Evaluation of a Standardized Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB (ST REAM) Nehemiah Nhando UZ-UCSF ANNUAL RESEARCH DAY 08 April 2016 Harare

2

3

DR-TB case detection in Zimbabwe 2010 – DR - TB cases initiated on treatment 381 (92%) DR-TB cases detected 412 (43%) Estimated DR-TB cases 950

DR-TB case detection in Zimbabwe

Why New drugs/ regimens for MDR TB? 6 Current WHO recommended standard of treatment for MDR TB lasts for two years or more - Shorten therapy Isoniazid and pyrazinamide remain are toxic - Decrease toxicity Multidrug-resistant TB, or intolerance to first-line drugs - Improve efficacy

Previous Studies Successful results from MDR-TB patients treated with a 9- month regimen in Bangladesh suggest there are better options even without the introduction of new drugs The most effective regimen required a minimum of 9 months of treatment with gatifloxacin, clofazimine, ethambutol, and pyrazinamide throughout the treatment period supplemented by prothionamide, kanamycin, and high-dose isoniazid during an intensive phase of a minimum of 4 months, giving a relapse-free cure of 87.9% (95% confidence interval, ) among 206 patients. Major adverse drug reactions were infrequent and manageable – 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):

The 9-month Bangladesh Regimen 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 8

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

STREAM International, multi-centre, parallel-group, open-label, randomised, controlled trial …… …….. To evaluate a Standardized Treatment Regimen of Anti- Tuberculosis Drugs for Patients with MDR-TB (STREAM)……. ………. Including patients with rifampicin resistant and isoniazid-sensitive TB. 10

Why a randomised controlled trial? 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 shorter MDR- TB treatment If successful, to provide a new standard of care for comparison with potentially better regimens 11

STREAM Stage 1 Primary Objectives 1. To assess whether the proportion of patients with a favourable efficacy outcome at Week 132 on Regimen B is not inferior to that on Regimen A (WHO approved MDR-TB regimen) 2. To compare the proportion of patients who experience grade 3 or greater adverse events, during treatment or follow- up, on Regimen B as compared to Regimen A. 12

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 13

Stage 1 trial entry, randomisation, treatment and follow-up 14

15 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

OUTCOME MEASURES FOR STAGE 1 Primary Outcome Measures The primary efficacy outcome measure comparison is the proportion of patients with a favourable outcome at Week 132 The primary safety outcome measure is the proportion of patients experiencing a grade 3 or greater adverse event, as defined by the DAIDS criteria, during treatment and follow-up. Favourable Outcome defined as negative last two culture results taken on separate visits; the latest of which being no more than six weeks earlier than Week 132 Secondary outcome measures  Time to sputum smear conversion  Time to sputum culture conversion  Time to unfavourable efficacy outcome  Time to cessation of clinical symptoms based on PI assessment  All-cause mortality during treatment or follow-up  Change of regimen for adverse drug reactions  Number of serious adverse reactions occurring on treatment and during the follow-up period  Adherence to treatment. In selected sites, costs and acceptability of Regimens A and B to stakeholders will be analysed in terms of:  Costs to the health system  Household costs  Patient treatment and support experiences  Health worker experiences 16.

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 Accrual closed: June 30th 2015 Primary endpoint at 30 months Last Patient Last Visit: Q Results from Stage 1 expected: Q1/

Trial recruitment Stages 18

STREAM Stage 2 … After the provisional licensing of bedaquiline consideration was made to determine: – Possibility of including 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 – To assess the shorter regimens in a variety of settings including sites with high levels of HIV-coinfection. 19

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 A total of at least 1155 participants from sites in a number of countries will be randomised to either Regimen A, Regimen B, Regimen C, or Regimen D in a ratio 1:2:2:2 (i.e. 165 allocated to Regimen A, 330 allocated to Regimen B, 330 allocated to Regimen C, and 330 allocated to Regimen D). Sample size for Stage 2 =

STREAM STAGE 2 OBJECTIVES 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) 21

Stage 2 trial entry, randomisation, treatment and follow-up 22 All Stage 2 Sites Regimen A Regimen B – 330 Regimen C – 330 Regimen D – 330 Total participants 1155 Zimbabwe Sites 100 participants

Regimens for Stage 2

OUTCOME MEASURES STAGE 2 Primary Outcome Measures The primary efficacy outcome measure of the Stage 2 comparisons is the proportion of patients with a favourable outcome at Week 76. Favourable outcome defined as negative last two culture results taken on separate visits; the latest of which being no more than six weeks earlier than Week 76. Secondary Outcome Measures  Time to sputum culture conversion  Time to sputum smear conversion  Efficacy status at end of follow-up  Time to unfavourable efficacy outcome  Time to cessation of clinical symptoms based on PI assessment All-cause mortality during treatment or follow-up  Proportion of patients experiencing a grade 3 or greater adverse event, as defined by the DAIDS criteria, during treatment and follow-up  Change of regimen for adverse drug reactions  Number of adverse events occurring on treatment and during the follow-up period  Pharmacokinetic outcomes  Adherence to treatment. In selected sites, costs and acceptability of the four regimens to stakeholders will be analysed in terms of:  Costs to the health system  Household costs  Patient treatment and support experiences  Health worker experiences. 24

STREAM STAGE 2 TRIAL TIMELINES in ZIMBABWE Partnership between The MoHCC, City of Harare, the Union MRC Clinical Trials Unit (UCL)and UZ-UCSF Research Program and Institute of Tropical Medicine Antwerp 2 sites have been assessed by the Union in late January BRIDH Harare - Khami Road Clinic in Bulawayo Applications for ethical and clinical trial regulatory authorities will start mid-March Approvals by July 2016 Training and implementation by August 2016 (start with Harare then activate Bulawayo site after 6 months) 25

Acknowledgements 26 Funder: USAID Design, Management, Analysis Impact Assessment: Liverpool School of Tropical Medicine Microbiology: Institute of Tropical Medicine, Antwerp Sponsor: The Union UZ-UCSF Collaborative Research Programme