Clinical Trial Results:
A multi-centre, multinational, open-label study to evaluate the long-term safety, tolerability and efficacy of selexipag / ACT 293987 (NS-304) in the treatment of pulmonary arterial hypertension in subjects aged 18 years and over (open-extension study to NS 304/-02)
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Summary
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EudraCT number |
2007-006453-12 |
Trial protocol |
HU AT FR BE GB IT DE |
Global end of trial date |
19 Dec 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Dec 2018
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First version publication date |
30 Dec 2018
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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 |
NS-304/-03
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Actelion Pharmaceuticals Ltd
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Sponsor organisation address |
Gewerbestrasse 16, Allschwil, Switzerland, 4123
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Public contact |
Clinical Trial Disclosure Desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@its.jnj.com
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Scientific contact |
Clinical Trial Disclosure Desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@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 |
20 Apr 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
19 Dec 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Dec 2017
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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 |
The primary objective of the study was to collect and evaluate long-term safety and tolerability data of selexipag treatment in subjects with pulmonary arterial hypertension (PAH).
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Protection of trial subjects |
The clinical trial was designed and conducted in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, and with the ethical principles laid down in the Declaration of Helsinki
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Background therapy |
Oral anticoagulants, calcium channel blockers, diuretics, cardiac glyocsides, supplement oxygen, endothelin receptor antagonists, phosphodiesterase inhibitors and riociguat were allowed. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Oct 2008
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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 |
Austria: 7
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Country: Number of subjects enrolled |
Belgium: 5
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Country: Number of subjects enrolled |
France: 9
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Country: Number of subjects enrolled |
Germany: 5
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Country: Number of subjects enrolled |
Hungary: 4
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Country: Number of subjects enrolled |
Italy: 2
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Country: Number of subjects enrolled |
Poland: 7
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Worldwide total number of subjects |
39
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EEA total number of subjects |
39
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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) |
27
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From 65 to 84 years |
12
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85 years and over |
0
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Recruitment
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Recruitment details |
39 subjects (31 previously randomized to selexipag and 8 previously randomized to placebo in the previous NS-304/-02 study) were enrolled into the open-label extension study NS-304/-03, from 7 sites in 7 countries. | ||||||||||||||||||||
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Pre-assignment
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Screening details |
Only the subjects who had completed Visit 7 (Week 17) of the preceding double-blind study NS-304/-02 and who signed the informed consent form to take part in the open-label extension study were eligible to be enrolled in NS-304/-03. | ||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (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 who received selexipag during NS-304/-02 continued with their maximal tolerated dose of selexipag. Subjects who received placebo during NS-304/-02 started with 200 μg selexipag b.i.d. from Day 1 to Day 3, then the dose was up-titrated in 200 μg b.i.d. increments up to the maximum tolerated dose (MTD) for each subject but not above 800 µg during the titration phase. Thereafter these subjects continued with their individual maximal tolerated dose. After Week 24, the dose could be adjusted (not exceeding 1600 µg following Amendment 5). | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Selexipag
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Investigational medicinal product code |
ACT-293987, NS-304
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Twice daily administration (b.i.d.) with an interval of approximately 12 hours
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Baseline characteristics reporting groups
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Reporting group title |
Selexipag
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Reporting group description |
Subjects who received selexipag during NS-304/-02 continued with their maximal tolerated dose of selexipag. Subjects who received placebo during NS-304/-02 started with 200 μg selexipag b.i.d. from Day 1 to Day 3, then the dose was up-titrated in 200 μg b.i.d. increments up to the maximum tolerated dose (MTD) for each subject but not above 800 µg during the titration phase. Thereafter these subjects continued with their individual maximal tolerated dose. After Week 24, the dose could be adjusted (not exceeding 1600 µg following Amendment 5). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Selexipag
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Reporting group description |
Subjects who received selexipag during NS-304/-02 continued with their maximal tolerated dose of selexipag. Subjects who received placebo during NS-304/-02 started with 200 μg selexipag b.i.d. from Day 1 to Day 3, then the dose was up-titrated in 200 μg b.i.d. increments up to the maximum tolerated dose (MTD) for each subject but not above 800 µg during the titration phase. Thereafter these subjects continued with their individual maximal tolerated dose. After Week 24, the dose could be adjusted (not exceeding 1600 µg following Amendment 5). | ||
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End point title |
Number of subjects with any treatment-emergent adverse events (TEAEs) [1] | ||||||
End point description |
A treatment emergent adverse event (TEAE) was defined as any AE with an onset on the first day of selexipag intake in NS-304/-03 up to 3 days after treatment discontinuation (EOT + 3 days), whether or not considered related to the study treatment.
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End point type |
Primary
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End point timeframe |
From Day 1 to EOT + 3 days
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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: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables. |
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End point title |
Number of subjects with TEAEs of mild, moderate or severe intensity [2] | ||||||||||||
End point description |
Treatment-emergent adverse events (TEAEs) were classified into three intensity categories: mild AE (usually transient and do not interfere with the subject daily's activities), moderate AE (low level of inconvenience to the subject and may interfere with daily's activities), severe AE (interruption of the subject's usual daily activities).
The number of subjects with at least one adverse event of mild, moderate or severe intensity was reported.
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End point type |
Primary
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End point timeframe |
from Day 1 to EOT + 3 days
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| Notes [2] - 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: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of subjects with TEAEs causally related to the study treatment [3] | ||||||
End point description |
The causal relationship between the study treatment (selexipag) and the adverse event (TEAE) was characterized as unrelated (no reasonable possibility that the study treatment caused the AE), unlikely (only a remote connection exists between the study treatment and the AE; other conditions appear to explain the AE), possible (the association of the AE with the study treatment is unknown; however the AE is not reasonably supported by other conditions) or probable (a reasonable temporal sequence of the AE with the study treatment administration exists).
The number of subjects with at least one TEAE characterized as "possible" or "probable" by the investigator was reported as causally related to the study treatment.
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End point type |
Primary
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End point timeframe |
From day 1 to EOT + 3 days
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| Notes [3] - 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: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of subjects with fatal treatment-emergent adverse events [4] | ||||||
End point description |
The number of subjects with at least one treatment-emergent adverse event leading to death was reported
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End point type |
Primary
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End point timeframe |
From Day 1 to EOT + 3 days
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| Notes [4] - 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: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of subjects with adverse events leading to study treatment discontinuation [5] | ||||||
End point description |
Subjects with at least one AE leading to permanent withdrawal of the study treatment (selexipag) were reported
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End point type |
Primary
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End point timeframe |
From day 1 up to treatment discontinuation
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| Notes [5] - 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: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables. |
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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 of special interest (AESI) [6] | ||||||||||||||||||
End point description |
AESI were defined based on the selexipag European Risk Management Plan (EU RMP) and included the following: Hypotension, Anemia / decrease in hemoglobin concentration, Hyperthyroidism, Major adverse cardiac event (MACE), Acute renal failure and renal impairment, Bleeding events, Light-dependent non-melanoma skin tumors, Ophthalmological effects associated with retinal vascular system, Gastrointestinal disturbances denoting intestinal intussusception.
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End point type |
Primary
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End point timeframe |
From Day 1 to EOT + 3 days
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| Notes [6] - 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: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Incidence of marked laboratory tests abnormalities [7] | ||||||||||||||||
End point description |
The number of subjects enrolled in NS-304/-03 with marked abnormalities in hematology or chemistry variables were to be reported. Marked abnormality was considered for subjects who presented an abnormality post-baseline which was not present at baseline.
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End point type |
Primary
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End point timeframe |
From Day 1 to Week 24
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| Notes [7] - 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: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Incidence of marked abnormalities in vital signs [8] | ||||||||||||||
End point description |
The number of subjects enrolled in NS-304/-03 with marked abnormalities in systolic / diastolic blood pressure (SBP/DBP) or pulse rate were to be reported. Marked abnormality was considered for subjects who presented an abnormality post-baseline which was not present at baseline.
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End point type |
Primary
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End point timeframe |
From Day 1 up to the last study visit
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| Notes [8] - 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: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Incidence of QTcF abnormalities [9] | ||||||||||||||||||||
End point description |
The number of subjects enrolled in NS-304/-03 with QTcF abnormalities as assessed by ECG were to be reported. Marked abnormality was considered for subjects who presented a QTcF prolongation post-baseline which was not present at baseline.
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End point type |
Primary
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End point timeframe |
From Day 1 to Week 24
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| Notes [9] - 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: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change from baseline in 6-minute walk distance over time | ||||||||||||||||||||||||||||||||||||||||
End point description |
Walk distance is measured during the 6-minute walk test (6MWT). 6MWT is a non-encouraged test, which measures the distance (in meters) covered by the subject during a 6-minute walk in a flat corridor. Change from baseline in 6MWT was analyzed at various timepoints during the study. Thirty-nine subjects had a 6MWT measure available at baseline. If the number of subjects included in the analysis for a specific timepoint was less than 10 this timepoint was not reported here.
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End point type |
Secondary
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End point timeframe |
From Day 1 to the last study visit
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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 |
From Day 1 to EOT + 3 days for non-serious and serious AEs and up to EOT + 30 days for deaths (all causes)
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Adverse event reporting additional description |
Day 1 is the first day of enrollment in the open-label phase (NS-304/-03)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Selexipag
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Reporting group description |
A total of 39 subjects received selexipag during NS-304/-03 for a median duration of 1712 days (range: 11-3347 days), with 20 and 8 subjects receiving selexipag for a cumulative duration of at least 48 months and 96 months, respectively. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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22 Oct 2008 |
Main reasons for amendment: Operation and sponsorship of the study was changed from Nippon Shinyaku Ltd to Actelion Pharmaceuticals Ltd; Study drug number NS-304 changed to ACT-293987 |
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25 Nov 2008 |
Main reasons for amendment: Because the results of an in vitro phototoxicity study suggested that selexipag and its active metabolite have phototoxic potential, this information was added as well as information on the precautions to be taken regarding sun exposure. A new inclusion criteria was introduced to include only subjects who were willing and able to refrain from sunbathing, prolonged exposure to sun and artificial sunlight (such as solarium), or UV-A/UV-B treatment, and to limit skin and eye exposure to sunlight by taking appropriate precautions (protective clothing, sunscreen, and sunglasses) from the first dose until 14 days after study treatment discontinuation. |
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10 Feb 2009 |
Main reasons for amendment:
Study duration was extended from the existing 24 weeks until the earliest of one of the following: approval of marketing authorization for selexipag in PAH, decision by Actelion Pharmaceuticals Ltd to stop the study, or decision by the subject or investigator to discontinue study treatment. |
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25 Jun 2009 |
Main reasons for amendment: Activities previously managed by the CRO (Quintiles) were taken over by Actelion Pharmaceuticals Ltd |
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03 Nov 2010 |
Main reasons for amendment:
-In accordance with the other ongoing studies (AC-065A302 and AC-065A303), the maximum dose of selexipag allowed in the present study was increased from 800 μg b.i.d. to 1600 μg b.i.d.;
-change in the manufacturer of the selexipag tablets from Nippon Shinyaku Ltd to Excella Pharma GmbH
- addition of new phase 1 study results. |
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17 Jun 2012 |
Main reasons for amendment:
-A phase 1 clinical trial studying the phototoxicity of selexipag did not indicate a clinically relevant phototoxic potential of selexipag at doses of 800 and 1200 µg b.i.d. after UV-A and UV-B irradiation in healthy male subjects. Therefore, a footnote was added to the inclusion criterion on sun exposure to indicate that no extra precautions were necessary regarding sun exposure;
- New findings from toxicologic studies in animals were added (retinal toxicity, nonmalignant neoplastic changes in the thyroid)
-Change in selexipag packager and packaging. |
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16 Jan 2014 |
Main reasons for amendment:
- ACT-293987 replaced by Selexipag in the protocol;
- new findings from non clinical studies were added (effects on platelet aggregation in vitro; effects liver drug metabolizin enzymes and thyroid hormones in mice) as well as update on Phase 1 and Phase 2 studies.
- Addition of an exclusion criteria: Females who were breast-feeding, pregnant or planned to become pregnant during the study and females who were not using a highly effective method of birth control with a failure rate of less than 1% per year, were to be excluded
- Specification on how to manage subjects with liver impairment (based on the results of a Phase 1 study): If, during the course of the study, a subject developed or progressed to Child-Pugh B liver impairment, it was the responsibility of the investigator to assess the benefit-risk of maintaining the subject on study treatment; if a subject developed or progressed to Child Pugh C liver impairment, study treatment was to be discontinued.
- ʻTime to aggravation of PAHʼ was added as a tertiary efficacy endpoint. |
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10 Apr 2015 |
Main reasons for amendment:
-The condition that the site should inform the sponsor before a subject’s dose was up titrated to a maximum of 1600 µg b.i.d. after Visit 5 was removed. However, it was clarified that the assessment/decision to up titrate was to be made only after a site visit (scheduled/unscheduled) was performed;
-In order to avoid any treatment interruption if there was a lag period between the time when marketing authorization was granted and the time when selexipag could be commercially available to the subjects, the duration of NS-304/-03 study was set up to commercial availability of selexipag in the subject’s country;
- A new discontinuation criterion was introduced for subjects who were diagnosed with PVOD;
- The concomitant use of selexipag and i.v., s.c., or inhaled prostacyclin and prostacyclin analogs was allowed temporarily when deemed medically justified;
- The process of temporarily switching a subject from oral selexipag to another IP receptor with a more convenient route of administration with regard to the subjectʼs medical condition and subsequently restarting selexipag was included in the protocol;
-Riociguat was added as an allowed concomitant PAH medication:
- because hyperthyroidism has been observed with selexipag and other IP receptor agonists, thyroid function tests were to be performed locally for individual subjects if deemed clinically indicated by the investigator. |
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24 Jan 2017 |
Main reasons for amendment:
- Concomitant administration of strong CYP2C8 inhibitors such as gemfibrozil was to be avoided and selxipag dose adjustment could be required following concomitant administration of moderate CYP2C8 inducer such as rifampicin . These recommendations were added taking into account the results of a phase 1 study. |
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30 Jun 2017 |
Main reasons for amendment:
- To include guidance for concomitant administration of selexipag and strong CYP2C8 inhibitors: concomitant administration of selexipag and strong CYP2C8 inhibitors such as gemfibrozil is prohibited until end-of-study in NS-304/-03.
– To include information on other potential drug-drug interactions: ʻThe effect of moderate inhibitors of CYP2C8, and strong inhibitors of UGT1A3 and UGT2B7 on the exposure to selexipag or its active metabolite has not been studied. Concomitant administration may result in a significant increase in exposure to selexipag or its active metaboliteʼ. |
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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 | |||
