Selexipag (ACT-293987) in Pulmonary Arterial Hypertension

Study Overview
=================
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.

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

Conditions
-----------------
Pulmonary Arterial Hypertension

Intervention / Treatment
-----------------
* Drug: Selexipag
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>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 | Drug: Selexipag<br>* Selexipag 200 µg tablets<br>* Other names: ACT-293987;|
| Placebo Comparator: 2<br>Matching placebo is administered orally with a dosing interval of approximately12 h. A (mock) up-titration scheme is followed | Drug: Placebo<br>* Placebo tablets matching selexipag<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough | 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. | Week 26 | 
| Absence of Worsening From Baseline to Week 26 in Modified NYHA/WHO Functional Class (WHO FC) |  | Week 26 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PAH, pulmonary arterial hypertension