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

The Need For New Trials

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

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

The Need For New Trials The TB Alliance’s vision

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

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

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-824 100mg +PZA 1500mg for 17weeks Moxifloxacin 400mg +Pa-824 200mg + PZA 1500mg for 17 weeks Moxifloxacin 400mg + Pa-824 200mg + PZA 1500mg for 26 weeks Control arm of 6months standard TB treatment Treatment arms for MDR TB (daily dose): Moxifloxacin 400mg +Pa-824 200mg + PZA 1500mg for 26 weeks

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

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

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

The NC006 Trial (STAND): Rationale

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

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

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

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

The NC006 trial (STAND):

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

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

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

References TB Alliance [Internet]. Inadequate Treatment. http://www.tballiance.org/why/inadequate- 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

Questions? Thank you