Welcome
Support Centre
25 July 2014 
ISRCTN Register - International Standard Randomized Controlled Trial Number
Trial registration
Unique identification scheme
International databases
home  |   my details  |   ISRCTN Register  |   mRCT  |   links  |   information  |   news
Find trials
ISRCTN Register
tips on searching

Registration
New application
Updating record

Information
introduction
governing board
ISRCTN FAQs
data set
letter of agreement
request information
guidance notes
statistics

[ ...Back to search results ] [ Print-friendly version ]
The evaluation of a standardised treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (MDR-TB)
ISRCTN ISRCTN78372190
DOI 10.1186/ISRCTN78372190
ClinicalTrials.gov identifier
EudraCT number
Public title The evaluation of a standardised treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (MDR-TB)
Scientific title The evaluation of a standardised treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (MDR-TB): a multi-centre international parallel group randomised controlled trial
Acronym STREAM
Serial number at source N/A
Study hypothesis To determine whether a standardised regimen utilising existing drugs that has been used in one country setting with excellent treatment outcomes can be used in other settings with comparable success.

Patients with Multidrug-Resistant Tuberculosis (MDR-TB) are currently treated for 18-24 months, based on recommendations by the World Health Organisation (WHO). Treatment success rates are poor.

In a study carried out by Dr. Van Deun (2010) in Bangladesh patients with MDR-TB were treated for only nine months with excellent results.

The STREAM trial assesses whether a treatment closely similar to that used in Bangladesh is as good as the treatment for MDR-TB recommended by WHO. If the results are positive, it will be possible to treat patients with MDR-TB in different countries for only nine months.

Please note, as of 28/09/2011 an update has been made to the trial record. The changes can be found under the aforementioned date of update in the relevant fields below.
1. Ethiopia and South Africa have been added to the countries of recruitment.
2. The start date has been updated from 03/01/2011 to 15/11/2011.

Please note that as of 13/11/2012, the following changes have been made to the record:
1. The anticipated end date for this trial has been updated from 15/05/2015 to 30/10/2016.
2. India has been added to the countries of recruitment

Please note that as of 15/11/2012, this trial is now recruiting
Lay summary http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=117
Ethics approval The International Union Against TB and Lung Disease’s Ethics Advisory Group on 19/04/2011 (ref: EAG Number 07/11). The trial was also approved in all participating countries.
Study design A non-inferiority multi-centre international parallel group randomised controlled trial
Countries of recruitment Ethiopia, India, South Africa, Viet Nam
Disease/condition/study domain Multidrug resistant pulmonary tuberculosis (MDR-TB)
Participants - inclusion criteria 1. Willing and able to give informed consent for treatment and follow-up (signed or witnessed consent if the patient is illiterate)
2. Aged 15 years or older, either sex
3. Has smear-positive pulmonary tuberculosis with initial laboratory result of resistance to rifampicin by line probe assay or other DST
4. Is willing to have an HIV test and if positive is willing to be treated with ART in accordance with national policies
5. Agrees to use effective barrier contraception or an intrauterine contraceptive device during treatment phase if a pre-menopausal woman
6. Has an identifiable address and expects to remain in the area for the duration of the study
7. Is willing to adhere to the follow-up schedule and to study procedures
Participants - exclusion criteria Current exclusion criteria as of 28/09/2011:

1. Is infected with a strain of M. tuberculosis resistant to a second-line injectable drug by line probe assay
2. Is infected with a strain of M. tuberculosis resistant to a fluoroquinolone by line probe assay
3. Has tuberculous meningitis or bone and joint tuberculosis
4. Is critically ill, and in the judgment of the investigator, unlikely to survive more than 4 months
5. Is known to be pregnant or breast-feeding
6. Is unable to attend or comply with treatment or follow-up schedule
7. Is unable to take oral medication
8. Has AST or ALT >5 times the upper limit of normal
9. Has any condition (social or medical) which in the opinion of the investigator would make study participation unsafe
10. Is taking any medications contraindicated with the medicines in either the trial or control regimen
11. Has a known allergy to any fluoroquinolone antibiotic
12. Is currently taking part in another trial of a medicinal product
13. Has a QTc interval ≥500msec at screening

Previous exclusion criteria:

1. Resistant to a second-line injectable drug by line probe assay
2. Resistant to a fluoroquinolone by line probe assay
3. Critically ill, and in the judgment of the investigator, unlikely to survive more than 4 months
4. Known to be pregnant or breast-feeding
5. Unable to attend or comply with treatment or follow-up schedule
6. Unable to take oral medication
7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 times the upper limit of normal
8. Any condition (social or medical) which in the opinion of the investigator would make study participation unsafe or complicate data interpretation
9. Taking any medications contraindicated with the medicines in the study regimen
10. Known allergy to any fluoroquinolone antibiotic
11. Currently taking part in another trial of a medicinal product
Anticipated start date 15/11/2011
Anticipated end date 30/10/2016
Status of trial Ongoing
Patient information material Not available in web format, please use the contact details below to request a patient information sheet
Target number of participants At least 400. Please note that as of 15/11/2012, this trial is now recruiting.
Interventions Current interventions as of 28/09/2011:

The study regimen is based on the regimen described by Van Deun 2010; it consists of moxifloxacin, clofazimine, ethambutol and pyrazinamide given for nine months (40 weeks), supplemented by kanamycin, isoniazid and prothionamide in the four months (16 weeks) of the intensive phase. All drugs are given daily (seven days a week) except for kanamycin which is given thrice weekly after 12 weeks.

Patients will be randomised to either the study regimen or the locally-used WHO-approved MDR-TB regimen.
Study regimen doses:
Kanamycin: 15 mg per kilogramme body weight (maximum 1 g)
Clofazimine: 50 mg (less than 33 kg), 100 mg (33 - 50 kg) or 100 mg (more than 50 kg)
Moxifloxacin: 400 mg (less than 33 kg), 600 mg (33 - 50 kg) or 800 mg (more than 50 kg)
Ethambutol: 800 mg (less than 33 kg), 800 mg (33 - 50 kg) or 1200 mg (more than 50kg)
Isoniazid: 300 mg (less than 33 kg), 400 mg (33 - 50 kg) or 600 mg (more than 50 kg)
Pyrazinamide: 1000 mg (less than 33 kg), 1500 mg (33 - 50 kg) or 2000 mg (more than 50 kg)
Prothionamide: 250 mg (less than 33 kg), 500 mg (33 - 50 kg) or 750 mg (more than 50 kg)

In the event of delayed smear conversion the intensive phase of the study regimen can be extended four or eight weeks, allowing a maximum total duration of 48 weeks treatment.
Patients on the control regimen will receive the locally-used WHO-approved MDR-TB regimen which should be given for a minimum of 18 months following culture conversion.

All patients in the study will be followed up to 27 months post-randomisation. Those randomised early in the study will be followed up to 33 months.

Previous interventions:

Patients will be randomised to either the study regimen or the locally used World Health Organization (WHO) approved multi-drug resistant (MDR)-TB regimen.

The trial intervention will be a 9-month regimen based on the one described by Van Deun, 20101 hereafter referred to as the study regimen: ethambutol, pyrazinamide, moxifloxacin and clofazimine throughout supplemented by kanamycin, prothionamide and isoniazid in the first four months (4KCMEHZP/5MEZC).

Study regimen doses:
Kanamycin: 15 mg per kilogramme body weight (maximum 1 g)
Clofazimine: 50 mg (less than 33 kg), 100 mg (33 - 50 kg) or 100 mg (more than 50 kg)
Moxifloxacin: 400 mg (less than 33 kg), 600 mg (33 - 50 kg) or 800 mg (more than 50 kg)
Ethambutol: 800 mg (less than 33 kg), 800 mg (33 - 50 kg) or 1200 mg (more than 50 kg)
Isoniazid: 300 mg (less than 33 kg), 400 mg (33 - 50 kg) or 600 mg (more than 50 kg)
Pyrazinamide: 1000 mg (less than 33 kg), 1500 mg (33 - 50 kg) or 2000 mg (more than 50 kg)
Prothionamide: 250 mg (less than 33 kg), 500 mg (33 - 50 kg) or 750 mg (more than 50 kg)

The only change from the regimen described by Van Deun 2010 is that moxifloxacin has been substituted for gatifloxacin because gatifloxacin was withdrawn by the original marketing authorisation holder and generic sources investigated did not meet WHO norms and standards for quality, safety and efficacy.

Patients on the study regimen will receive nine months of treatment (four months intensive phase, 5 months continuation phase) and a further 18 months of follow-up, i.e. 27 months post-randomisation. In the event of delayed smear conversion the four month intensive phase of the study regimen can be extended by one or two months, allowing a maximum total duration of eleven months treatment.

The control regimen will be the locally used regimen in each country that follows the WHO MDR-TB treatment guidelines. This may differ in each country but will be the best standardised regimen in that country as recognised by the National Treatment Programme. Patients on the control regimen will also be followed up to 27 months post-randomisation.
Primary outcome measure(s) Current primary outcome measures as of 28/09/2011:

The primary efficacy outcome is the proportion of patients with a favourable outcome 27 months after randomisation, having not previously had an unfavourable outcome or been retreated.

The primary safety outcome is the proportion of patients experiencing a grade 3 or greater adverse event during treatment and follow-up.

Previous primary outcome measures:

Measured at the end of follow-up:
1. Efficacy: proportion of patients with a favourable outcome. A patient will be classified as favourable if they have a negative culture result at the end of follow-up having not been previously classified as unfavourable. A patient will be classified as unfavourable if:
1.1. They are discontinued from treatment and restarted on MDR-TB treatment, or
1.2. They are restarted on MDR-TB treatment after the end of the treatment phase.
Change of regimen for any reason other than the replacement of a single drug will result in the patient being classified as having an unfavourable outcome. In addition, the following will also be classified as unfavourable:
1.3. All deaths at any point during treatment or follow-up
1.4. A patient who has a positive culture result at the end of follow-up or if withdrawn from the study or lost to follow-up, was culture positive when last seen
2. Safety: proportion of patients experiencing a grade 3 or greater adverse event during the study
Secondary outcome measure(s) Current secondary outcome measures as of 28/09/2011:

1. Time to sputum (smear and culture) conversion
2. Time to unfavourable efficacy outcome
3. Efficacy status at the end of follow-up (33 months for those with extended follow-up)
4. All cause mortality during treatment and follow-up
5. Change of regimen for adverse drug reactions
6. Number of adverse reactions occurring on treatment
7. Adherence to treatment
8. Acceptability of regimen to all stakeholders on terms of:
8.1 Costs to the health system related to delivering the regimen and conducting follow-up tests
8.2 Household costs
8.3 Patient treatment and support experiences (frequency of health facility visits, side effects)
8.4 Health worker experiences of delivering treatment and support

Previous secondary outcome measures:

Measured at the end of follow-up:
1. Time to sputum culture conversion
2. Time to sputum smear conversion
3. All-cause mortality during treatment and follow-up
4. Adherence to treatment
5. Time to unfavourable efficacy outcome
6. Time to cessation of clinical symptoms
7. Cost per patient (from both health system and patient perspectives)
Sources of funding Current sources of funding as of 28/09/2011:
The United States Agency for International Development (USAID) (USA)

Previous sources of funding:
International Union Against Tuberculosis and Lung Disease (The Union) (France)
Trial website http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=117
Publications
Contact name Prof  Andrew  Nunn
  Address MRC Clinical Trials Unit
Aviation House
125 Kingsway
  City/town London
  Zip/Postcode WC2B 6NH
  Country United Kingdom
Sponsor International Union Against Tuberculosis and Lung Disease (IUATLD, Inc.) (USA)
  Address 61 Broadway,
Suite 1720,
  City/town New York
  Zip/Postcode 10006
  Country United States of America
  Sponsor website: http://www.theunion.org/
Date applied 04/10/2010
Last edited 19/11/2012
Date ISRCTN assigned 14/10/2010
Submit your trial protocol
Submit to Trials journal
Follow us on Twitter
© 2014 ISRCTN unless otherwise stated.