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

2. Status of MDR-TB world-wide
Burden of disease
In 2015, of the estimated 580,000 people eligible for MDR-TB treatment, only (~ 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

3. Outcomes of MDR TB treatment
Source: Global Tuberculosis Report 2016

4. Where does MDR TB occur?

5. 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

6. 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

7. 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

8. 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. 9
How is DR TB treated?
Introdion
Objectif
Méthodes
Conclusion

10. Conventional/longer regimens for MDR-TB
Usually between 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

11. 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

12. Emerging evidence for new regimens12
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):

13. Results of 9-month regimen–Bangladesh
Introdion
Objectif
Méthodes
Conclusion
Published cohort (206 pts)
Cure 82.5%
Completion 5.3%
Default %
Death %
Failure %
Relapse %
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%
84.5% (95% CI 0.81, 0.88)
Aung et all, IJTLD 18(10):1180–1187, 2014

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

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

16. 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

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

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

19. 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.

20. 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

21. The study regimen (B) – 9 months
Weeks Drug doses by weight group
Drug < 33 kg kg > 50 kg
Kanamycin* mg per kilogramme body weight
Isoniazid (H) mg mg mg
Prothionamide mg mg mg
Clofazimine mg mg mg
Moxifloxacin mg mg mg
Ethambutol mg mg mg
Pyrazinamide mg mg 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

22. 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

23. 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

24. 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.

25. 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

26. 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.

27. STREAM Stage 2 regimens

28. 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)

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. Thank you