best way to study the difference in outcome in the end. The patients are monitored daily for general health, drug side-effects and mental status. Blood and brain fluid (cerebrospinal fluid) testing is carried out on multiple occasions. Patients are monitored daily by a study doctor while in the hospital until they are discharged, generally after one month of treatment. When in hospital, blood will be drawn each week, or if the treating doctor thinks it is necessary it will be checked more often. They are then followed up each month at the outpatient department until the end of treatment at 9 total months or until the patient dies or withdraws from the study. Lumbar punctures (taking fluid from the spine by a hollow needle in the lower back) will be carried out when admitted to hospital and after 1, 2 and 9 months, in order to see if the infection is clearing. If the treating doctor thinks it is necessary they may be done more often. As per hospital procedure, patients may object to the procedure - this will not influence their treatment.

What are the possible benefits and risks of participating?
These drugs are generally known to be safe. There is a lot of information about side affects of these drugs in patients with tuberculosis or with other infections and in general the side effects are mild. The most common side effects are abdominal (stomach) problems, such as vomiting or diarrhoea and inflammation of the liver for rifampicin. Levofloxacin is also well tolerated, but can cause abdominal problems, headache and dizziness and in very rare cases inflammation of tendons and cardiac problems. Some patients with cardiac problems in the past may be at greater risk for developing cardiac side effects, so all patients in the study will get an ECG done on separate occasions to check whether it is safe to give this drug and whether problems develop during treatment. The treatment and tests during the study period will be paid for by the study team. For poor patients this may be a benefit of being in the study.

Where is the study run from?
This study is run by researchers at the Oxford University Clinical Research Unit in Vietnam, in partnership with the Hospital for Tropical Diseases and Pham Ngoc Thach Hospital in Ho Chi Minh City, the two study sites.

When is the study starting and how long is it expected to run for?
The study began in April 2011 and is expected to finish in March 2015.

Who is funding the study?
The Wellcome Trust (UK).

Who is the main contact?
Clinical Trials Unit at the Oxford University Clinical Research Unit in Vietnam
Tel: +84 839 241 983

Trial website

Contact information

Type

Scientific

Primary contact

Dr Laura Merson

ORCID ID

Contact details

Hospital for Tropical Diseases
Wellcome Trust Major Overseas Programme
Oxford University Clinical Research Unit
190 Ben Ham Tu
District 5
Ho Chi Minh City
-
Viet Nam
+84 (0)8 923 7954
lmerson@oucru.org

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

OXTREC No 33/09; 084253

Study information

Scientific title

A randomised, double-blind, placebo-controlled trial to investigate the effect of intensified treatment with high dose rifampicin and levofloxacin for adult patients with tuberculous meningitis

Acronym

05TB

Study hypothesis

Intensifying the induction phase of treatment of tuberculous (TB) meningitis will result in reduced mortality.

On 24/02/2011 the anticipated start and end dates for this trial were updated:
1. The overall trial start date was changed from 01/01/2010 to 01/04/2011.
2. The overall trial end date was changed from 01/12/2012 to 01/12/2013.

On 14/11/2013 the overall trial end date was changed from 01/12/2013 to 01/05/2015.

On 25/07/2014 the following changes were made to the trial record:
1. The overall trial start date was changed from 01/04/2011 to 18/04/2011.
2. The overall trial end date was changed from 01/05/2015 to 15/03/2015.
3. The target number of participants was changed from '750' to '750 with at least 350 HIV-positive participants. Enrollment completed; final enrollment 817'.

Ethics approval

1. Oxford Tropical Medicine Research Ethics Committee (OXTREC) (UK), 11/08/2009, ref: 33/09
2. Research Ethics Board of the Hospital for Tropical Diseases, Ho Chi Minh City (Vietnam), 09/09/2010
3. Research Ethics Board of the Pham Ngoc Thach Hospital, Ho Chi Minh City (Vietnam), 28/04/2010

Study design

Randomised double-blind placebo-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

Tuberculous meningitis

Intervention

Patients will be randomised to one of two treatment groups:
Group A: Rifampicin 15 mg/kg/day, levofloxacin 20 mg/kg/day, isonazid 5 mg/kg once daily (od) orally (po) (maximum of 300 mg/day), pyrazinamide 25 mg/kg od po (maximum of 2 g/day) and ethambutol 20 mg/kg od po (maximum of 1.2 g/day) or streptomycin 20 mg/kg od intramuscularly (im) (maximum of 1 g/day) for two months followed by standard therapy for 8.5 months
Group B: Rifampcin 10 mg/kg/day, placebo, isonazid 5 mg/kg od po (maximum of 300 mg/day), pyrazinamide 25 mg/kg od po (maximum of 2 g/day) and ethambutol 20 mg/kg od po (maximum of 1.2 g/day) or streptomycin 20 mg/kg od im (maximum of 1 g/day) for two months followed by standard therapy for 8.5 months

Standard therapy is according to the Vietnam National Tuberculous Programme guidelines. After the first two months detailed above, patients will be treated with rifampicin 10 mg/kg od po, isonazid 5 mg/kg od po (maximum of 300 mg/day), pyrazinamide 25 mg/kg od po (maximum of 2 g/day) and ethambutol 20 mg/kg od po (maximum of 1.2 g/day) or streptomycin 20 mg/kg od im (maximum of 1 g/day) for 2.5 months, followed by 6 months of rifampcin 10 mg/kg od po and isonazid 5 mg/kg od po (maximum of 300 mg/day).

Patients will also be treated as per clinical care guidelines with dexamethasone at enrolment and anti-retrovirals for human immunodeficiency virus (HIV) positive patients.

Intervention type

Drug

Phase

Phase IV

Drug names

Rifampicin, levofloxacin, isonazid, pyrazinamide, ethambutol, streptomycin

Primary outcome measures

Overall survival during a follow-up period of 9 months

Secondary outcome measures

1. Neurological disability at 9 months as assessed using the 'simple questions' and Rankin score
2. Time to new neurological event. Neurological events are defined as:
2.1. Any of the following adverse events: cerebellar symptoms, coma, hemiplegia, neurological deteoriation, paraplegia, seizures, cerebral herniation or cranial nerve palsy
2.2. A fall in Glasgow Coma Score by greater than or equal to 2 points for greater than or equal to 2 days from highest previously recorded Glasgow Coma Score (including baseline)
3. Any grade 3 or 4 adverse event
4. Rate of treatment interruption for adverse events
5. The rates of asymptomatic transaminitis and symptomatic hepatitis
6. Time to new or recurrent acquired immune deficiency syndrome (AIDS) defining illness or death (in HIV-positive patients only)
7. Time to undetectable viral load, CD4 count at end of therapy (in HIV-positive patients only)

Overall trial start date

18/04/2011

Overall trial end date

15/03/2015

Reason abandoned

Eligibility

Participant inclusion criteria

Greater or equal to 15 years of age (either sex) with a clinical diagnosis of tuberculous meningitis

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

750 with at least 350 HIV-positive participants. Enrollment completed; final enrollment 817

Participant exclusion criteria

1. Positive cerebrospinal fluid (CSF) Gram or India Ink stain
2. Known or suspected pregnancy
3. Known hypersensitivity/intolerance to fluoroquinolones or rifampicin
4. Estimated glomerular filtration rate (GFR) less than 40 ml/min
5. Laboratory contraindications to antituberculous therapy:
5.1. Bilirubin greater than 2.5 x upper limit of normal (ULN)
5.2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 5 x ULN
6. Lack of consent

Recruitment start date

18/04/2011

Recruitment end date

18/06/2014

Locations

Countries of recruitment

Viet Nam

Trial participating centre

Hospital for Tropical Diseases
Ho Chi Minh City
-
Viet Nam

Sponsor information

Organisation

University of Oxford (UK)

Sponsor details

Centre of Clinical Vaccinology and Tropical Medicine (CCVTM)
Churchill Hospital
Old Road
Oxford
OX3 7LJ
United Kingdom

Sponsor type

University/education

Website

http://www.ox.ac.uk/

Funders

Funder type

Charity

Funder name

Wellcome Trust

Alternative name(s)

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

Results - basic reporting

Publication summary

2011 protocol in http://www.ncbi.nlm.nih.gov/pubmed/21288325
2011 protocol in http://www.ncbi.nlm.nih.gov/pubmed/21288326
2016 results in http://www.ncbi.nlm.nih.gov/pubmed/26760084

Publication citations

  1. Protocol

    Heemskerk D, Day J, Chau TT, Dung NH, Yen NT, Bang ND, Merson L, Olliaro P, Pouplin T, Caws M, Wolbers M, Farrar J, Intensified treatment with high dose rifampicin and levofloxacin compared to standard treatment for adult patients with tuberculous meningitis (TBM-IT): protocol for a randomized controlled trial., Trials, 2011, 12, 25, doi: 10.1186/1745-6215-12-25.

  2. Protocol

    Wolbers M, Heemskerk D, Chau TT, Yen NT, Caws M, Farrar J, Day J, Sample size requirements for separating out the effects of combination treatments: randomised controlled trials of combination therapy vs. standard treatment compared to factorial designs for patients with tuberculous meningitis., Trials, 2011, 12, 1, 26, doi: 10.1186/1745-6215-12-26.

Additional files

Editorial Notes

14/01/2016: Publication reference added.