STREAM & TRUNCATE trials Andrew Nunn MRC Clinical Trials Unit at UCL Institute of Clinical Trials and Methodology University College, London, UK

Why STREAM? Results from the last of six successive cohorts of patients with MDR-TB in Bangladesh treated with a 9-month regimen suggested there are better options even without the introduction of new drugs – Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru P, et al. Short, Highly Effective, and Inexpensive Standardized Treatment of Multidrug-resistant Tuberculosis. Am J Respir Crit Care Med. 2010; 182(5):

Results of the 9-month regimen in Bangladesh Introdion ObjectifMéthodes Conclusion Published cohort (206 pts) Cure82.5% Completion 5.3% Default 5.8% Death 5.3% Failure 0.5% Relapse 0.5% Overall success rate: 87.9% (95% CI 82.7, 92.6) Am J Respir Crit Care Med Vol –692, 2010 Cohort update (515 pts) 81.2% 3.3% 7.8% 5.6% 1.4% 0.8% Overall success rate: 84.5% (95% CI 0.81, 0.88) Aung et all, IJTLD 18(10):1180–1187, 2014

Why is a randomised controlled trial needed? To eliminate risk that patient selection biased results obtained from cohort studies To assess the 9-month regimen in a variety of settings including high levels of HIV-coinfection To develop a better evidence base for MDR-TB treatment If successful, to provide a new standard of care for comparison with potentially better regimens 4

A parallel approach to assessing the effectiveness of the Bangladesh regimen Cohort studies African countries including: Cameroon Benin Niger Swaziland Afghanistan Uzbekistan Randomised trial STREAM

STREAM Stage 1 study design STREAM is a randomised controlled trial of non-inferiority design currently being conducted in Ethiopia, South Africa, Vietnam and Mongolia The control regimen (A) is the locally used WHO recommended regimen in the participating countries The study regimen (B) is closely similar to the regimen used in Bangladesh with the exception that high dose moxifloxacin replaces high dose gatifloxacin

The 9-month regimen (B) WeeksDrug doses by weight group Drug 50 kg Kanamycin* mg per kilogramme body weight Isoniazid (H) mg 400 mg 600 mg Prothionamide mg 500 mg 750 mg Clofazimine mg 100 mg 100 mg Moxifloxacin mg 600 mg 800 mg Ethambutol mg 800 mg 1200 mg Pyrazinamide mg 1500 mg 2000 mg Kanamycin 3 times/week after week 12 The intensive phase may be extended by 4 or 8 weeks if smear conversion has not occurred by 16 or 20 weeks 7

8 STREAM Study Population Adults (18 years or older) who has given consent for treatment and follow-up Smear-positive pulmonary tuberculosis, or if HIV positive may be smear negative Evidence of initial resistance to rifampicin on line-probe assay, GeneXpert or other DST No evidence of initial resistance to fluoroquinolone or 2 nd -line injectables on line-probe assay No pre-existent QT prolongation >500msec If pre-menopausal woman, not pregnant or breast feeding and agrees to use effective barrier contraception/IUCD during treatment

Stage 1: current status Enrolment to Stage 1 commenced: July 2012 Sites: Ethiopia (2), South Africa (3), Vietnam and Mongolia 424 of initial target of 400 patients enrolled Intake closed: June 30th 2015 Primary endpoint at 30 months Last patient visit: Q Results from Stage 1 expected: Q1/

STREAM Stage 1 Partners MONGOLIA  NCCD, Ulaanbataar Funder: USAID SOUTH AFRICA  Sizwe Tropical Diseases Hospital  King Dinuzulu Hospital, Durban  Doris Goodwin Hospital, Pietermaritzburg/THINK Design, Management, Analysis ETHIOPIA  Armaeur Hansen Research Institute (AHRI)  St. Peter’s Tuberculosis Specialised Hosp./ Global Health Committee Impact Assessment: Liverpool School of Tropical Medicine Microbiology: Institute of Tropical Medicine, Antwerp VIETNAM  Ho Chi Minh City Hospital Sponsor: The Union

STREAM Stage 2 Following the provisional licensing of bedaquiline we were asked to consider: – is it possible to include additional regimens to the STREAM trial in its present form? – if so, what would be the appropriate regimen(s) to evaluate? After extensive discussions between the study partners and other experts it was agreed that the primary interest to patients and programmes would be: – a fully oral regimen (no kanamycin) and/or – a shorter and simpler regimen 11

Regimens for Stage 2

STREAM Stage 2 Collaboration Funding : USAID and Janssen; Sponsor: The Union Including as many of the Stage 1 sites as possible, with additional sites (inc. Eastern Europe) Primary objectives: To assess whether the proportion of patients with a favourable efficacy outcome on Regimen C, the fully oral regimen, is as effective as Regimen B at 76 weeks (18 months) To assess whether the proportion of patients with a favourable efficacy outcome on Regimen D, the 6-month regimen, is as effective as Regimen B at 76 weeks (18 months) 13

STREAM Stage 2 design Because it is possible that Regimen B might not be found to be non-inferior to Regimen A it was decided to continue to enrol patients to Regimen A Secondary objectives include the comparisons of Regimen C and Regimen D to Regimen A; these will be particularly important if Regimen B is found to be inferior to Regimen A Sample size for Stage 2 =

TRUNCATE Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for drug-sensitive Tuberculosis (TB): a randomised controlled non- inferiority trial with a multi-arm multi-stage design led by National University of Singapore, and run in collaboration with MRC CTU at UCL 15

TRUNCATE: why so short? In 1981 Wallace Fox reviewed the current status of short course chemotherapy; he noted that even in regimens of only 3 or 4 months duration using standard drugs over 80% of patients had a relapse-free cure. What if new drugs were added and treatment was given for only 2 months? Equally good or better results might be achieved. If relapsing patients could be successfully retreated such a strategy might be very attractive both the patients and TB programmes. 16

TRUNCATE – a strategy trial Objective: To test whether the TRUNCATE-TB strategy is non-inferior to the standard 6-monthTB strategy TRUNCATE treatment strategy o Treatment can be extended from 8 to 12 weeks for patients responding slowly o Patients smear positive at 12 weeks or missing more than 2 weeks treatment to be given 6 months’ treatment o Regimens behaving badly stopped early (MAMS design) o Close monitoring for relapse Primary outcome: assessed by the proportion of patients with unsatisfactory outcome 2 years after randomisation 17

China Beijing Chest Hospital Wuhan Center for TB Control Tianjin Haihe Hospital Indonesia FMUI, Jakarta University of Padjadjaran, Bandung Hasanuddin University, Makassar Philippines Philippine Tuberculosis Society Lung Centre of the Philippines Singapore National University Hospital Singapore General Hospital Changi General Hospital Thailand Siriraj Hospital – Mahidol University Chulalongkorn Hospital Bamrasnaradura Hospital Vietnam Hanoi Lung Hospital Thanh Hoa TB and Lung Hospital TB REGIONAL CLINICAL TRIALS NETWORK