STREAM 2 - The evaluation of a standard treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis

ISRCTN	ISRCTN18148631
DOI	https://doi.org/10.1186/ISRCTN18148631
ClinicalTrials.gov number	NCT02409290
Secondary identifying numbers	N/A

Submission date: 26/01/2016
Registration date: 10/02/2016
Last edited: 07/10/2024

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

Background and study aims
Tuberculosis (TB) is a common, infectious condition caused by a bacteria infection. It is generally spread by breathing in tiny droplets released into the air by an infected person coughing or sneezing. TB usually affects the lungs, but it can also affect other areas of the body such as the bones, brain and kidneys. Despite the availability and effectiveness of affordable six-month treatments for tuberculosis (TB), the worldwide control of this disease is currently being impacted by the emergence of multidrug resistant TB (MDR-TB). MDR-TB is where the powerful first-line drugs used to treat TB (at least isoniazid and rifampicin) are ineffective, leading to the spread of an infection that is much more difficult to treat. Currently the standard treatments for MDR-TB can last as long as 24 months with a success rate of no more than 50%. With an approximately 500,000 new cases every year there is an urgent need to develop shorter and more effective treatments. The aim of this study is to compare three different shorter drug regimens to the standard 18-month MDR-TB regimen, in order to find the most effective treatment.

Who can participate?
Adults who have multidrug resistant tuberculosis (TB).

What does the study involve?
The study involves four Regimens A-D. Those allocated to regimen A are given the standard MDR-TB regimen, which they take for 18 months. Those allocated to regimen B are given clofazimine, ethambutol, moxifloxacin or levofloxacin, and pyrazinamide given for 40 weeks, supplemented by isoniazid, kanamycin, and prothionamide in the first 16 weeks. Those allocated to regimen C begin a newly designed 40 week all-oral (by mouth) treatment programme which consists of the drugs bedaquiline, clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for the first 16 weeks. Those in regimen D are given a newly designed 28-week regimen consisting of the drugs bedaquiline, clofazimine, levofloxacin, and pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks.

Randomisation is currently mainly to Regimen B and C and in some sites to Regimen D. Participants are no longer randomised to Regimen A as countries are implementing the WHO 2016 short regimen or to Regimen D as the use of an injectable is seen as less attractive than a fully oral regimen for participants. However, participants already randomised to Regimens A and D will complete their course of treatment and continue in follow-up.

The effectiveness of regimen B and C are compared at 132 weeks using blood samples.

What are the possible benefits and risks of participating?
Participants benefit from receiving more information about their health from the results of the tests done and are able to talk to a study councilor about any concerns they may have. For patients that receive the shorter treatment regimes, they may also benefit from a quicker recovery. Risks of taking part involve the general risks of taking the study drugs, as well as the risk of pain and bruising when blood samples are taken.

Where is the study run from?
1. Vital Strategies (Formally The United States Agency for International Development, Sponsor) (USA)
2. Medical Research Council at University College London (UK)
3. Institute of Tropical Medicine (Belgium)

When is the study starting and how long is it expected to run for?
March 2016 to August 2022

Who is funding the study?
1. The United States Agency for International Development (USA)
2. Janssen Research and Development (USA)
3. Medical Research Council (UK)
4. Department of International Development (UK)

Who is the main contact?
Professor Andrew Nunn

Study website

Contact information

Prof Andrew Nunn
Scientific

Medical Research Council Clinical Trials Unit
University College London
90 High Holborn
2nd Floor
London
WC1V 6LJ
United Kingdom

Study information

Study design	Non-inferiority multi-centre international parallel-group open-label randomized controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
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
Study acronym	STREAM 2
Study objectives	Current study hypothesis as of 18/02/2019: Stage Two of the STREAM trial involves the investigation of an alternative regimen, a variation on Regimen B (the 9 month regimen evaluated in Stage 1 against the WHO recommended regimen), incorporating the newly available drug bedaquiline. This regimen, Regimen C, involves the removal of the injectable, kanamycin, which has known associated risks of ototoxicity and renal toxicity. Study aim: 1. To assess whether Regimen C is non inferior to Regimen B 3Stage one of the study can be found via http://www.isrctn.com/ISRCTN78372190 Previous study hypothesis: Stage Two of the STREAM trial involves the investigation of two alternative regimens, both variations on Regimen B (the 9 month regimen evaluated in Stage 1 against the WHO recommended regimen), incorporating the newly available drug bedaquiline. The first of these investigational regimens, Regimen C, involves the removal of the injectable, kanamycin, which has known associated risks of ototoxicity and renal toxicity. The second investigational regimen, Regimen D, investigates the possibility of treatment being further shortened to 28 weeks, with a shorter duration of the initial intensive phase containing kanamycin and isoniazid and the dropping of ethambutol, which is considered to be of limited efficacy, and prothionamide, which is commonly associated with severe gastric symptoms. Study aims: 1. To assess the superiority of Regimen C over Regimen B; this is a US FDA requirement. 2. To assess whether Regimen C is not inferior to Regimen B 3. To assess whether Regimen D is non-inferior to Regimen B Stage one of the study can be found via http://www.isrctn.com/ISRCTN78372190
Ethics approval(s)	The International Union Against TB and Lung Disease’s Ethics Advisory Group: 15/04/2015 ref: EAG number 97/14
Health condition(s) or problem(s) studied	Multi-drug resistant pulmonary tuberculosis (MDR-TB)
Intervention	Current interventions as of 18/02/2019: Patients consent to screening at their first visit at which stage they are assigned a unique study number. The patient is then evaluated for their eligibility according to the inclusion and exclusion criteria. If a patient is screened successfully and satisfies the criteria to participate in STREAM, the patient will then complete the randomisation consent and complete the Week 0 assessment prior to randomisation. Patients should be randomised no more than 4 weeks after screening consent. Randomisation occurs using a web-based randomisation system at a ratio of 1:2:2:2 in favour of Regimen B, Regimen C, and Regimen D. Patients are then assessed at Week 1, Week 2, Week 3, Week 4, after which they will be seen 4-weekly until Week 52, after which they will be seen 8-weekly until Week 84, after which they will be seen 12-weekly until Week 132 post randomisation. In 2018, the study was modified and participants are no longer randomised to Regimen A and Regimen D. Randomisation to Regimen B and C is at a ratio of 1:1. Regimen A - The locally-used World Health Organization (WHO) approved MDR-TB regimen, which should be given for a minimum of 18 months. Regimen B - This is based on the regimen described by Van Deun 2010 consisting of clofazimine, ethambutol, moxifloxacin or levofloxacin, and pyrazinamide given for 40 weeks, supplemented by isoniazid, kanamycin, and prothionamide in the first 16 weeks). Dose Schedule: Kanamycin: 15 mg per kilogram 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) Levofloxacin: 750 mg (less than 33 kg), 750 mg (33 - 50 kg) or 1000 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) Regimen C - A 40-week all-oral regimen consisting of bedaquiline, clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for the first 16 weeks. Dose schedule: Bedaquiline 400 mg once daily for the first 14 days, then 200mg thrice weekly therefeafter Clofazimine: 50 mg (less than 33 kg), 100 mg (33 - 50 kg) or 100 mg (more than 50 kg) Levofloxacin 750 mg (less than 33 kg), 750 mg (33 - 50 kg) or 1000 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) Regimen D - A 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks. Dose schedule: Bedaquiline 400 mg once daily for the first 14 days, then 200mg thrice weekly thereafter Clofazimine: 50 mg (less than 33 kg), 100 mg (33 - 50 kg) or 100 mg (more than 50 kg) Levofloxacin 750 mg (less than 33 kg), 750 mg (33 - 50 kg) or 1000 mg (more than 50 kg) Isoniazid: 400 mg (less than 33 kg), 500 mg (33 – less than 40 kg), 600 mg (40-50kg), 800mg (more than 50 kg – 60kg) or 900 mg (more than 60kg). Dose is taken once daily for first 14 days and thrice weekly thereafter. Pyrazinamide: 1000 mg (less than 33 kg), 1500 mg (33 - 50 kg) or 2000 mg (more than 50 kg) Kanamycin: 15 mg per kilogram body weight (maximum 1 g) Previous interventions: Patients consent to screening at their first visit at which stage they are assigned a unique study number. The patient is then evaluated for their eligibility according to the inclusion and exclusion criteria If a patient is screened successfully and satisfies the criteria to participate in STREAM, the patient will then complete the randomisation consent and complete the Week 0 assessment prior to randomisation. Patients should be randomised no more than 4 weeks after screening consent. Randomisation occurs using a web-based randomisation system at a ratio of 1:2:2:2 in favour of Regimen B, Regimen C, and Regimen D. Patients are then assessed at Week 1, Week 2, Week 3, Week 4, after which they will be seen 4-weekly until Week 52, after which they will be seen 8-weekly until Week 84, after which they will be seen 12-weekly until Week 132 post-randomisation. Regimen A - The locally-used World Health Organization (WHO) approved MDR-TB regimen, which should be given for a minimum of 18 months. Regimen B - This is based on the regimen described by Van Deun 2010 consisting of clofazimine, ethambutol, moxifloxacin, and pyrazinamide given for 40 weeks, supplemented by isoniazid, kanamycin, and prothionamide in the first 16 weeks). Dose Schedule: Kanamycin: 15 mg per kilogram 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) Regimen C - A 40-week all-oral regimen consisting of bedaquiline, clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for the first 16 weeks. Dose schedule: Bedaquiline 400 mg once daily for the first 14 days, then 200mg thrice weekly therefeafter Clofazimine: 50 mg (less than 33 kg), 100 mg (33 - 50 kg) or 100 mg (more than 50 kg) Levofloxacin 750 mg (less than 33 kg), 750 mg (33 - 50 kg) or 1000 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) Regimen D - A 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks. Dose schedule: Bedaquiline 400 mg once daily for the first 14 days, then 200mg thrice weekly thereafter Clofazimine: 50 mg (less than 33 kg), 100 mg (33 - 50 kg) or 100 mg (more than 50 kg) Levofloxacin 750 mg (less than 33 kg), 750 mg (33 - 50 kg) or 1000 mg (more than 50 kg) Isoniazid: 400 mg (less than 33 kg), 500 mg (33 – less than 40 kg), 600 mg (40-50kg), 800mg (more than 50 kg – 60kg) or 900 mg (more than 60kg). Dose is taken once daily for first 14 days and thrice weekly there after. Pyrazinamide: 1000 mg (less than 33 kg), 1500 mg (33 - 50 kg) or 2000 mg (more than 50 kg) Kanamycin: 15 mg per kilogram body weight (maximum 1 g)
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Clofazimine, ethambutol, moxifloxacin, levofloxacin, pyrazinamide, isoniazid, kanamycin, prothionamide, bedaquiline
Primary outcome measure	Current primary outcome measures as of 18/02/2019: The primary efficacy outcome is the proportion of patients with a favourable outcome at Week 76 defined as two negative cultures taken on separate visits, the latest of which being no more than six weeks earlier or later than week 76, provided the outcome has not previously been classified as unfavourable. Unfavourable efficacy outcomes: 1. They are discontinued from their allocated study treatment and subsequently restarted on a different MDR-TB regimen 2. Treatment is extended beyond the scheduled end of treatment for any reason other than making up of days when no treatment was given (missed treatment) for a maximum of eight weeks 3. They are restarted on any MDR-TB treatment after the scheduled end of treatment, but before 76 weeks after randomisation. 4. They change their allocated study treatment for any reason other than the replacement of a single drug 5. Bedaquiline is started where the allocated regimen did not originally contain that drug (Regimen A or B). 6. A drug from the class of nitroimidazoles is started 7. They die at any point during treatment or follow-up 8. At least one of their last two culture results, from specimens taken on separate occasions, is positive 9. They do not have a culture result within the Week 76 window for the Stage 2 comparison 10. The failure or recurrence specimen at or before the Week 76 window was a different strain to their randomisation specimen, i.e. re-infection Previous primary outcome measures: The primary efficacy outcome is the proportion of patients with a favourable outcome at Week 76 defined as two negative cultures taken on separate visits, the latest of which being no more than six weeks earlier or later than week 76, provided the outcome has not previously been classified as unfavourable.
Secondary outcome measures	Current secondary outcome measures as of 18/02/2019: 1.Time to sputum culture conversion is recorded during 132 weeks of follow-up 2. Time to sputum smear conversion is recorded during 132 weeks of follow-up 3. Efficacy status at end of follow-up, based on the same definition as the primary endpoint, but at week 132 5. All-cause mortality is recorded during 132 weeks of follow-up 6. Proportion of patients experiencing a grade 3 or greater adverse event, as defined by the DAIDS criteria is recorded during 132 weeks of follow-up 7. Change of regimen for adverse drug reactions are recorded throughout the study period 8. Number of adverse events occurring on treatment and during 132 weeks of follow-up 9. Pharmacokinetic outcomes are measured at selected visits using a validated and sensitive liquid chromatography-mass spectrometry method 10. Adherence to treatment during the treatment period is calculated from daily DOT (directly observed treatment) treatment cards Previous secondary outcome measures: 1. Time to sputum culture conversion is recorded during 132 weeks of follow-up 2. Time to sputum smear conversion is recorded during 132 weeks of follow-up 3. Efficacy status at end of follow-up, based on the same definition as the primary endpoint, but at week 132 4. Time to unfavourable efficacy outcome* is recorded during 132 weeks of follow-up 5. The proportion of participants in each category who meet the WHO classification of outcome as applicable at the time of analysis is determined at Week 76 and Week 132 6. Time to cessation of clinical symptoms based on PI assessment is recorded during 132 weeks of follow-up 7. All-cause mortality is recorded during 132 weeks of follow-up 8. Proportion of patients experiencing a grade 3 or greater adverse event, as defined by the DAIDS criteria is recorded during 132 weeks of follow-up 9. Change of regimen for adverse drug reactions are recorded throughout the study period 10. Number of adverse events occurring on treatment and during 132 weeks of follow-up 11. Pharmacokinetic outcomes are measured at selected visits using a validated and sensitive liquid chromatography-mass spectrometry method 12. Adherence to treatment during the treatment period is calculated from daily DOT (directly observed treatment) treatment cards *Unfavourable efficacy outcomes: 1. They are discontinued from their allocated study treatment and subsequently restarted on a different MDR-TB regimen 2. Treatment is extended beyond the scheduled end of treatment for any reason other than making up of days when no treatment was given (missed treatment) for a maximum of eight weeks 3. They are restarted on any MDR-TB treatment after the scheduled end of treatment, but before 76 weeks after randomisation. 4. They change their allocated study treatment for any reason other than the replacement of a single drug 5. Bedaquiline is started where the allocated regimen did not originally contain that drug (Regimen A or B). 6. A drug from the class of nitroimidazoles is started 7. They die at any point during treatment or follow-up 8. At least one of their last two culture results, from specimens taken on separate occasions, is positive 9. They do not have a culture result within the Week 76 window for the Stage 2 comparison 10. The failure or recurrence specimen at or before the Week 76 window was a different strain to their randomisation specimen, i.e. re-infection
Overall study start date	01/03/2016
Completion date	09/08/2022

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	15 Years
Sex	Both
Target number of participants	At least 530 participants
Total final enrolment	588
Key inclusion criteria	Current participant inclusion criteria as of 18/02/2019: 1. Is willing and able to give informed consent to participate in the trial treatment and follow-up (signed or witnessed consent if the patient is illiterate). If the patient is below the age of consent (according to local regulations), the parent/caregiver should be able and willing to give consent, and the patient be informed about the study and asked to give positive assent, if feasible 2. Is aged 15 years or older 3. Has a positive AFB sputum smear result at screening (at least scanty), or a positive GeneXpert result (with a cycle threshold (Ct) value of 25 or lower) within four weeks prior to screening 4. Has evidence of resistance to rifampicin either by line probe assay (Hain Genotype), GeneXpert or culture-based drug susceptibility testing (DST), from a test performed at screening or from a test performed within the four weeks prior to screening 5. Is willing to have an HIV test and, if positive, is willing to be treated with ART in accordance with the national policies but excluding ART contraindicated for use with bedaquiline 6. Is willing to use effective contraception (men who have not had a vasectomy must agree to use condoms; pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilised must agree to use two methods of contraception, for example a hormonal method and a barrier method) 7. Resides in the area and expected to remain for the duration of the study 8. Has had a chest X-ray that is compatible with a diagnosis of pulmonary TB (if such a chest X-ray taken within 4 weeks of randomisation is available, a repeat X-ray is not required) 9. Has normal K+, Mg2+ and corrected Ca2+ at screening. Previous participant inclusion criteria as of 29/10/2018: 1. Is willing and able to give informed consent to participate in the trial treatment and follow-up (signed or witnessed consent if the patient is illiterate). If the patient is below the age of consent (according to local regulations), the parent/caregiver should be able and willing to give consent, and the patient be informed about the study and asked to give positive assent, if feasible 2. Is aged 15 years or older 3. Has a positive AFB sputum smear result at screening (at least scanty), unless they are HIV positive in which case a positive GeneXpert result within four weeks prior to screening is sufficient 4. Has evidence of resistance to rifampicin either by line probe assay (Hain Genotype21), GeneXpert or culture-based drug susceptibility testing (DST), from a test performed at screening or from a test performed within the four weeks prior to screening 5. Is willing to have an HIV test and, if positive, is willing to be treated with ART in accordance with the national policies but excluding ART contraindicated for use with bedaquiline 6. Is willing to use effective contraception (men who have not had a vasectomy must agree to use condoms; pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilised must agree to use two methods of contraception, for example a hormonal method and a barrier method) 7. Resides in the area and expected to remain for the duration of the study 8. Has had a chest X-ray at that is compatible with a diagnosis of pulmonary TB (if such a chest X-ray taken within 4 weeks of randomisation is available, a repeat X-ray is not required) 9. Has normal K+, Mg2+ and corrected Ca2+ at screening. Previous participant inclusion criteria: 1. Is willing and able to give informed consent to participate in the trial treatment and follow-up (signed or witnessed consent if the patient is illiterate) 2. Is aged 18 years or older 3. Has a positive AFB sputum smear result at screening (at least scanty), unless they are HIV positive in which case a positive GeneXpert result within four weeks prior to screening is sufficient 4. Has evidence of resistance to rifampicin either by line probe assay (Hain Genotype21), GeneXpert or culture-based drug susceptibility testing (DST), from a test performed at screening or from a test performed within the four weeks prior to screening 5. Is willing to have an HIV test and, if positive, is willing to be treated with ART in accordance with the national policies but excluding ART contraindicated for use with bedaquiline 6. Is willing to use effective contraception (men who have not had a vasectomy must agree to use condoms; pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilised must agree to use two methods of contraception, for example a hormonal method and a barrier method) 7. Resides in the area and expected to remain for the duration of the study 8. Has had a chest X-ray at that is compatible with a diagnosis of pulmonary TB (if such a chest X-ray taken within 4 weeks of randomisation is available, a repeat X-ray is not required) 9. Has normal K+, Mg2+ and corrected Ca2+ at screening.
Key exclusion criteria	Participant exclusion criteria as of 29/10/2018: 1. Is infected with a strain of M. tuberculosis resistant to a second-line injectables by line probe assay (Hain Genotype) from a test performed at screening or from a test performed within the four weeks prior to screening 2. Is infected with a strain of M. tuberculosis resistant to a fluoroquinolone by line probeassay (Hain Genotype) from a test performed at screening or from a test performed within the four weeks prior to screening 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 or unwilling to comply with the treatment, assessment, or follow-up schedule 7. Is unable to take oral medication 8. Has AST or ALT more than 3 times the upper limit of normal for Stage 2 9. Has any condition (social or medical) which in the opinion of the investigator would make study participation unsafe 10. In the investigator’s opinion the patient is likely to be eligible for treatment with bedaquiline according to local guidelines due a pre-existing medical condition such as hearing loss or renal impairment 11. Is taking any medications contraindicated with the medicines in any trial regimen 12. Has a known allergy to any fluoroquinolone antibiotic 13. Is currently taking part in another trial of a medicinal product 14. Has a QT or QTcF interval at screening or immediately prior to randomisation of more than or equal to 450 ms for Stage 2. 15. Has experienced one or more of the following risk factors for QT prolongation: 15.1. confirmed prolongation of the QT or QTcF more than or equal to 450 ms in the screening ECG (retesting to reassess eligibility will be allowed once using an unscheduled visit during the screening phase) 15.2. Pathological Q-waves (defined as Q-wave more than 40 ms or depth more than 0.4-0.5 mV) 15.3. Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome) 15.4. Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block 15.5. Evidence of second or third degree heart block 15.6. Intraventricular conduction delay with QRS duration more than 120 ms 15.7. Bradycardia as defined by sinus rate less than 50 bpm 15.8. Personal or family history of Long QT Syndrome 15.9. Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, with the exception of sinus arrhythmia 15.10. Syncope (i.e. cardiac syncope not including syncope due to vasovagal or epileptic causes) 15.11. Risk factors for Torsades de Pointes (e.g., heart failure, hypokalaemia, or hypomagnesemia) 16. Has received treatment for MDR-TB in the 12 weeks prior to screening 17. Has a history of cirrhosis and classified as Child’s B or C at screening or a bilirubin more than 1.5 times upper limit of normal. 18. Has an estimated creatinine clearance (CrCl) less than 30 mL/min based on the Cockcraft-Gault equation 19. Is HIV positive and has a CD4 count less than 50 cells/mm3 20. Has pancreatic amylase elevation more than two times above the upper limit of normal 21. Has a history of alcohol and/or drug abuse 22. Has had previous treatment with bedaquiline 23. Has taken rifampicin in the seven days prior to randomisation 24. There has been a delay of more than four weeks between the screening consent and randomisation 25. Is an employee or family member of the investigator or study site staff with direct involvement in the proposed study Previous participant exclusion criteria: 1. Is infected with a strain of M. tuberculosis resistant to a second-line injectables by line probe assay (Hain Genotype) 2. Is infected with a strain of M. tuberculosis resistant to a fluoroquinolone by line probeassay (Hain Genotype) 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 or unwilling to comply with the treatment, assessment, or follow-up schedule 7. Is unable to take oral medication 8. Has AST or ALT more than 3 times the upper limit of normal for Stage 2 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 any trial 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 QT or QTcF interval at screening or immediately prior to randomisation of more than or equal to 450 ms for Stage 2. 14. Has experienced one or more of the following risk factors for QT prolongation: 14.1. confirmed prolongation of the QT or QTcF more than or equal to 450 ms in the screening ECG (retesting to reassess eligibility will be allowed once using an unscheduled visit during the screening phase) 14.2. Pathological Q-waves (defined as Q-wave more than 40 ms or depth more than 0.4-0.5 mV) 14.3. Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome) 14.4. Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block 14.5. Evidence of second or third degree heart block 14.6. Intraventricular conduction delay with QRS duration more than 120 ms 14.7. Bradycardia as defined by sinus rate less than 50 bpm 14.8. Personal or family history of Long QT Syndrome 14.9. Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, with the exception of sinus arrhythmia 14.10. Syncope (i.e. cardiac syncope not including syncope due to vasovagal or epileptic causes) 14.11. Risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, or hypomagnesemia) 15. Has received treatment for MDR-TB in the 12 weeks prior to screening 16. Has a history of cirrhosis and classified as Child’s B or C at screening or a bilirubin more than 1.5 times upper limit of normal. 17. Has an estimated creatinine clearance (CrCl) less than 30 mL/min based on the Cockcraft-Gault equation 18. Is HIV positive and has a CD4 count less than 50 cells/mm3 19. Has amylase elevation more than two times above the upper limit of normal 20. Has a history of alcohol and/or drug abuse 21. Has had previous treatment with bedaquiline 22. Has taken rifampicin in the seven days prior to randomisation 23. There has been a delay of more than four weeks between the screening consent and randomisation 24. Is an employee or family member of the investigator or study site staff with direct involvement in the proposed study
Date of first enrolment	01/03/2016
Date of final enrolment	28/01/2020

Locations

Countries of recruitment

Ethiopia
Georgia
India
Moldova
Mongolia
South Africa
Uganda

Study participating centres

National Center of Infectious Diseases

Ulaanbaatar
13335
Mongolia

St. Peter's TB Specialized Hospital

Addis Ababa
N/A
Ethiopia

Armauer Hansen Research Institute (AHRI)

Addis Ababa
N/A
Ethiopia

King Dinuzulu Hospital Complex

Durban
N/A
South Africa

Doris Goodwin Hospital

Pietermaritzburg
N/A
South Africa

Institute of Phthisiopneumology "Chiril Draganiuc"

Chisinau
-
Moldova

Makerere University

Kampala
-
Uganda

The National Center for TB and Lung Diseases

Tbilisi
-
Georgia

The National Institute for Research in Tuberculosis

Chennai
-
India

BJ Medical College Civil Hospital

Ahmedabad
-
India

Empilweni TB Hospital

Port Elizabeth
-
South Africa

Helen Joseph Hospital

Johannesburg
-
South Africa

Rajan Babu TB Institute of Pulmonary Medicine and Tuberculosis

Kingsway Camp GTB Nagar
Delhi
110007
India

Sponsor information

Vital Strategies (Formally International Union Against Tuberculosis and Lung Disease)
Research organisation

61 Broadway
Suite 1720
New York
10006
United States of America

Website	http://www.treattb.org/overview
"ROR"	https://ror.org/05mdyn772

Funders

Funder type

Research organisation

United States Agency for International Development
Government organisation / National government

Alternative name(s): U.S. Agency for International Development, Agency for International Development, USAID
Location: United States of America

Medical Research Council
Government organisation / National government

Alternative name(s): Medical Research Council (United Kingdom), UK Medical Research Council, MRC
Location: United Kingdom

Department for International Development, UK Government
Government organisation / National government

Alternative name(s): Department for International Development, UK, DFID
Location: United Kingdom

Janssen Research and Development
Private sector organisation / For-profit companies (industry)

Alternative name(s): Janssen R&D, Janssen Research & Development, Janssen Research & Development, LLC, Janssen Research & Development LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Research & Development at Janssen, JRD, J&J PRD
Location: United States of America

Results and Publications

Intention to publish date	31/12/2023
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	1. Planned publication of results in a peer reviewed journal 2. Sharing of study results with participants through mechanisms and materials reviewed and approved by The Union’s Ethics Advisory Group and other relevant stakeholders
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request from I.D. Rusen, STREAM@vitalstrategies.org

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article	Economic evaluation protocol for bedaquiline-containing regimen	21/12/2020	08/03/2021	Yes	No
Other publications	Design changes	07/06/2022	08/06/2022	Yes	No
Statistical Analysis Plan	version 5.0	21/04/2022	01/09/2022	No	No
Results article		07/11/2022	14/11/2022	Yes	No
Results article	Economic evaluation of bedaquiline-containing regimens	21/12/2022	28/12/2022	Yes	No
Results article	Long-term outcomes	01/10/2024	07/10/2024	Yes	No

Additional files

ISRCTN18148631_SAP_v5.0_21Apr22.pdf

Editorial Notes

07/10/2024: Publication reference added.
28/12/2022: Publication reference added.
14/11/2022: Publication reference added.
08/09/2022: Trial website address updated.
01/09/2022: Statistical analysis plan uploaded.
11/07/2022: The following changes were made to the trial record:
1. The overall end date was changed from 31/07/2022 to 09/08/2022.
2. The plain English summary was updated to reflect these changes.
08/06/2022: Publication reference added.
08/03/2021: Publication reference added.
05/02/2020: The recruitment end date has been changed from 20/01/2020 to 28/01/2020.
04/02/2020: The following changes have been made:
1. The recruitment end date has been changed from 31/12/2019 to 20/01/2020.
2. The overall trial end date has been changed from 30/06/2022 to 31/07/2022.
3. The final enrolment number has been added.
4. Rajan Babu TB Institute of Pulmonary Medicine and Tuberculosis has been added to the trial participating centres.
24/10/2019: The following changes have been made:
1. The recruitment end date has been changed from 30/09/2019 to 31/12/2019.
2. The overall trial end date has been changed from 31/03/2021 to 30/06/2022.
3. The intention to publish date has been changed from 30/09/2022 to 31/12/2023.
01/03/2019: Minor change to plain English summary.
18/02/2019: The following changes have been made:
1. The plain English summary was updated.
2. The trial website was updated.
3. The study hypothesis was updated.
4. The interventions were updated.
5. The primary outcome measures were updated.
6. The secondary outcome measures were updated.
7. The participant inclusion criteria was updated.
8. The target number of participants was changed from 1155 to 530.
9. The trial participating centres were updated.
29/10/2018: The following changes were made:
1. The plain English summary was updated.
2. The participant inclusion criteria was updated.
3. The participant inclusion criteria: age group was updated from "Adult" to "Mixed".
4. The participant exclusion criteria was updated.
5. The recruitment end date was updated from 30/03/2019 to 30/09/2019.
6. The countries of recruitment were updated from "Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, Uganda, Vietnam" to "Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, Uganda".
7. The trial participating centres were updated
30/01/2018: The participant level data sharing statement has been added.
25/01/2018: The following changes have been made:
1. Gondar University Hospital has been removed as a trial participating centre.
2. The follow have been added as trial participating centres: Institute of Phthisiopneumology "Chiril Draganiuc, Makerere University, The National Center for TB and Lung Diseases, The National Institute for Research in Tuberculosis,and BJ Medical College Civil Hospital
3. The address of University College London has been updated.
4. The trial website has been added.