Treatment for Multi-drug Resistant TB STREAM Clinical Trial [INSERT NAME OF PRESENTER]

Status of MDR-TB world-wide Burden of disease In 2015, of the estimated 580,000 people eligible for MDR-TB treatment, only 125 000 (~ 1 in 5) were started on treatment Outcomes of MDR/RR-TB patients in the 2013 cohort: 52% were successfully treated 17% died 15% were lost to follow-up 9% were determined to be treatment failure 7% had no outcome information

Outcomes of MDR TB treatment Source: Global Tuberculosis Report 2016

Where does MDR TB occur?

Treatment of drug sensitive TB Two main drugs for treatment of DS TB Isoniazid Rifampicin Treatment taken 6 months by mouth Treatment very successful >90% cure for patients who take their medication If resistance to rifampicin occurs treatment takes much longer more side effects does not work as well

How does resistance to TB medicines happen? Acquired resistance happens when Patients with drug sensitive TB can’t or don’t take medications as required Miss doses or not given the correct doses to take Pharmacy runs out of medicines Get side effects and stop treatment Transmitted resistance happens when Patients get infected with resistant TB TB organism that infects the patient is resistant to medication from the start of treatment

What if TB resistance exists? Rifampicin is the best currently available TB medicine If resistance to Rifampicin exists, more medications have to be given: not as strong worse side effects Patients have to have injections for 6 months Treatment less effective Only ~50% of patients are cured

Definitions of TB Drug Resistance Multi-drug resistant Rifampicin Isoniazid Extensively drug resistant Fluoroquinolne Amikacin or kanamycin or capreomycin RESISTANT Pre-XDR or Drug Sensitive

9 How is DR TB treated? Introdion Objectif Méthodes Conclusion

Conventional/longer regimens for MDR-TB Usually between 20-24 months, with 2 phases Intensive phase Quinolone (moxifloxacin) Injectable agent (amikacin, kanamycin or capreomycin) PZA Ethionamide Terizidone/cycloserine Ethambutol (depends on local prevalence or resistance) Continuation phase

New WHO recommendation for shorter regimens - 2016 For most patients with MDR-TB, a shorter regimen (9-12 months) can be used instead of a longer, conventional regimen But: WHO’s recommendation acknowledges that additional evidence is required

Emerging evidence for new regimens 12 Emerging evidence for new regimens Results for six groups of patients with MDR-TB in Bangladesh who received a shortened regimen indicated there might be better treatment options for MDR-TB, even without 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): 684-92.

Results of 9-month regimen–Bangladesh Introdion Objectif Méthodes Conclusion Published cohort (206 pts) Cure 82.5% 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 182. 684–692, 2010 Cohort update (515 pts) 81.2% 3.3% 7.8% 5.6% 1.4% 0.8% 84.5% (95% CI 0.81, 0.88) Aung et all, IJTLD 18(10):1180–1187, 2014

Bangladesh regimen–Intensive Phase Quinolone (moxifloxacin/ gatifloxacin) Injectable agent (Amikacin, kanamycin or capreomycin) PZA Ethionamide/prothionamide High dose INH Clofazamine Ethambutol

Bangladesh regimen–Continuation Phase Quinolone (moxifloxacin/gatifloxacin) PZA Clofazamine Ethambutol No injectable agent

Conclusions Drug resistant TB affects > half a million people worldwide Only half of those who are treated for Drug resistant TB are successfully treated Until recently, treatment for Drug Resistant TB was based on very low quality evidence Promising new treatment regimens for MDR-TB are emerging: Better treatment outcomes Shorter Still includes injectable agents Do not yet incorporate new drugs However, there continues to be an urgent need for research

[INSERT NAME OF PRESENTER] The STREAM Trial [INSERT NAME OF PRESENTER]

Building evidence for better MDR-TB regimens Cohort studies Randomized trials Cameroon Benin Niger Swaziland Other African countries Uzbekistan STREAM

Bangladesh regimen w/ Moxi STREAM objectives Shorter regimen (6 months) Conventional regimen (20-24 months) Bangladesh regimen w/ Moxi (9 months) vs. STREAM Stage 2 vs. STREAM Stage 1 All oral regimen (9 months) vs.

STREAM Stage 1 Control regimen (A)  Study regimen (B)  STREAM Stage 1 sites Sites: Ethiopia (2), South Africa (3), Vietnam and Mongolia (1) Control regimen (A)  locally used WHO- recommended regimen Study regimen (B)  similar to Bangladesh shorter regimen but high-dose moxifloxacin replaces high-dose gatifloxacin

The study regimen (B) – 9 months Weeks Drug doses by weight group Drug < 33 kg 33 - 50 kg > 50 kg Kanamycin* 1 - 16 15 mg per kilogramme body weight Isoniazid (H) 1 - 16 300 mg 400 mg 600 mg Prothionamide 1 - 16 250 mg 500 mg 750 mg Clofazimine 1 - 40 50 mg 100 mg 100 mg Moxifloxacin 1 - 40 400 mg 600 mg 800 mg Ethambutol 1 - 40 800 mg 800 mg 1200 mg Pyrazinamide 1 - 40 1000 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

STREAM Stage 1 study population Adults who have given consent Smear-positive pulmonary tuberculosis or, if HIV positive, may be smear negative Resistance to rifampicin No resistance to fluoroquinolone or 2nd-line injectables No pre-existing QT prolongation >500msec If pre-menopausal woman, not pregnant or breast feeding and agrees to use effective barrier contraception/IUCD during treatment

STREAM Stage 1 status Enrolment started July 2012 424 patients enrolled Target reached and exceeded Intake closed June 30th 2015 Retention rates are high Last patient visit expected Q4 2017 Results from Stage 1 expected Q1/2 2018

Bangladesh regimen w/ Moxi STREAM Stage 2 Shorter regimen (6 months) Conventional regimen (20-24 months) Bangladesh regimen w/ Moxi (9 months) vs. STREAM Stage 2 vs. All oral regimen (9 months) vs.

STREAM Stage 2 history After provisional licensing of first new TB drug for ~50 years (bedaquiline) in 2013, STREAM trial sponsor asked: Is it possible to add regimens to the STREAM trial? What would be the appropriate regimen(s) to add? After extensive discussions with experts it was agreed that the primary interest to patients and programmes would be: A fully oral regimen (no kanamycin) and/or A shorter/simpler regimen

STREAM Stage 2 regimens STREAM Stage 2 patients take one of four regimens: A: the locally used WHO approved MDR-TB regimen B: the modified 9-month Bangladesh regimen studied in Stage 1 C: a fully oral 9-month regimen D: a six-month regimen Both regimens C and D will contain bedaquiline throughout.

STREAM Stage 2 regimens

STREAM Stage 2 objectives Assess whether Regimen C, the fully oral regimen, is as effective as Regimen B at 76 weeks (18 months) Assess whether Regimen D, the 6-month regimen, is as effective as Regimen B at 76 weeks (18 months)

STREAM Stage 2 status Enrolment began in March 2016 STREAM Stage 2 sites Current sites: Ethiopia (2), South Africa (3), Mongolia (1), Moldova (1) Enrolment began in March 2016 >70 patients enrolled Currently enrolling patients in Ethiopia, Mongolia, South Africa and Moldova Trial planned for 9 countries and 15+ sites

STREAM Stage 2 study population The same criteria as Stage 2 with Additional safety criteria for liver, kidney, pancreatic and electrolytes function Increased focus on excluding risk factors for cardiac arrhythmias A chest X-ray compatible with a diagnosis of pulmonary TB HIV infected participants must CD4 count more than 50 cells/mm3

STREAM Stage 2 timeline Plan to complete enrolment in less than 3 years Last patient enrolled Q4 of 2018 Last patient reaches 18 months post- randomisation Q2 of 2020 Last patient completes long term follow-up Q2 of 2021

Design, Management, Analysis STREAM Partners Funder: USAID Design, Management, Analysis Impact Assessment: Liverpool School of Tropical Medicine Microbiology: Institute of Tropical Medicine, Antwerp Sponsor: Funder: Janssen Pharmaceuticals (Stage 2 only) Trial sites

Conclusions Drug resistant TB affects > half a million people worldwide Only half of those who are treated for drug resistant TB are successfully treated Until recently, treatment for drug resistant TB was based on very low quality evidence Promising new treatment regimens for MDR-TB are emerging: Better treatment outcomes Shorter Still includes injectable agents Do not yet incorporate new drugs However, there continues to be an urgent need for research

Conclusions STREAM aims to improve the evidence base for better MDR-TB treatment regimens Shorter regimens (Stage 1 and 2) All-oral regimen (Stage 2) New drugs (Stage 2) STREAM uses a randomized control trial design to strengthen quality of evidence Results from Stage 1 expected shortly Stage 2 still scaling up Results not expected until after 2021

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