Clinical Trial Results:
A Prospective, Multicenter, Single-arm, Open-label, Phase 4 Study to Evaluate the Effects of Macitentan on Right vEntricular Remodeling in Pulmonary ArterIal HypeRtension Assessed by Cardiac Magnetic Resonance Imaging
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Summary
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EudraCT number |
2014-004066-20 |
Trial protocol |
GB NL DE IT |
Global end of trial date |
08 Aug 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Sep 2020
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First version publication date |
20 Sep 2020
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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 |
AC-055-403
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02310672 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Actelion Pharmaceutical Ltd.
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Sponsor organisation address |
Gewerbestrasse 16, Allschwil, Switzerland, 4123
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Public contact |
Global Medical Information, Actelion Pharmaceutical Ltd., medinfo@actelion.com
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Scientific contact |
Global Medical Information, Actelion Pharmaceutical Ltd., medinfo@actelion.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 |
08 Aug 2019
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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 |
08 Aug 2019
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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 purpose of the study is to evaluate the effect of macitentan on right ventricular and on hemodynamic properties in subjects with symptomatic 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. Safety was evaluated based on adverse events (AEs), clinical laboratory tests (hematology, serum chemistry, coagulation tests, and pregnancy test), vital sign measurements, and physical examinations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Jun 2015
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Ethical reason | ||
Long term follow-up duration |
13 Months | ||
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 |
Germany: 12
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Country: Number of subjects enrolled |
France: 14
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Country: Number of subjects enrolled |
United Kingdom: 3
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Country: Number of subjects enrolled |
Hong Kong: 7
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Country: Number of subjects enrolled |
Israel: 2
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Country: Number of subjects enrolled |
Italy: 3
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Country: Number of subjects enrolled |
Malaysia: 8
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Country: Number of subjects enrolled |
Netherlands: 12
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Country: Number of subjects enrolled |
Russian Federation: 11
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Country: Number of subjects enrolled |
Singapore: 9
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Country: Number of subjects enrolled |
United States: 6
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Worldwide total number of subjects |
87
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EEA total number of subjects |
44
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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) |
75
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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 |
- | ||||||||||||||||
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Pre-assignment
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Screening details |
Total of 112 subjects was screened out of them 89 subjects were enrolled in the study and 87 subjects received study medication. Two subjects who did not receive study treatment were wrongly classified as enrolled by the sites. | ||||||||||||||||
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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 |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Arm title
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Macitentan 10 mg | ||||||||||||||||
Arm description |
Subjects received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Macitentan
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Investigational medicinal product code |
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Other name |
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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 Macitentan 10 mg tablets once daily.
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Baseline characteristics reporting groups
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Reporting group title |
Macitentan 10 mg
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Reporting group description |
Subjects received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52. | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Macitentan 10 mg
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Reporting group description |
Subjects received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52. | ||
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End point title |
Change From Baseline in Right Ventricular Stroke Volume (RVSV) at Week 26 [1] | ||||||||
End point description |
Change from baseline in RVSV assessed by cardiac magnetic resonance imaging (MRI) from pulmonary artery flow was reported at Week 26. The primary analysis was based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is. The Modified full analysis set (mFAS) included all screened subjects who received at least one dose of the study drug and who had a baseline as well as a post-baseline measurement taken between 16 weeks and 30 weeks of treatment.
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End point type |
Primary
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End point timeframe |
Baseline and 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: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR) [2] | ||||||||
End point description |
Ratio of Week 26 to baseline PVR as assessed by RHC was reported. PVR represents the resistance against which the right ventricle needs to pump. PVR is determined by right heart catheterization (RHC). PVR was calculated as 80*(Mean pulmonary arterial pressure [mPAP] –[Pulmonary capillary wedge pressure {PCWP} or Left ventricular end diastolic pressure {LVEDP} if PCWP not available/cardiac output [CO]). The primary analysis was based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is. mFAS included all screened subjects who received at least one dose of study drug and who had a baseline as well as a post-baseline measurement taken between 16 weeks and 30 weeks of treatment.
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End point type |
Primary
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End point timeframe |
Baseline and Week 26
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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: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Right Ventricular End Diastolic Volume (RVEDV) to Week 26 | ||||||||
End point description |
Change from baseline to Week 26 in RVEDV assessed by cardiac MRI was reported. Safety set included all screened subjects who received at least one dose of study drug. Here ‘N’ (number of subjects analyzed) signifies the number of 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 in Right Ventricular End Systolic Volume (RVESV) to Week 26 | ||||||||
End point description |
Change from baseline to Week 26 in RVESV assessed by cardiac MRI was reported. Safety set included all screened subjects who received at least one dose of study drug. Here ‘N’ (number of subjects analyzed) signifies the number of subjects evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Right Ventricular Ejection Fraction (RVEF) to Week 26 (% Blood Volume) | ||||||||
End point description |
Change from baseline to Week 26 in RVEF based on pulmonary artery flow assessed by cardiac MRI was reported. Safety set included all screened subjects who received at least one dose of study drug. Here ‘N’ (number of subjects analyzed) signifies the number of subjects evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Right Ventricle (RV) Mass to Week 26 | ||||||||
End point description |
Change from baseline to Week 26 in RV mass assessed by cardiac MRI was reported. Safety set included all screened subjects who received at least one dose of study drug. Here ‘N’ (number of subjects analyzed) signifies the number of 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 in Six Minutes Walk Distance (6MWD) to Week 26 | ||||||||
End point description |
6MWD is a non-encouraged test performed in a 30 meter (m) long flat corridor, where the subject is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. This test is used to assess exercise capacity. The test was performed about 30 minutes after study drug administration. Any increase in the walk distance was considered improvement from baseline. Safety Set included all screened subjects who received at least one dose of study drug. Here ‘N’ (number of subjects analyzed) signifies the number of 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 in World Health Organization Functional Class (WHO FC) to Week 26 | ||||||||||||||||
End point description |
WHO FC is a classification which reflects disease severity based on symptoms. WHO Functional Classification of pulmonary hypertension comprises of Class I (subjects with pulmonary hypertension but without resulting limitation of physical activity), II (subjects with pulmonary hypertension resulting in slight limitation of physical activity), III (subjects with pulmonary hypertension resulting in marked limitation of physical activity) and IV (subjects with pulmonary hypertension with inability to carry out any physical activity without symptoms). Changes from baseline to Week 26 included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or unchanged/stable (same FC at baseline and at the post-baseline time point). Safety Set included all screened subjects who received at least one dose of study drug.
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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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Adverse events information
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Timeframe for reporting adverse events |
Up to 420 Days
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Adverse event reporting additional description |
Safety Set included all screened subjects who received at least one dose of study drug.
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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 |
22.0
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Reporting groups
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Reporting group title |
Macitentan 10 mg
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Reporting group description |
Subjects received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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17 Feb 2015 |
This amendment included the following changes: initial combination therapy with macitentan and a PDE-5 inhibitor was allowed in treatment-naive participants; pressure-volume endpoints were to be analyzed as exploratory endpoints instead of secondary endpoints; MRI variables were removed from the metabolism substudy. |
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13 Aug 2015 |
This amendment included the following changes: RHC data obtained at the study site before informed consent signature were accepted if RHC was performed between Day −28 and Day 1; spirometry eligibility criteria were simplified. |
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30 May 2016 |
This amendment included the following changes: eligibility criteria were modified to include participants with PAH associated with connective tissue disease, elderly participants up to 74 years of age, and subjects with a cMRI-compatible pacemaker; the window to perform cMRI and RHC within 7 days of each other was extended to 21 days. |
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08 Nov 2016 |
This amendment included the following change: an interim analysis for efficacy was added to the protocol to allow for study termination if both primary endpoints were met early. |
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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 | |||
