1 / 19

Seraphin : results from a landmark study

Seraphin : results from a landmark study. SERAPHIN: Creating a robust morbidity and/or mortality primary endpoint. Inclusion of a 3 rd criterion for PAH worsening (need for new treatment(s) for PAH). Complexity & robustness. Measurable definition of PAH worsening (6-MWD & FC).

ankti
Download Presentation

Seraphin : results from a landmark study

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Seraphin: resultsfrom a landmarkstudy

  2. SERAPHIN: Creating a robust morbidity and/or mortality primary endpoint Inclusion of a 3rd criterion for PAH worsening (need for new treatment(s) for PAH) Complexity & robustness Measurable definition of PAH worsening (6-MWD & FC) Committee for adjudication of events One criteria to define PAH worsening Morbidity/mortality as primary endpoint – event driven Secondary endpoint – time driven Dana Point1 SERAPHIN2 TTCW • McLaughlin VV, et al. J Am Coll Cardiol 2009; 54:S97-107. • SERAPHIN Study Protocol AC-055-302.

  3. SERAPHIN: A landmark study in PAH 1. Channick RN, et al. Lancet 2001. 2. Badesch D, et al. Curr Ther Res 2002. 3. Rubin LJ, et al. N Engl J Med 2002. 4. Galiè N, et al. Lancet 2008. 5. Galiè N, et al. Circulation 2008. 6. Oudiz R, et al. Chest 2006. 7. Oudiz RJ, et al. J Am Coll Cardiol 2009. 8. Galiè N, et al. N Engl J Med 2005. *Mean study drug exposure 9. Galiè N, et al. Circulation 2009. 10. www.clinicaltrials.gov, NCT00660179.

  4. Exposure to macitentan (SERAPHIN) compared with all other PAH drugs combined All PAH studies 47,000*1 Macitentan in SERAPHIN ≈ 71,000†2 0 20,000 40,000 60,000 80,000 Treatment exposure (patient weeks) *Estimated from Galiè N, et al. (2009) Meta-analysis of RCTs in PAH3 †Treatment exposure up to April 2012 1. Galiè N, et al. Eur Heart J 2009; 30:394-403. 2. Actelion data on file.

  5. The SERAPHIN study: Objectives and endpoints Objective: To study long-term efficacy and safety of macitentan in PAH using an event-driven trial design Primary endpoint Time to the first morbidity and/or mortality event up to end of double-blind treatment Secondary endpoints 6-minute walk distance (6-MWD) at month 6 WHO functional class (FC) at month 6 Time to death due to PAH or hospitalisation for PAH All-cause mortality Safety and tolerability Pulido T et al. NEJM 2013; 369:809-18

  6. SERAPHINA long-term, event-driven RCT in PAH 742 patients were randomised 1:1:1 between May 2008 and December 2009 Mean exposure 103.9 weeks Macitentan 10 mg o.d. 99.5 weeks Macitentan 3 mg o.d. 85.3 weeks Placebo Time (months) 5 10 15 0 Screening 28 days Treatment period Randomisation EOS (285 confirmed morbidity/mortality events) EOT(discontinuation of study drug) EOS: end of study EOT: end of treatment Pulido T et al. NEJM 2013; 369:809-18

  7. SERAPHIN morbidity and/or mortality primary endpoint Robust nature of the primary endpoint = only clinically relevant events are captured Morbidity/mortality as primary endpoint is considered more clinically relevant as it reflects the true progression of PAH All-cause death OR Atrialseptostomy All events adjudicated by a blinded clinical events committee OR Time to 1st morbidity and/or mortality event Lung transplantation OR Initiation of i.v. or s.c.prostanoids OR Other worsening of PAH Other worsening of PAH OR Pulido T et al. NEJM 2013; 369:809-18

  8. SERAPHIN primary endpoint: Other worsening of PAH A decrease in 6-MWD of at least 15%, confirmed by 2 tests on different days AND Worsening of PAH symptoms, which must include either: An increase in FC, or Appearance or worsening of symptoms of RHF All events adjudicated by a blinded clinical events committee Other worsening of PAH AND Need for new PAH treatment(s): Oral or inhaled prostanoids Oral PDE-5 inhibitors ERA after study discontinuation Intravenous diuretics Pulido T et al. NEJM 2013; 369:809-18

  9. Demographics and baseline characteristics All patients, n = 739; placebo, n = 249; macitentan 3 mg, n = 248; macitentan 10 mg, n = 242 Pulido T et al. NEJM 2013; 369:809-18

  10. Patient demographics: PAH aetiology Total number of patients: 742 Actelion data on file. *Simple shunt at least 1 year post-surgical repair

  11. Primary endpoint: Morbidity and/or mortality up to end of treatment Risk reduction of primaryendpoint event vs placebo 100 80 Macitentan 10 mg: 45% • Macitentan 3 mg: 30% 60 Patients without the event (%) 40 Macitentan 10 mg 20 Macitentan 3 mg Placebo 0 0 6 12 18 24 30 36 Patients at risk Time from treatment start (months) 242 208 187 1711559141 250 213 188 166 147 80 32 250 188 160 135 122 64 23 Pulido T et al. NEJM 2013; 369:809-18

  12. Morbidity and/or mortality in patients on background PAH therapy Macitentan 10 mg: 38% 100 80 • Risk reduction of primaryendpoint event vs placebo 60 • Macitentan 3 mg: 17% Patients without the event (%) 40 Macitentan 10 mg 20 Macitentan 3 mg Placebo 0 0 6 12 18 24 30 36 Patients at risk Time from treatment start (months) • 154 134 119 107 97 53 24 • 139 125 107 91 51 19 • 122 106 90 80 40 10 Pulido T et al. NEJM 2013; 369:809-18

  13. Morbidity and/or mortality in patients not on background PAH therapy Macitentan 10 mg: 55% 100 Risk reduction of primaryendpoint event vs placebo 80 Macitentan 3 mg: 47% 60 Patients without the event (%) 40 Macitentan 10 mg 20 Macitentan 3 mg Placebo 0 0 6 12 18 24 30 36 Time from treatment start (months) Patients at risk 88 746864583817 86 746359562913 96 665445422413 Pulido T et al. NEJM 2013; 369:809-18

  14. Secondary endpoint: Death due to PAH and/or hospitalisation for PAH Macitentan 3 mg: 33% 100 Risk reduction of death due to PAH or hospitalisation for PAH event vs placebo 80 Macitentan 10 mg: 50% 60 Patients without the event (%) 40 Macitentan 10 mg 20 Macitentan 3 mg Placebo 0 0 6 12 18 24 30 36 Patients at risk Time from treatment start (months) 242 2031831661528639 250 208 181 159 144 77 31 250 188 165 132 119 62 22 Pulido T et al. NEJM 2013; 369:809-18

  15. Secondary endpoint: Change from baseline to month 6 in WHO FC p = 0.006 p = 0.04 • Patients on macitentan 3 mg had a 54% greater chance to improve FC status • Patients on macitentan 10 mg had a 74% greater chance to improve FC status Pulido T et al. NEJM 2013; 369:809-18

  16. Treatment-emergent adverse events Pulido T et al. NEJM 2013; 369:809-18

  17. Adverse events and laboratory abnormalities previously associated with ERAs Up to 28 days after study drug discontinuation Pulido T et al. NEJM 2013; 369:809-18

  18. Summary I Macitentan 10 mg significantly reduced the risk of morbidity and/or mortality events up to 45% vs placebo Treatment effect with macitentan 10 mg was consistent in patients on or not on background PAH therapy Macitentan also significantly improved clinically important secondary endpoints including 6-MWD,WHO FC and PAH-related death or hospitalisation

  19. Summary II • Rates of transaminase elevations and oedema were similar in placebo and macitentan groups • A greater decrease in haemoglobin levels was observed in the active treatment groups • This laboratory abnormality has been reported in other clinical trials investigating ERAs • The most common adverse events, not associated with PAH and reported at a higher incidence than placebo, were headache, nasopharyngitis and anaemia

More Related