Clinical Trial Results:
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)
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Summary
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EudraCT number |
2019-004783-22 |
Trial protocol |
NL DE GB FR |
Global end of trial date |
28 Jul 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Aug 2024
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First version publication date |
02 Aug 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
67896049PAH4005
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04435782 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Janssen-Cilag International NV
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Sponsor organisation address |
Turnhoutseweg 30, Beerse, Belgium,
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Public contact |
Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
13 Sep 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Jul 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Main objective of the trial was to assess the effects of selexipag on right ventricle (RV) function in subjects with pulmonary arterial hypertension (PAH).
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 Jul 2021
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Korea, Republic of: 5
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Country: Number of subjects enrolled |
Malaysia: 1
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Country: Number of subjects enrolled |
Netherlands: 1
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Country: Number of subjects enrolled |
Singapore: 1
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Worldwide total number of subjects |
9
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EEA total number of subjects |
1
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
9
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||
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Pre-assignment
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Screening details |
A total of 25 subjects were screened, out of which 9 subjects were enrolled and were treated with selexipag. | ||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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Selexipag | ||||||||||
Arm description |
Subjects with PAH received a 200 micrograms (mcg) selexipag tablet orally on the evening of Day 1, followed by twice-daily dosing starting from Day 2. The dose of selexipag was increased by 200 mcg each week to allow each subject to reach their individual maximum dose (iMD), up to 1600 mcg twice daily, by the end of Week 12. From Week 13 onwards, subjects received their iMD of 1600 mcg selexipag tablets orally twice daily until Week 52. Subjects were then followed for safety up to 30 days after the last dose of selexipag. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Selexipag
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Investigational medicinal product code |
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Other name |
ACT-293987, JNJ-67896049
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received selexipag 200 mcg tablet orally on Day 1 in the evening then twice daily starting from Day 2. Dose of selexipag was up-titrated every week by 200 mcg to allow each subject to reach their iMD to 1,600 mcg twice daily orally by end of Week 12. Starting from Week 13, subjects received iMD of selexipag 1600 mcg tablet orally twice daily up to Week 52.
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Baseline characteristics reporting groups
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Reporting group title |
Selexipag
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Reporting group description |
Subjects with PAH received a 200 micrograms (mcg) selexipag tablet orally on the evening of Day 1, followed by twice-daily dosing starting from Day 2. The dose of selexipag was increased by 200 mcg each week to allow each subject to reach their individual maximum dose (iMD), up to 1600 mcg twice daily, by the end of Week 12. From Week 13 onwards, subjects received their iMD of 1600 mcg selexipag tablets orally twice daily until Week 52. Subjects were then followed for safety up to 30 days after the last dose of selexipag. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Selexipag
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Reporting group description |
Subjects with PAH received a 200 micrograms (mcg) selexipag tablet orally on the evening of Day 1, followed by twice-daily dosing starting from Day 2. The dose of selexipag was increased by 200 mcg each week to allow each subject to reach their individual maximum dose (iMD), up to 1600 mcg twice daily, by the end of Week 12. From Week 13 onwards, subjects received their iMD of 1600 mcg selexipag tablets orally twice daily until Week 52. Subjects were then followed for safety up to 30 days after the last dose of selexipag. | ||
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End point title |
Change from Baseline to Week 26 in Right Ventricular Stroke Volume (RVSV) Assessed by Pulmonary Artery Flow Magnetic Resonance Imaging (MRI) [1] | ||||||||||||||||||||
End point description |
Change from baseline to Week 26 in RVSV assessed by pulmonary artery flow MRI was reported. Safety analysis set included all subjects who received at least 1 dose of study intervention. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for specified rows. As pre-specified in the statistical analysis plan (SAP), subject wise data was collected and reported due to very limited number of subjects enrolled.
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End point type |
Primary
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End point timeframe |
Baseline, Week 26
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change from Baseline to Week 26 in Right Ventricular End-Diastolic Volume (RVEDV) Assessed by MRI | ||||||||||||||||||||
End point description |
Change from baseline to Week 26 in RVEDV assessed by MRI was reported. Safety analysis set included all subjects who received at least 1 dose of study intervention. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for specified rows. As pre-specified in the SAP, subject wise data was collected and reported due to very limited number of subjects enrolled.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change from Baseline to Week 26 in Right Ventricular End-Systolic Volume (RVESV) Assessed by MRI | ||||||||||||||||||||
End point description |
Change from baseline to Week 26 in right ventricular end-systolic volume (RVESV) assessed by MRI was reported. Safety analysis set included all subjects who received at least 1 dose of study intervention. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for specified rows. As pre-specified in the SAP, subject wise data was collected and reported due to very limited number of subjects enrolled.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change from Baseline to Week 26 in Right Ventricular Ejection Fraction (RVEF) Assessed by MRI | ||||||||||||||||||||
End point description |
Change from baseline to Week 26 in right ventricular ejection fraction (RVEF) assessed by MRI was reported. Right ventricular ejection fraction (RVEF) was the fraction of the end-diastolic volume (EDV) that is ejected out of right ventricle with each contraction. EDV is the volume of blood within a ventricle immediately before a contraction. Safety analysis set included all subjects who received at least 1 dose of study intervention. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for specified rows. As pre-specified in the SAP, subject wise data was collected and reported due to very limited number of subjects enrolled.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change from Baseline to Week 26 in Right Ventricular (RV) Mass Index Assessed by MRI | ||||||||||||||||||||
End point description |
Change from baseline to Week 26 in RV mass index assessed by MRI was reported. Safety analysis set included all subjects who received at least 1 dose of study intervention. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for specified rows. As pre-specified in the SAP, subject wise data was collected and reported due to very limited number of subjects enrolled.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change from Baseline to Week 26 in RIght Ventricular Global Longitudinal Strain (RVGLS) Assessed by MRI | ||||||||||||||||||||
End point description |
Change in RVGLS was a measure of longitudinal percent change in length of endocardium at Week 26 from baseline length assessed by MRI. Safety analysis set included all subjects who received at least 1 dose of study intervention. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for specified rows. As pre-specified in the SAP, subject wise data was collected and reported due to very limited number of subjects enrolled.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of Subjects With Change from Baseline to Week 26 in World Health Organization (WHO) Functional Class | ||||||||||||||||||||
End point description |
WHO functional classification for PAH ranged from Class I (no limitation in physical activity, ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope), Class II (slight limitation of physical activity, ordinary physical activity cause undue dyspnea or fatigue, chest pain or near syncope), Class III (marked limitation of physical activity, less than ordinary activity cause undue dyspnea or fatigue, chest pain or near syncope) & Class IV (cannot perform a physical activity without any symptoms, dyspnea and/or fatigue may even be present at rest). Change from baseline in WHO functional class was classified into "Improved", "No change" and "Worsened". Improvement =reduction in functional class; worsened =increase in functional class; and no change = no change in functional class. Safety set included all subjects who received at least 1 dose of study intervention. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change from Baseline to Week 26 in N-terminal-Pro-Hormone Brain Natriuretic Peptide (NT-proBNP) | ||||||||||||||||||||
End point description |
NT pro-BNP is a cardiac biomarker that is released in the blood in response to changes in the pressure inside of the heart. Levels go up when heart failure develops or gets worse, and levels go down when heart failure is stable or improves. This biomarker helps to measure the changes in the severity of heart failure over time in response to therapy. Safety analysis set included all subjects who received at least 1 dose of study intervention. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for specified rows. As pre-specified in the SAP, subject wise data was collected and reported due to very limited number of subjects enrolled.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change from Baseline to Week 26 in 6-Minute Walk Distance (6MWD) | ||||||||||||||||||||
End point description |
6MWD was the distance that a subjects could walk in 6 minutes. Subjects were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Safety analysis set included all subjects who received at least 1 dose of study intervention. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for specified rows. As pre-specified in the SAP, subject wise data was collected and reported due to very limited number of subjects enrolled.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | ||||||||||
End point description |
An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was any untoward medical occurrence that at any dose resulted in death, was life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a suspected transmission of any infectious agent via a medicinal product. Any AE occurring at or after the initial administration of study intervention through the day of last dose plus 3 days was considered as treatment emergent. Safety analysis set included all subjects who received at least 1 dose of study intervention.
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End point type |
Secondary
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End point timeframe |
Day 1 up to 3 days after last dose of study drug (up to 52 weeks and 3 days that is 367 days)
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Subjects With Adverse Events (AEs) Leading to Premature Discontinuation of Study Drug | ||||||
End point description |
Number of subjects with AEs leading to premature discontinuation of study drug were reported. An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Safety analysis set included all subjects who received at least 1 dose of study intervention.
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End point type |
Secondary
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End point timeframe |
Day 1 up to last dose of study drug (up to Week 52)
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects With Adverse Events Adverse Events of Special Interest (AESI) | ||||||
End point description |
Number of subjects with AESI were reported. An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. AESI were anaemia, bleeding events, gastrointestinal disturbances denoting intestinal intussusception (manifested as ileus or obstruction), hyperthyroidism, hypotension, light-dependent non-melanoma skin malignancies, major adverse cardiovascular events (MACE), medication errors, ophthalmological effects associated to retinal vascular system, pregnancy, pulmonary venoocclusive disease associated with pulmonary oedema, renal function impairment / acute renal failure. Safety analysis set included all subjects who received at least 1 dose of study intervention.
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End point type |
Secondary
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End point timeframe |
Day 1 up to 3 days after last dose of study drug (up to 52 weeks and 3 days that is 367 days)
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects With Treatment-Emergent Marked Laboratory Abnormalities | ||||||
End point description |
Number of subjects with treatment-emergent marked laboratory abnormalities in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, creatinine, sodium, potassium, hemoglobin, hematocrit; EVF; PCV (male), hematocrit; EVF; PCV (female), platelets (assuming no platelet cluster), leukocytes; white blood cells, Neutrophils (Abs), Eosinophils (Abs), lymphocytes (Abs) were reported. Abnormalities that occurred after study treatment start and up to last dose, that were not present at baseline, were treatment-emergent. Treatment-emergent marked laboratory abnormalities were determined at the investigator's discretion. Safety analysis set included all subjects who received at least 1 dose of study intervention.
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End point type |
Secondary
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End point timeframe |
Day 1 up to 3 days after last dose of study drug (up to 52 weeks and 3 days that is 367 days)
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| No statistical analyses for this end point | |||||||
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End point title |
Change from Baseline to Week 26 in Number of Non-invasive Low-risk Criteria Among the 8 Variables | ||||||||||||||||||||
End point description |
Risk score is derived for each subject considering following non-invasive low-risk criteria among 8 variables: absence of clinical signs of right heart failure, absence of symptoms progression, absence of syncope, WHO FC I-II, 6MWD >440 meter, NT-proBNP <300 ng/L, Right atrial (RA) area <18 centimeter square (cm^2) as determined by echocardiography (Echo), absence of pericardial effusion, as determined by Echo. Number of low-risk criteria at baseline & Week 26 constitutes risk score & were derived for each subject by adding ‘1’ for each of above criteria met. Number of low-risk criteria among 8 variables for each subject can vary from 0 (worse subjects) to 8 (healthier subjects). Higher score indicated healthier subjects. Safety set. Here, N (number of subjects analysed) =subjects evaluable for this endpoint & "n" signifies subjects evaluable for specified rows. As pre-specified in SAP, subject wise data was collected and reported due to very limited number of subjects enrolled.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change from Baseline to Week 26 in Number of Non-invasive Low-risk Criteria Among the 3 Variables | ||||||||||||||||||||
End point description |
The risk score is derived for each subject considering the following non-invasive low-risk criteria among the 3 variables: WHO FC I-II, 6MWD >440 m, NT-proBNP < 300 ng/L. Number of low-risk criteria at baseline and Week 26 constitutes risk score and were derived for each subject by adding ‘1’ for each of above criteria met. Number of low-risk criteria among the 3 variables for each subject can vary from 0 (worse subjects) to 3 (healthier subjects). Higher score indicated healthier subjects. Safety analysis set included all subjects who received at least 1 dose of study intervention. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for specified rows. As pre-specified in the SAP, subject wise data was collected and reported due to very limited number of subjects enrolled.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
All Cause Mortality: Day 1 up to 30 days after last dose of drug (up to Week 56), SAEs and non-SAEs: Day 1 up to 3 days after last dose of study drug (up to 52 weeks and 3 days that is 367 days)
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Adverse event reporting additional description |
Safety analysis set included all subjects who received at least 1 dose of study intervention.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.0
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Reporting groups
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Reporting group title |
Selexipag
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Reporting group description |
Subjects with PAH received a 200 micrograms (mcg) selexipag tablet orally on the evening of Day 1, followed by twice-daily dosing starting from Day 2. The dose of selexipag was increased by 200 mcg each week to allow each subject to reach their individual maximum dose (iMD), up to 1600 mcg twice daily, by the end of Week 12. From Week 13 onwards, subjects received their iMD of 1600 mcg selexipag tablets orally twice daily until Week 52. Subjects were then followed for safety up to 30 days after the last dose of selexipag. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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08 Jan 2021 |
The overall reason for this protocol amendment was to provide clarification for several inclusion and exclusion criteria to better define the target population that may benefit from the study intervention, to add exploratory objectives and endpoints for long-term outcomes, to adapt to changed internal safety language and reporting processes, to align with TransCelerate template and to implement minor corrections and editorial revisions. |
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25 Mar 2022 |
Overall reasons for this protocol amendment was to clarify selected inclusion and exclusion criteria to better define the target population that might benefit from the study intervention and to clarify the definition of end of study (EOS) for the subjects continuing selexipag treatment in a continued access program. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
