1. STAND Trial NC-006 (M-Pa-Z) Dr Suzanne Staples Principal Investigator at THINK 26 Mar 2015

3. The Need For New Trials

4. The Need For New Trials
It is second only to HIV as the leading infectious killer of adults
TB is the cause of death in approx. 25% of HIV infected patients
TB is curable¹

5. The Need For New Trials
The current regimen was designed more than 40years ago
Cure takes very long: 6-24months
Complicated to administer and includes an injectable. This adds to poor adherence
The drugs can be very toxic for example ototoxicity
New, faster and better drugs are urgently needed¹

6. The Need For New Trials
The TB Alliance’s vision

7. The NC006 Trial (STAND)
Title: : A Phase 3 Open-Label Partially randomized Trial to Evaluate the Efficacy, Safety and Tolerability of combinations of Moxifloxacin plus PA-824 plus pyrazinamide after 4 and 6 months of treatment in Adult Subjects with Drug-Sensitive, Smear-Positive Pulmonary Tuberculosis and after 6 months of Treatment in Adult Subjects with Multi Drug-Resistant, Smear- Positive Pulmonary Tuberculosis.
Name: STAND: Shortening Treatment by Advancing Novel Drugs
Sponsor: TB Alliance

8. The NC006 Trial (STAND):Trial Design
Phase 3 trial
Multi-centre, world wide
Open-label, partially randomised into 5 parallel treatment groups
Up to 1500 male and female participants, diagnosed with DS or MDR smear positive pulmonary TB
1200 DS-TB (300 per treatment arm)
Up to 300 MDR-TB subjects

9. The NC006 Trial (STAND):Trial Design
Trial Medication: PA-824 (Pretomanid), Moxifloxacin, Pyrazinamide
Pretomanid: Nitroimidazole with bactericidal en sterilizing activity in mice
Treatment arms for Drug-Sensitive TB (daily dose):
Moxifloxacin 400mg + Pa mg +PZA 1500mg for 17weeks
Moxifloxacin 400mg +Pa mg + PZA 1500mg for 17 weeks
Moxifloxacin 400mg + Pa mg + PZA 1500mg for 26 weeks
Control arm of 6months standard TB treatment
Treatment arms for MDR TB (daily dose):
Moxifloxacin 400mg +Pa mg + PZA 1500mg for 26 weeks

10. The NC006 Trial (STAND):Trial Design
Trial duration:
Total study duration: 4 years
Enrollment: 18 months
Treatment: Drug sensitive: 4month treatment Drug resistant: only 6months!
Follow up 24 months after treatment start
Trial participant will be fully managed by the study

11. The NC006 Trial (STAND): Rationale
Follow up of the phase 2b study NC-002
Data from Mouse Model and Phase 2 Human studies
Nearly twice (71%) as many TB patients treated with PaMZ had no TB in their sputum when cultured at the end of the 2-month course of the trial compared to patients treated with standard therapy (38%).
Phase 2b NC-002 met primary and 3 of 5 secondary endpoints with statistical significance
Patients with MDR treated with PaMZ had similar reductions in sputum colony counts over 8 weeks as patients with DS-TB treated with RHZE
A rapid molecular test will allow evaluation of PZA susceptibility for patients with MDR-TB during the screening period in Phase 3

12. The NC006 Trial (STAND): Rationale
Safety of PaMZ over 8 weeks in >200 patients was similar to the HRZE regimen and acceptable to take to a phase 3 trial
The PaMZ regimen has the potential to give relapse-free cure of pulmonary TB in patients with DS-TB treated for 4months and in patients with MDR-TB treated for 6 months
Full results have been published in The Lancet

13. The NC006 Trial (STAND): Rationale

14. The NC006 Trial (STAND): Objectives
Trial Objective: To assess the efficacy, safety and tolerability of the regimen compared to:
RHZE for Drug Sensitive TB
the DS outcome after 6months of treatment for MDR-TB
Primary Trial Endpoint:
Incidence of bacteriological failure or relapse or clinical failure at 12months from the start of therapy

15. The NC006 Trial (STAND): Objectives
Secondary Trial Endpoints
Efficacy: Rate of change in time to positivity, change from baseline symptoms etc
Safety and tolerability: Incidence of treatment related adverse events, ECG’s measurements, ophthalmology data and safety laboratory testing
Pharmacokinetics - Pharmacodynamics: To build a population PK model that will be used to explore trends in safety and efficacy data from the trial

16. The NC006 Trial (STAND): Study Population
Inclusion criteria:
Provide written, informed consent prior to all trial‐related procedures
Body weight of ≥30 kg or greater (in light clothing and no shoes)
Willingness and ability to attend scheduled follow‐up visits and undergo study assessments
Sputum smear positive
Male or female, aged 18 and over
Chest X‐Ray picture consistent with pulmonary TB
Be of non‐childbearing potential or using effective methods of birth control

17. The N006 Trial (STAND): Study Population
Exclusion Criteria
Generally unwell patients
CD4 less than 100
Allergic to study drug
Previously participated in trial using these drugs
Alcohol/drug use that could affect their safety or follow up
Severely abnormal Blood results
Pregnant or Breastfeeding²

18. The NC006 trial (STAND):

19. Other Trials Currently Running
The NC005
total of 38months: 12 months recruitment, 2months of treatment and 24months of follow up Phase 2b trial in DS and MDR TB
Open-label partially randomized.
Approximately 180 DS and 60 MDR TB patients.
2months of treatment with: Bedaquiline, Pa-824 and Pyrazinamide
Control arm of Rifafour
To determine safety efficacy and tolerability of this combination
Transferred back to standard of care once the two months are completed³

20. Other Trials Currently Running
STREAM (Bangladesh regimen)
The evaluation of a standardized treatment regimen of anti-tuberculosis drugs for patients with MDR-TB
Open-label randomized control trial
International multi-site trial
400 MDR TB patients
9month regimen using existing drugs. 16 week intensive phase with daily Kanamycin
Control arm of a locally –used WHO approved MDR-TB regimen
To determine whether the proportion of patients with a favorable outcome at week 120 is not inferior to standard of care. Also to compare the proportion of patients with grade 3 or greater adverse events during treatment or follow-up in both arms⁴

21. Future Trials currently running
NIX
4month regimen in XDR patients (option to extend to 9months if culture positive at 4months)
Includes: Linazolid, Pretomanid and Bedaquiline
Total of 200 patients with a slow start up
3 sites globally⁵
Jansen –Pediatric Bedaquiline Trial
Stream Phase 2: Including Bedaquiline to investigate the possibility of replacing Kanamycin

22. References
TB Alliance [Internet]. Inadequate Treatment. treatment.php (15 March 2015)
TB Global Alliance, Protocol Title: A Phase 3 Open-Label Partially randomized Trial to Evaluate the Efficacy, Safety and Tolerability of combinations of Moxifloxacin plus PA-824 plus pyrazinamide after 4 and 6 months of treatment in Adult Subjects with Drug-Sensitive, Smear-Positive Pulmonary Tuberculosis and after 6 months of Treatment in Adult Subjects with Multi Drug-Resistant, Smear- Positive Pulmonary Tuberculosis. TB Global Alliance, Protocol Version 1.0; 14 April 2014
TB Global Alliance: : A Phase 2 Open-Label Partially randomized Trial to Evaluate the Efficacy, Safety and Tolerability of combinations of Bedaquiline, Moxifloxacin, PA-824 and pyrazinamide during 8weeks of treatment in Adult Subjects with Newly Diagnosed Drug-Sensitive or Multi Drug- Resistant, Smear-Positive Pulmonary Tuberculosis, Protocol Version 1.1, 19 September 2014
The MRC UK, STREAM: : The evaluation of a standardized treatment regimen of anti-tuberculosis drugs for patients with MDR-TB, Protocol version 5.0, March 2013
TB Global Alliance, Protocol Title: A Phase 3 open-label trial assessing the safety and efficacy of bedaquiline plus pretomanid plus linezolid in Subjects with pulmonary infection of either extensively drug-resistant tuberculosis (XDR-TB) or treatment intolerant / non-responsive multi- drug resistant tuberculosis (MDR-TB). Protocol version 2.0, Dec 2014

23. Questions? Thank you