A Study in Participants With Sarcoidosis-associated Pulmonary Hypertension (SAPH) to Assess the Efficacy and Safety of Oral Selexipag

Study Overview
=================
Brief Summary
-----------------
Oral selexipag is commercially available in several countries for the treatment of a particular group of pulmonary hypertension (PH) called pulmonary arterial hypertension (PAH). The aim of the present study is to investigate whether selexipag could be helpful to treat patients with another form of PH called sarcoidosis-associated pulmonary hypertension (SAPH).

Detailed Description
-----------------
Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and can complicate several cardiovascular and respiratory diseases. Sarcoidosis is a multisystemic disorder that is characterized by non-caseating granulomas which are present in multiple tissues, particularly in the lung and lymphatic system. Severe untreated pulmonary hypertension (PH) carries a poor prognosis and is associated with higher mortality in participants with interstitial lung diseases and sarcoidosis. While there is no approved treatment for SAPH, PH-specific treatments are frequently used. Selexipag is a selective, orally available and long-acting non-prostanoid agonist of the prostacyclin receptor (prostacyclin [IP] receptor) for the treatment of patients with PAH. The rationale for this study is based on the unmet medical need for new therapeutic options for patients with SAPH and is supported by the established efficacy and safety of selexipag in the PAH indication, the shared pathomechanism between SAPH and PAH, and the available data on the efficacy and safety of PH-specific therapies in SAPH. This study consists of screening period, main observation period and double blind extension period and safety follow-up period. The duration of individual participation in the study will be different for each individual participant (between approximately 15 months and up to approximately 3.5 years) and will depend on the time of each participant's individual date of entering the study and the total recruitment time. The efficacy assessments include right heart catheterization (RHC), assessment of exercise capacity, dyspnea, pulmonary function tests, etc. Safety and tolerability will be evaluated throughout the study and includes review of concomitant medications and adverse events (AEs), clinical laboratory tests, 12-lead electrocardiogram (ECG), vital signs, physical examination, and pregnancy testing.

Official Title
-----------------
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study in Participants With Sarcoidosis-Associated Pulmonary Hypertension (SAPH) to Assess the Efficacy and Safety of Oral Selexipag.

Conditions
-----------------
Sarcoidosis-associated Pulmonary Hypertension

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Main Inclusion Criteria: Confirmed diagnosis of sarcoidosis as per American Thoracic Society (ATS) criteria Sarcoidosis-associated precapillary PH, confirmed by RHC (at rest) within 90 days prior to randomization. PH severity according to modified WHO FC II-IV at Screening and randomization; participants in WHO FC IV must be in a stable condition and able to perform a 6MWT. Either not receiving treatment with PH-specific treatment or oral PH-specific monotherapy (ie, riociguat or PDE5i or ERA); if on oral PH-specific monotherapy then treatment had to be stable (ie, no introduction of new therapies or changes in dose) for at least 90 days prior to both and the RHC qualifying for enrollment and randomization Stable sarcoidosis treatment regimen, ie, no new specific anti-inflammatory treatment for sarcoidosis for at least 90 days, and stable dose(s) for at least 30 days prior to both the RHC qualifying for enrollment and randomization 6-minute walk distance (6MWD) greater than or equal to (>=) 50 meters both at Screening and at the time of randomization. Participants can use their usual walking aids during the test (example, cane, crutches). The same walking aid should be used for all 6-minute walk test (6MWTs). Walkers are not allowed Forced Vital Capacity (FVC) greater than (>) 50 percent (%) and Forced Expiratory Volume (in 1 second) (FEV1) > 50% of predicted at Screening Diffusing capacity of the lung for carbon monoxide (DLCO) >= 40% of predicted. If DLCO less than (<) 40% of predicted, the extent of emphysema should not be greater than that of fibrosis as assessed by high resolution computerized tomography (CT) scan Women of childbearing potential must have a negative pregnancy test at screening and randomization, must agree to undertake monthly urine pregnancy tests, and to practice an acceptable method of contraception and agreeing to remain on an acceptable method while receiving study intervention and until 30 days after last dose of study intervention A woman only using hormonal contraceptives must have been using this method for at least 30 days prior to randomization Main Exclusion Criteria: PH due to left heart disease (PAWP >15 mmHg). History of left heart failure (LHF) as assessed by the investigator including cardiomyopathies, and cardiac sarcoidosis, with a left ventricular ejection fraction (LVEF) <40%. Treatment with prostacyclin, prostacyclin analogues or IP receptor agonists (ie, selexipag) within 90 days prior to randomization and/or prior to the RHC qualifying for enrollment, except those given at vasodilator testing during RHC. SBP <90 mmHg at Screening or at randomization. Included on a lung transplant list or planned to be included until Visit 6 / Week 39. Change in dose or initiation of new diuretics and/or calcium channel blockers within 1 week prior to RHC qualifying for enrollment. Any condition for which, in the opinion of the investigator, participation would not be in the best interests of the participant (eg, compromise well-being), or that could prevent, limit, or confound the protocol-specified assessments. Any acute or chronic impairment that may influence the ability to comply with study requirements such as to perform RHC, a reliable and reproducible 6MWT, or lung function tests. Any other criteria as per selexipag Summary of Product Characteristics (SmPC)

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: Selexipag 200 micro gram (μg)<br>Study intervention will be up-titrated to allow each participant to reach their individual maximum tolerated dose (iMTD), in the range of 200 μg to1600 μg (ie, 1 to 8 tablets) twice daily/once daily. Dosing frequency will be twice daily, except for participants with moderate hepatic impairment (Child-Pugh Class B) or who are concomitantly taking (a) moderate CYP2C8 inhibitor(s), who receive study intervention once daily. The dose will be up-titrated by the investigator/delegate in 200 μg twice daily/once daily increments at weekly intervals during scheduled TCs until reaching the iMTD. If the dose regimen is not well tolerated or symptoms cannot be fully managed with symptomatic treatment, the duration of the titration step can be prolonged to 2 weeks. If needed, the dose can be reduced by 200 μg twice daily/once daily. | Drug: Selexipag<br>* Oral tablets containing 200 µg of selexipag. Depending on the iMTD, participants will receive 1 (200 µg) to 8 (1600 µg) tablets at each administration<br>* Other names: JNJ-678896049; ACT-293987;|
| Placebo Comparator: Placebo<br>The comparator will be administered similarly to the experimental intervention. | Drug: Placebo<br>* Oral tablets without active compound. Participants can receive 1 to 8 tablets at each administration.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary Vascular Resistance (PVR) on Study Intervention up to Week 26 | PVR is measured by right heart catheterization (RHC) and expressed as percent of baseline value. | Up to week 26, within 2-5 hours post-dose | 

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