Main objective:To assess the effects of selexipag on right ventricular (RV) function in participants with PAH.Secondary objectives:- To further assess the effects of selexipag on RV function using MRI.- To assess the effects of selexipag on disease…
ID
Source
Brief title
Condition
- Lower respiratory tract disorders (excl obstruction and infection)
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from baseline to Week 26 in RV stroke volume (RVSV) assessed by
pulmonary artery flow magnetic resonance imaging (MRI).
Secondary outcome
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
Background summary
Pulmonary Arterial Hypertension (PAH) is a disease of the small pulmonary
arteries that is characterized by vascular proliferation and remodeling. It
results in a progressive increase in pulmonary vascular resistance (PVR) and
ultimately, right ventricular failure and death. PAH is histologically
characterized by endothelial and smooth muscle cell proliferation, medial
hypertrophy, and thrombosis in situ. The pathogenesis of PAH remains unclear.
Advances in understanding the molecular mechanisms involved in this disease
suggest that endothelial dysfunction plays a key role. Subjects with PAH have
been shown to have a deficiency in PGI2 and PGI2 synthase, which led to the
hypothesis that targeting the PGI2 pathway with IP receptor agonists could be
beneficial. IV therapy was developed and outcomes for subjects improved.
However, due to its short half-life and chemical instability, long-term IV
(epoprostenol) therapy requires a permanently implanted central venous catheter
and a portable infusion pump, exposing subjects to a series of complications.
Selexipag is the first orally available non-prostanoid IP receptor agonist that
has been developed and approved for the treatment of PAH. Selexipag was
approved on the basis of long-term clinical efficacy; however, short-term
cardiac imaging data on selexipag are lacking.
Study objective
Main objective:
To assess the effects of selexipag on right ventricular (RV) function in
participants with PAH.
Secondary objectives:
- 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.
Study design
This is an open-label, multicenter, single-arm, interventional study to assess
the effect of selexipag in adult participants (>=18 to <65 years) with a
diagnosis of PAH up to 52 weeks on study intervention.
Intervention
All subjects will be randomized to the study drug Selexipag. Dosing with
selexipag will start at 200 µg twice daily (on Day 1, the participant will
receive only 1 dose, and at each dose change, the first intake of the new dose
should be taken in the evening). The site will call the participant once a week
from the end of Week 1 to the end of Week 12 and decide whether to increase the
dose by 200 µg twice daily if possible. Up-titration will be flexible and can
be adapted in case of adverse effects that cannot be relieved with symptomatic
treatment. In this case, the site may either postpone up-titration by 1 week or
down-titrate study drug. The dose reached at end of Week 12 will be considered
the participant*s individual maintenance dose (IMD) and will be maintained
until EOT (Week 52).
Study burden and risks
Selexipag was previously administered to 1156 adult participants with PAH in
randomized, long-term study called GRIPHON. This study was the first study to
demonstrate the long-term outcome benefit of selexipag. Selexipag proved to
delay disease progression and reduce the risk of hospitalization for PAH.
The short and long-term safety profile of selexipag has been established in PAH
patients and is mainly characterized by prostacyclin-associated adverse events
(AEs) linked with the mode of action of selexipag (a selective prostacyclin
receptor (IP) agonist). AEs typically occur during the initial phase of
individualized dose titration, and the susceptibility varies between
individuals. Adverse reactions included headache, diarrhea, nausea and
vomiting, jaw pain, myalgia, pain in extremity, arthralgia, and flushing.
Selexipag has a favorable safety profile with known risks consistent with its
mechanism of action. No new observations regarding the safety profile of
selexipag have been identified since its approval in the USA on 21 December
2015.
Gewerbestrasse 16
Allschwil 4123
CH
Gewerbestrasse 16
Allschwil 4123
CH
Listed location countries
Age
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-topulmonary 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
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 moderate or 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 preexisting
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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004783-22-NL |
| ClinicalTrials.gov | NCT04435782 |
| CCMO | NL74159.056.20 |