Selexipag (ACT-293987) in Pulmonary Arterial Hypertension (GRIPHON)

• ClinicalTrials.gov Identifier: NCT01106014
• Recruitment Status: Completed
• First Posted: April 19, 2010
• Results First Posted: March 1, 2016
• Last Update Posted: January 11, 2018
• Sponsor: Actelion
• Information provided by (Responsible Party): Actelion

Tracking Information

• First Submitted Date: April 2, 2010
• First Posted Date: April 19, 2010
• Results First Submitted Date: February 2, 2016
• Results First Posted Date: March 1, 2016
• Last Update Posted Date: January 11, 2018
• Study Start Date: December 1, 2009
• Actual Primary Completion Date: April 1, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 2, 2016)

Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake [ Time Frame: Up to 7 days after end of double-blind treatment (maximum: 4.3 years) ]

Time from randomization to the first occurrence of a morbidity event or death (all causes) was analyzed with the Kaplan-Meier method (event-free KM estimates at different time points). Morbidity event was defined as any of the following events confirmed by the Critical Event committee:

• Hospitalization for worsening of pulmonary arterial hypertension (PAH),
• Worsening of PAH resulting in need for lung transplantation or balloon atrial septostomy,
• Initiation of parenteral prostanoid therapy or chronic oxygen therapy due to worsening of PAH,
• Disease progression which was defined by a decrease in 6-minute walk distance from baseline (>=15%, confirmed by a 2nd test on a different day) combined with worsening of WHO FC for patients belonging to WHO FC II/III at baseline, or combined with the need for additional PAH-specific therapy for patients belonging to WHO FC III/IV at baseline.

Note: The number of patients at risk decreased over time but this cannot be captured below

• Original Primary Outcome Measures (submitted: April 16, 2010): Demonstrate the effect of ACT-293987 on time to first clinical worsening in pts. with PAH. Clinical worsening is delineated according to the definition of the Dana Point 4th World Symposium of PH McLaughlin VV. et al. JACC 2009; 54 (S1): S97-S107 [ Time Frame: Baseline (day 1) to over a period of up to 3.5 years ]

Current Secondary Outcome Measures (submitted: February 2, 2016)

• Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough [ Time Frame: Week 26 ]
  The 6-minute walk distance test (6MWD) is a non-encouraged test performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. If the patient was used to taking bronchodilators before a walk, he/she was given them 5 to 30 min before the test. Also if the patient was on chronic oxygen therapy, oxygen was given at their standard rate during the test. Absolute change from baseline to Week 26 in 6MWD was measured at trough, i.e., either on the next day after the last study drug administration or at least 12 hours after study drug administration if on the same day.
• Absence of Worsening From Baseline to Week 26 in Modified NYHA/WHO Functional Class (WHO FC) [ Time Frame: Week 26 ]

• Original Secondary Outcome Measures (submitted: April 16, 2010): Evaluate the effect of ACT-293987 on exercise capacity (6-minute walk distance & Borg dyspnea index) & other secondary & exploratory efficacy endpoints in patients with PAH [ Time Frame: Baseline (day 1) to over a period of up to 3.5 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Selexipag (ACT-293987) in Pulmonary Arterial Hypertension
• Official Title: A Multicenter, Double-blind, Placebo-controlled Phase 3 Study Assessing the Safety and Efficacy of Selexipag on Morbidity and Mortality in Patients With Pulmonary Arterial Hypertension
• Brief Summary: The AC-065A302 (GRIPHON) study is an event-driven Phase 3 study to demonstrate the effect of selexipag on time to first morbidity or mortality event in patients with pulmonary arterial hypertension.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Pulmonary Arterial Hypertension

Intervention

• Drug: Selexipag
  Selexipag 200 µg tablets
  Other Name: ACT-293987
• Drug: Placebo
  Placebo tablets matching selexipag

Study Arms

• Experimental: 1
  Selexipag is up-titrated from Day 1 to Week 12 to each patient's maximum tolerated dose in the range of 200-1600 µg twice a day (b.i.d.) in 200 µg steps starting with one 200 µg oral tablet on Day 1. From Day 2 onwards, a b.i.d. dose regimen with an interval of approximately 12 hours is followed. If this dose (selexipag 200 μg b.i.d.) is well-tolerated, selexipag is up-titrated with weekly increments of 200 µg. Up-titration is followed by a stable maintenance treatment period from Week 12 onwards, up to Week 26, at the maximum tolerated dose
  Intervention: Drug: Selexipag
• Placebo Comparator: 2
  Matching placebo is administered orally with a dosing interval of approximately12 h. A (mock) up-titration scheme is followed
  Intervention: Drug: Placebo

Publications *

• Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galie N, Ghofrani HA, Hoeper MM, Lang IM, Preiss R, Rubin LJ, Di Scala L, Tapson V, Adzerikho I, Liu J, Moiseeva O, Zeng X, Simonneau G, McLaughlin VV; GRIPHON Investigators. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015 Dec 24;373(26):2522-33. doi: 10.1056/NEJMoa1503184.
• Galie N, Gaine S, Channick R, Coghlan JG, Hoeper MM, Lang IM, McLaughlin VV, Lassen C, Rubin LJ, Hsu Schmitz SF, Sitbon O, Tapson VF, Chin KM. Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension. Adv Ther. 2022 Jan;39(1):796-810. doi: 10.1007/s12325-021-01898-1. Epub 2021 Oct 30.
• Gaine S, Sitbon O, Channick RN, Chin KM, Sauter R, Galie N, Hoeper MM, McLaughlin VV, Preiss R, Rubin LJ, Simonneau G, Tapson V, Ghofrani HA, Lang I. Relationship Between Time From Diagnosis and Morbidity/Mortality in Pulmonary Arterial Hypertension: Results From the Phase III GRIPHON Study. Chest. 2021 Jul;160(1):277-286. doi: 10.1016/j.chest.2021.01.066. Epub 2021 Feb 3.
• Chin KM, Rubin LJ, Channick R, Di Scala L, Gaine S, Galie N, Ghofrani HA, Hoeper MM, Lang IM, McLaughlin VV, Preiss R, Simonneau G, Sitbon O, Tapson VF. Association of N-Terminal Pro Brain Natriuretic Peptide and Long-Term Outcome in Patients With Pulmonary Arterial Hypertension. Circulation. 2019 May 21;139(21):2440-2450. doi: 10.1161/CIRCULATIONAHA.118.039360.
• McLaughlin VV, Hoeper MM, Channick RN, Chin KM, Delcroix M, Gaine S, Ghofrani HA, Jansa P, Lang IM, Mehta S, Pulido T, Sastry BKS, Simonneau G, Sitbon O, Souza R, Torbicki A, Tapson VF, Perchenet L, Preiss R, Verweij P, Rubin LJ, Galie N. Pulmonary Arterial Hypertension-Related Morbidity Is Prognostic for Mortality. J Am Coll Cardiol. 2018 Feb 20;71(7):752-763. doi: 10.1016/j.jacc.2017.12.010.
• Coghlan JG, Channick R, Chin K, Di Scala L, Galie N, Ghofrani HA, Hoeper MM, Lang IM, McLaughlin V, Preiss R, Rubin LJ, Simonneau G, Sitbon O, Tapson VF, Gaine S. Targeting the Prostacyclin Pathway with Selexipag in Patients with Pulmonary Arterial Hypertension Receiving Double Combination Therapy: Insights from the Randomized Controlled GRIPHON Study. Am J Cardiovasc Drugs. 2018 Feb;18(1):37-47. doi: 10.1007/s40256-017-0262-z.
• Gaine S, Chin K, Coghlan G, Channick R, Di Scala L, Galie N, Ghofrani HA, Lang IM, McLaughlin V, Preiss R, Rubin LJ, Simonneau G, Sitbon O, Tapson VF, Hoeper MM. Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. Eur Respir J. 2017 Aug 17;50(2):1602493. doi: 10.1183/13993003.02493-2016. Print 2017 Aug.
• Krause A, Machacek M, Lott D, Hurst N, Bruderer S, Dingemanse J. Population Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension. CPT Pharmacometrics Syst Pharmacol. 2017 Jul;6(7):477-485. doi: 10.1002/psp4.12202. Epub 2017 May 27.
• Skoro-Sajer N, Lang IM. Selexipag for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2014 Feb;15(3):429-36. doi: 10.1517/14656566.2014.876007. Epub 2014 Jan 7.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 28, 2013): 1156
• Original Estimated Enrollment (submitted: April 16, 2010): 670
• Actual Study Completion Date: October 1, 2014
• Actual Primary Completion Date: April 1, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male and female patients 18-75 years old, with symptomatic PAH
• PAH belonging to the following subgroups of the updated Dana Point Clinical Classification Group 1 (Idiopathic, or Heritable, or Drug or toxin induced, or Associated (APAH) with Connective tissue disease, Congenital heart disease with simple systemic-to-pulmonary shunt at least 1 year after surgical repair, or HIV infection)
• Documented hemodynamic diagnosis of PAH by right heart catheterization, performed at any time prior to Screening
• Six minute walk distance (6MWD) between 50 and 450 m at Screening within 2 weeks prior to the Baseline Visit
• Signed informed consent

Exclusion Criteria:

• Patients with pulmonary hypertension (PH) in the Updated Dana Point Classification Groups 2-5, and PAH Group 1 subgroups that are not covered by the inclusion criteria
• Patients who have received prostacyclin or its analogs within 1 month before Baseline Visit, or are scheduled to receive any of these compounds during the trial
• Patients with moderate or severe obstructive lung disease
• Patients with moderate or severe restrictive lung disease
• Patients with moderate or severe hepatic impairment (Child-Pugh B and C)
• Patients with documented left ventricular dysfunction
• Patients with severe renal insufficiency
• Patients with BMI <18.5 Kg/m2
• Patients who are receiving or have been receiving any investigational drugs within 1 month before the Baseline Visit
• Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements, in particular with 6MWT
• Recently conducted or planned cardio-pulmonary rehabilitation program based on exercise training
• Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
• Life expectancy less than 12 months
• Females who are lactating or pregnant or plan to become pregnant during the study
• Known hypersensitivity to any of the excipients of the drug formulations

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belarus, Belgium, Canada, Chile, China, Colombia, Czechia, Denmark, France, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Korea, Republic of, Malaysia, Mexico, Netherlands, Peru, Poland, Romania, Russian Federation, Serbia, Singapore, Slovakia, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01106014
• Other Study ID Numbers: AC-065A302
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Actelion
• Original Responsible Party: Same as current
• Current Study Sponsor: Actelion
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Aline Frey; Actelion

• PRS Account: Actelion
• Verification Date: December 2017