| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary arterial hypertension (PAH) is a serious chronic disorder of the pulmonary circulation |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the effects of selexipag on right ventricular (RV) function in participants with PAH. |
|
| E.2.2 | Secondary objectives of the trial |
- 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.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. Criterion modified per Amendment 2
4.1 Criterion modified per Amendment 3
4.2 Diagnosis of PAH within 3 years prior to initiation of Selexipag (Day 1), and most recent right heart catheterization (RHC) within 1 year prior to initiation of selexipag (Day 1) showing:
• mPAP ≥25 mmHg and
• PA wedge pressure (PAWP) or LV end-diastolic pressure (LVEDP) ≤15
mmHg and
• PVR >5 WU (400 dyn.s.cm-5) and
• RVSV ≤ 60 mL as shown in RHC.
5. Criterion modified per Amendment 2
5.1 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. Criterion modifed per Amendment 2
6.1 Criterion modified per Amendment 3
6.2 NT-proBNP ≥300 ng/L (≥300 pg/mL; ≥35.5 pmol/L) at screening.
Note: If local assessment of BNP (instead of NT-proBNP) is used for
eligibility, BNP measurement of ≥50 ng/L (≥50 pg/mL; 14.4 pmol/L)
will be considered as meeting the inclusion criterion.
7. Criterion modified per Amendment 2
7.1 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. Criterion modified per Amendment 2
8.1 Criterion modified per Amendment 3
8.2 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 acceptable 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. New criterion modified per Amendment 2
9.1 6MWD ≥150 m during screening period. |
|
| E.4 | Principal 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 4 weeks (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. Criterion modified per Amendment 3
5.1 Decompensated cardiac failure requiring hospitalization, emergency room visit or intravenous (iv) diuretics in the 10 weeks (70 days) before Day 1 inclusive.
6. Severe coronary heart disease or unstable angina.
7. Cerebrovascular events (eg, transient ischemic attack, stroke) within 3 months (90 days) 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 (180 days) prior to Day 1.
10. Criterion modified per Amendment 2
10.1 Body mass index >40 kg/m2 or body weight <40 kg.
11. Criterion modified per Amendment 2
11.1 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 *b.
• Forced expiratory volume in 1 second <60% of predicted *b.
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. Criterion modified per Amendment 3
15.1 Severe renal impairment (estimated glomerular filtration rate by
Modification of Diet in Renal Disease (MDRD) formula ≤30 mL/min/1.73 m2 or serum creatinine >2.5 mg/dL at screening) or ongoing or planned dialysis.
16. Criterion modified per Amendment 2
16.1 Criterion modified per Amendment 3
16.2 Known and documented severe hepatic impairment (with or
without cirrhosis) at screening, defined as Child-Pugh Class C *c.
17. Known or suspected uncontrolled thyroid disease (hypo- or
hyperthyroidism).
18. Criterion modified per Amendment 3
18.1 Any hospitalization within 10 weeks (70 days) prior to Day 1,
inclusive (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. Criterion modified per Amendment 3
20.1 Hemoglobin <80 g/L (<8 g/dL; <4.96 mmol/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. Criterion modified per Amendment 2
22.1 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)*d.
27. Criterion modified per Amendment 3
27.1
-Cardiac arrythmia assessed severe by the investigator
-Conditions that could interfere with proper cardiac gating eg, atrial
fibrillation, multiple premature ventricular or atrial contractions.
*b: Pulmonary function tests may be performed either with or without the use of bronchodilators, as per local clinical
practice.
*c: The assessment of hepatic impairment (Child-Pugh Score) must be fully documented for participants who have
clinical signs and/or evidence (from central and/or local lab) of hepatic impairment. Absence of hepatic impairment
must be documented in the source data as well.
*d: Local MRI team's advice should be sought in case of doubt.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline to Week 26 in RV stroke volume (RVSV) assessed by pulmonary artery flow magnetic resonance imaging (MRI). |
|
| E.5.1.1 | 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) |
|
| E.5.2 | 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 |
|
| E.5.2.1 | 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 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Prospective, Multicenter, Single-Arm, Open-Label, Phase 4 Study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| China |
| Hong Kong |
| Israel |
| Korea, Republic of |
| Malaysia |
| Saudi Arabia |
| Singapore |
| United Arab Emirates |
| United States |
| France |
| Netherlands |
| Germany |
| Russian Federation |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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