A clinical trial to study the effects of selexipag on the heart in patients with Pulmonary Arterial Hypertension

• Register: EUCTR
• Last refreshed on: 3 May 2021
• Main ID: EUCTR2019-004783-22-NL
• Date of registration: 30/06/2020
• Prospective Registration: Yes
• Primary sponsor: ACTELION Pharmaceuticals Ltd.
• Public title: A clinical trial to study the effects of selexipag on the heart in patients with Pulmonary Arterial Hypertension
• Scientific title: A Prospective, Multicenter, Single-Arm, Open-Label, Phase 4 Study of the Effects of Selexipag on Right Ventricular Remodeling in Pulmonary Arterial Hypertension Assessed by Cardiac Magnetic Resonance Imaging - RESTORE
• Date of first enrolment: 03/12/2020
• Target sample size: 80
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-004783-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Prospective, Multicenter, Single-Arm, Open-Label, Phase 4 Study; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Argentina, Brazil, China, France, Germany, Hong Kong, Israel, Korea, Republic of, Malaysia, Netherlands, Russian Federation, Saudi Arabia, Singapore, United Arab Emirates, United Kingdom, United States

Contacts

• Name: Clinical Registry group
• Affiliation: Janssen-Cilag International NV

• Name: Clinical Registry group
• Affiliation: Janssen-Cilag International NV

Key inclusion & exclusion criteria

Inclusion criteria:
1.Signed informed consent prior to any study-mandated procedure
2.WHO FC II or III. Enrollment will be stratified by WHO FC II or III. Proportion of participants with WHO FC II and WHO FC III are expected to be approximately 40% and 60%, respectively.
3.PAH etiology belonging to one of the following groups according to classification:
• Idiopathic PAH
• Heritable PAH
• Drugs or toxins induced
• PAH associated with connective tissue disease
• PAH associated with congenital heart disease, with simple systemic-to-pulmonary shunt at least 1 year after surgical repair
4.First hemodynamic diagnosis of PAH by right heart catheterization (RHC) within 12 months prior to initiation of selexipag, showing:
• mPAP =25 mmHg and
• PA wedge pressure (PAWP) or LV end-diastolic pressure =15 mmHg and
• PVR >5 WU (400 dyn.s.cm-5) and
• RVSV = 60 mL as shown in RHC (CO/HR)
5. Patients already receiving PAH-specific oral mono or dual therapy (ie, phosphodiesterase type 5 inhibitors (PDE-5i) or soluble guanylate cyclase stimulators (sGCs) and/or ERA) or patients who are not candidates for these therapies. If on oral PAH-specific therapy, treatment has to be stable (ie, no introduction of new therapies or changes in dose) for at least 90 days prior to both ICF signature and Day 1
6.NT-proBNP =300 ng/L at screening
7.Men or women =18 years (or the legal age of consent in the jurisdiction in which the study is taking place if greater than 18) and <65 years
8.Women of childbearing potential (Section 10.5) must meet the following criteria:
• Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and
• Agree to use reliable methods of contraception from Day 1 to at least 30 days after study intervention discontinuation (Section 10.5), and
• If only using hormonal contraception, have used it for at least 1 month (30 days) before Day 1, and
• Agree to perform monthly pregnancy tests to at least 30 days after study intervention discontinuation
9. 6MWD =150 m during screening period
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 80
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1.Prior use of IP-receptor agonist, prostacyclin, or prostacyclin analog. Use of such treatments for vasoreactivity testing is not exclusionary; intermittent use of such treatments for digital ulcers or Raynaud’s phenomenon is not exclusionary if stopped >6 months (180 days) prior to Day 1
2.Treatment with strong inhibitors of CYP2C8 (eg, gemfibrozil) within 28 days prior to Day 1
3.Treatment with another investigational drug planned or taken within 12 weeks (84 days) prior to Day 1
4.Cardiopulmonary rehabilitation programs based on exercise between informed consent and expected Week 26 visit date
5.Decompensated cardiac failure requiring hospitalization, emergency room visit or intravenous diuretics in the 6 weeks before informed consent
6.Severe coronary heart disease or unstable angina
7.Cerebrovascular events (eg, transient ischemic attack, stroke) within 3 months prior to Day 1
8.Left atrial volume indexed for body surface area =43 mL/m2, assessed by Echo or cardiac MRI
9.Myocardial infarction within 6 months prior to Day 1
10.Body mass index >40 kg/m2 or body weight <40 kg
11.Presence of one or more of the following signs of relevant lung disease at any time up to Day 1 - if pulmonary function test results are missing, then exclusion 11 is considered as met
• Diffusing capacity of the lung for carbon monoxide <40% of predicted UNLESS computed tomography reveals no or mild interstitial lung disease
• Forced vital capacity <60% of predicted
• Forced expiratory volume in 1 second <60% of predicted
12.Known or suspected pulmonary veno-occlusive disease (PVOD)
13.Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension
14.SBP <90 mmHg at screening or on Day 1
15.Severe renal impairment (estimated creatinine clearance =30 mL/min/1.73 m2 or serum creatinine >2.5 mg/dL at screening) or ongoing or planned dialysis
16.Known and documented severe hepatic impairment (with or without cirrhosis) at screening, defined as Child-Pugh Class C
17.Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism)
18.Any hospitalization within 6 weeks prior to informed consent (except elective hospitalizations for surgery or standard monitoring of pre-existing conditions that did not worsen)
19.Concomitant life-threatening disease with a life expectancy of less than 12 months
20.Hemoglobin <80 g/L at screening
21.Hypersensitivity to selexipag or any study intervention excipient (mannitol, maize starch, hydroxypropylcellulose, magnesium stearate, hypromellose, propylene glycol, titanium dioxide, carnauba wax, iron oxide red, iron oxide yellow, iron oxide black)
22.Pregnancy, breastfeeding, or intention to become pregnant during the study
23.Any factor or condition likely to affect compliance with study intervention or visit plan, as judged by the investigator
24.Claustrophobia
25.MRI-incompatible permanent cardiac pacemaker, automatic internal cardioverter
26.Metallic implant (eg, defibrillator, neurostimulator, hearing aid, permanent use of infusion device, dental brace, metal-containing tattoo ink)
27.Severe arrythmia, atrial fibrillation, multiple premature ventricular or atrial contractions, or any other condition that would interfere with proper cardiac gating during MRI


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Pulmonary Arterial Hypertension
MedDRA version: 21.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Intervention(s)

Trade Name: Uptravi
Product Name: Selexipag
Product Code: ACT-293987
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SELEXIPAG
Current Sponsor code: ACT-293987/JNJ-67896049
Other descriptive name: SELEXIPAG
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 200-

Trade Name: Uptravi
Product Name: Selexipag
Product Code: ACT-293987
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SELEXIPAG
Current Sponsor code: ACT-293987/JNJ-67896049
Other descriptive name: SELEXIPAG
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 400-

Trade Name: Uptravi
Product Name: Selexipag
Product Code: ACT-293987
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SELEXIPAG
Current Sponsor code: ACT-293987/JNJ-67896049
Other descriptive name: SELEXIPAG
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 600-

Trade Name: Uptravi
Product Name: Selexipag
Product Code: ACT-293987
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SELEXIPAG
Current Sponsor code: ACT-293987/JNJ-67896049
Other descriptive name: SELEXIPAG
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 800-

Trade Name: Uptravi
Product Name: Selexipag
Product Code: ACT-293987
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SELEXIPAG
Current Sponsor code: ACT-293987/JNJ-67896049
Other descriptive name: SELEXIPAG
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 1000-

Trade Name: Uptravi
Product Name: Selexipag
Product Code: ACT-293987
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SELEXIPAG
Current Sponsor code: ACT-293987/JNJ-67896049
Other descriptive name: SELEXIPAG
Concentration unit: µg micro

Primary Outcome(s)

Main Objective: To assess the effects of selexipag on right ventricular (RV) function in participants with PAH.

Primary end point(s): Change from baseline to Week 26 in RV stroke volume (RVSV) assessed by pulmonary artery flow magnetic resonance imaging (MRI).

Timepoint(s) of evaluation of this end point: Week 26
The null statistical hypothesis is that the mean change from baseline to Week 26 in RVSV is equal to zero. The alternative statistical hypothesis is that the mean change from baseline to Week 26 in RVSV is different from zero.
The primary efficacy analysis will be performed on the FAS. RVSV will be summarized by timepoint (baseline and Week 26)

Secondary Objective: - To further assess the effects of selexipag on RV function using MRI.
- To assess the effects of selexipag on disease severity and exercise capacity.
- To evaluate the safety and tolerability of selexipag.
- To evaluate the effects of selexipag on risk stratification in PAH.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: week 26
Change from baseline to Week 26 in RVEDV, RVESV, RVEF, RV mass, RVGLS, 6MWD, and number of low-risk criteria will be summarized descriptively by timepoint

Secondary end point(s): Change from baseline to Week 26 assessed by MRI:
• RV end-diastolic volume (RVEDV)
• RV end-systolic volume (RVESV)
• RV ejection fraction (RVEF)
• RV mass
• RV global longitudinal strain (RVGLS)
Change from baseline to Week 26:
• World Health Organization (WHO) Functional Class (FC)
• N-terminal-pro-hormone brain natriuretic peptide (NT-proBNP)
• 6-minute walk distance (6MWD)
• Treatment-emergent adverse events (AEs)
• Serious adverse events (SAEs)
• AEs leading to premature discontinuation of study drug
• AEs of special interest
• Treatment-emergent marked laboratory abnormalities
Change from baseline to Week 26 in number of non-invasive low-risk criteria among the following 8 variables:
• Absence of clinical signs of right heart failure
• Absence of symptoms progression
• Absence of syncope
• WHO FC I–II
• 6MWD >440 m
• NT-proBNP <300 ng/L
• Right atrial (RA) area <18 cm2, as determined by echocardiography (Echo)
• Absence of pericardial effusion, as determined by Echo
Change from baseline to Week 26 in number of non-invasive low-risk criteria among the following 3 variables:
• WHO FC I–II
• 6MWD >440 m
• NT-proBNP <300 ng/L

Secondary ID(s)

67896049PAH4005

Source(s) of Monetary Support

Actelion Pharmaceuticals Ltd

Ethics review

Status: Approved
Approval date: 03/12/2020
Contact: