Clinical Trial Results:
Prospective, randomized, placebo-controlled, double-blind, multicenter, parallel-group, 24-week study to assess the efficacy, safety and tolerability of macitentan in subjects with inoperable chronic thromboembolic pulmonary hypertension
Summary
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EudraCT number |
2013-002950-56 |
Trial protocol |
CZ DE AT BE GB HU NL LT |
Global end of trial date |
28 Sep 2016
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Results information
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Results version number |
v3(current) |
This version publication date |
11 Jun 2020
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First version publication date |
18 Oct 2017
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Other versions |
v1 , v2 |
Version creation reason |
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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-055E201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02021292 | ||
WHO universal trial number (UTN) |
- | ||
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@actelion.com
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Scientific contact |
Clinical Trial Disclosure Desk, Actelion Pharmaceuticals Ltd., clinical-trials-disclosure@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 |
25 Oct 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Sep 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Sep 2016
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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 |
To evaluate the effect of macitentan 10 mg on pulmonary vascular resistance (PVR) at rest in comparison with placebo in subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).
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Protection of trial subjects |
Prior to the start of the trial the study center consulted an Independent Ethics Committee (IEC), i.e., a review panel that was responsible for ensuring the protection of the rights, safety, and well-being of human patients involved in a clinical investigation. The sponsor ensured that the IEC consulted was adequately constituted to provide assurance of that protection, and maintained a list of committee members and their qualifications. The protocol and any material provided to the patient (such as a subject information sheet or description of the study used to obtain informed consent) were reviewed and approved by the appropriate IEC before the study was started. This study was conducted in full conformance with the principles of the ‘Declaration of Helsinki’ and with the laws and regulations of the country in which the research was conducted. Both Actelion and the investigator had the right to terminate the study at any time, and in such a case, were responsible for protecting the patients’ interests. Written informed consent was obtained from each individual participating in the study prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study. It was made clear to each patient that he or she was completely free to refuse to enter the study, or to withdraw from it at any time for any reason. A description of any incentives to participate in the study was provided in the informed consent form.
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Background therapy |
49 of 80 randomized subjects (61.3%) received PAH-specific background therapy at baseline (24 or 60% of subjects on macitentan and 25 or 62.5% of subjects on placebo). | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Aug 2014
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Safety | ||
Long term follow-up duration |
4 Years | ||
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 |
Belgium: 1
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Country: Number of subjects enrolled |
China: 24
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Country: Number of subjects enrolled |
Czech Republic: 2
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Country: Number of subjects enrolled |
France: 3
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Hungary: 4
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Country: Number of subjects enrolled |
Korea, Republic of: 1
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Country: Number of subjects enrolled |
Lithuania: 2
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Country: Number of subjects enrolled |
Mexico: 2
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Country: Number of subjects enrolled |
Poland: 3
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Country: Number of subjects enrolled |
Russian Federation: 21
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Country: Number of subjects enrolled |
Switzerland: 1
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Country: Number of subjects enrolled |
Thailand: 4
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Country: Number of subjects enrolled |
Turkey: 2
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Country: Number of subjects enrolled |
Ukraine: 4
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Country: Number of subjects enrolled |
United Kingdom: 3
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Worldwide total number of subjects |
80
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EEA total number of subjects |
21
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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) |
52
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From 65 to 84 years |
28
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 48 sites in 20 countries screened subjects for recruitment. The study was conducted (i.e., randomized subjects) in a total of 36 sites across 16 countries: Belgium, China, Czech Republic, France, Germany, Hungary, Lithuania, Mexico, Poland, Russia, Thailand, Turkey, South Korea, Switzerland, Ukraine, and the United Kingdom. | |||||||||||||||||||||
Pre-assignment
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Screening details |
The target screening period from Visit 1 up to Randomization was a maximum of 30 days, but a longer period (up to 60 days) was permitted with pre-approval from Actelion. A total of 186 subjects were screened. | |||||||||||||||||||||
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 |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Macitentan | |||||||||||||||||||||
Arm description |
Macitentan 10 mg, oral tablet, to be taken once daily. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Macitentan
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Investigational medicinal product code |
ACT-064992
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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 |
10 mg tablet, once daily
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Matching placebo oral tablet, to be taken once daily. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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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 |
Placebo, once-daily
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Baseline characteristics reporting groups
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Reporting group title |
Macitentan
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Reporting group description |
Macitentan 10 mg, oral tablet, to be taken once daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Matching placebo oral tablet, to be taken once daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Full analysis set (FAS)
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Full Analysis Set (FAS) included all subjects assigned to a study treatment. In order to adhere to the intention-to-treat principle as much as possible: 1) subjects were evaluated according to the study treatment they have been assigned to; and 2) all available data were included.
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End points reporting groups
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Reporting group title |
Macitentan
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Reporting group description |
Macitentan 10 mg, oral tablet, to be taken once daily. | ||
Reporting group title |
Placebo
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Reporting group description |
Matching placebo oral tablet, to be taken once daily. | ||
Subject analysis set title |
Full analysis set (FAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Full Analysis Set (FAS) included all subjects assigned to a study treatment. In order to adhere to the intention-to-treat principle as much as possible: 1) subjects were evaluated according to the study treatment they have been assigned to; and 2) all available data were included.
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End point title |
Change from baseline to Week 16 in pulmonary vascular resistance (PVR) at rest. | ||||||||||||
End point description |
The primary efficacy endpoint is defined as the PVR at rest at Week 16 expressed as percent of baseline PVR at rest. Full analysis set included all subjects assigned to a study treatment.
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End point type |
Primary
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End point timeframe |
From baseline to Week 16
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Statistical analysis title |
Analysis of change in PVR | ||||||||||||
Statistical analysis description |
The null hypothesis (change of PVR at rest in Week 16 in percent of baseline PVR in subjects treated with placebo or macitentan is the same) is tested on the primary endpoint by means of an analysis of covariance (ANCOVA) model on the log(e) transformed % of baseline PVR at rest at Week 16.
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Comparison groups |
Macitentan v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.041 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
ratio of geometric means | ||||||||||||
Point estimate |
0.84
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.7 | ||||||||||||
upper limit |
0.99 | ||||||||||||
Notes [1] - ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate. |
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End point title |
Change from baseline to Week 24 in exercise capacity, as measured by the 6-minute walk distance (6MWD). | |||||||||||||||||||||
End point description |
The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. Full analysis set included all subjects assigned to a study treatment.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 24
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Statistical analysis title |
Analysis of change in 6MWD | |||||||||||||||||||||
Statistical analysis description |
Statistical model is ANCOVA including 6MWD at baseline as a covariate, with treatment as factor in the model. The least squares (LS) mean difference of change from baseline to Week 24 (treatment difference: macitentan vs placebo) was 34.04 m (95% confidence limit: 2.9, 65.2, p = 0.0326).
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Comparison groups |
Macitentan v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | |||||||||||||||||||||
P-value |
= 0.0326 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
Least square (LS) mean difference | |||||||||||||||||||||
Point estimate |
34.04
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
2.9 | |||||||||||||||||||||
upper limit |
65.2 | |||||||||||||||||||||
Notes [2] - To control for multiplicity across primary and secondary endpoints, all secondary endpoints were analyzed in sequence using hierarchical approach based on order and significance as pre-specified in protocol eliminating further adjustment for multiple comparisons. |
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End point title |
Change from baseline to Week 24 in Borg dyspnea index collected at the end of the 6-minute walk test (6MWT). | |||||||||||||||||||||
End point description |
This outcome measures the difference in the Borg dyspnea index at Week 24 compared to baseline. The index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 (‘Nothing at all’) to 10 (‘Very, very severe – maximal’). Full analysis set included all subjects assigned to a study treatment.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 24
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Statistical analysis title |
Analysis of change in Borg dyspnea index | |||||||||||||||||||||
Statistical analysis description |
Statistical model is Analysis of Covariance including Borg dyspnea index at baseline as a covariate, with Treatment as factor in the model. The least squares (LS) mean difference of change from baseline to Week 24 (macitentan vs placebo) was -0.39 (95% confidence limit: –1.21, 0.43; p=0.3492).
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Comparison groups |
Macitentan v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | |||||||||||||||||||||
P-value |
= 0.3492 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
Least square (LS) mean difference | |||||||||||||||||||||
Point estimate |
-0.39
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
-1.21 | |||||||||||||||||||||
upper limit |
0.43 | |||||||||||||||||||||
Notes [3] - To control for multiplicity across primary and secondary endpoints, all secondary endpoints were analyzed in sequence using hierarchical approach based on order and significance as pre-specified in protocol eliminating further adjustment for multiple comparisons. |
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End point title |
Proportion of subjects with worsening in WHO functional class from baseline to Week 24. | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
WHO functional classes are defined as follows: 1) class I: no symptoms with exercise or at rest. No limitation of activity. 2) class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). 3) class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. 4) class IV: symptoms at rest (such as dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms (e.g. may faint especially while bending over with their heads lowered). Patients in class IV manifest signs of right heart failure. Shifting to a higher class (e.g. from class III to class IV) represents a 'worsening' while shifting to a lower class (e.g. from class III to class II) means an 'improvement'. Full analysis set included all subjects assigned to a study treatment.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 24
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Statistical analysis title |
Analysis of worsening in WHO functional class | |||||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is odds of worsening are the same in placebo and macitentan group. Logistic regression is used for macitentan vs placebo comparison with treatment and WHO functional class at baseline as factors in the model. The odds ratio for worsening WHO functional class at Week 24 (macitentan vs placebo) was 0.212 (95% confidence limit: < 0.001, 1.464, p = 0.0962).
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Comparison groups |
Macitentan v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | |||||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.0962 | |||||||||||||||||||||||||||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||||||||||||||||||||||||||
Point estimate |
0.212
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Confidence interval |
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level |
95% | |||||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.001 | |||||||||||||||||||||||||||||||||||||||||||||
upper limit |
1.464 | |||||||||||||||||||||||||||||||||||||||||||||
Notes [4] - To control for multiplicity across primary and secondary endpoints, all secondary endpoints were analyzed in sequence using hierarchical approach based on order and significance as pre-specified in protocol eliminating further adjustment for multiple comparisons. |
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End point title |
Post-hoc analysis of change from baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at rest including subjects with corrected hemodynamic values | ||||||||||||
End point description |
The main analysis of the primary efficacy endpoint of PVR was repeated after the voluntary right heart catheterization source data verification (SDV) and independent medical review of hemodynamic data corrected for 13 subjects reported after the clinical database closure. Full analysis set for this post-hoc analysis included all subjects assigned to a study treatment with SDV values.
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End point type |
Post-hoc
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End point timeframe |
From baseline to Week 16
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Statistical analysis title |
Analysis of PVR change with corrected PVR values | ||||||||||||
Statistical analysis description |
The same statistical model as for the predefined analysis (ANCOVA) was applied, including 13 subjects with corrected hemodynamic values.
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Comparison groups |
Macitentan v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Post-hoc
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Analysis type |
superiority [5] | ||||||||||||
P-value |
= 0.0098 [6] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Model-adjusted geometric mean ratio | ||||||||||||
Point estimate |
0.81
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.7 | ||||||||||||
upper limit |
0.95 | ||||||||||||
Notes [5] - ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate. [6] - This is the post-hoc analysis and p-value is an exploratory p-value. |
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End point title |
Post-hoc Analysis of change from baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at rest Excluding Subjects with Corrected Hemodynamic Values | ||||||||||||
End point description |
The main analysis of the primary efficacy endpoint of PVR was repeated which excluded data for 13 subjects with corrected hemodynamic values. The hemodynamic values were reported after the SDV assessment clinical database closure. Full analysis set excluding subjects with corrected hemodynamic values.
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End point type |
Post-hoc
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End point timeframe |
From baseline to Week 16
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Statistical analysis title |
Post-hoc statistical analysis 1 | ||||||||||||
Comparison groups |
Macitentan v Placebo
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Number of subjects included in analysis |
67
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Analysis specification |
Post-hoc
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Analysis type |
superiority [7] | ||||||||||||
P-value |
= 0.0061 [8] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Model-adjusted geometric mean ratio | ||||||||||||
Point estimate |
0.79
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.68 | ||||||||||||
upper limit |
0.93 | ||||||||||||
Notes [7] - ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate. [8] - This is the post-hoc analysis and p-value is an exploratory p-value. |
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End point title |
Post-hoc Analysis of change from baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at rest Excluding Subjects with Implausible Hemodynamic Findings | ||||||||||||
End point description |
The main analysis of the primary efficacy endpoint of PVR was repeated which excluded 14 subjects with implausible hemodynamic findings. Full analysis set excluding subjects with implausible hemodynamic findings.
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End point type |
Post-hoc
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End point timeframe |
From baseline to Week 16
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Statistical analysis title |
Post-hoc statistical analysis 1 | ||||||||||||
Comparison groups |
Macitentan v Placebo
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Number of subjects included in analysis |
66
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Analysis specification |
Post-hoc
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Analysis type |
superiority [9] | ||||||||||||
P-value |
= 0.0414 [10] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Geometric mean ratio | ||||||||||||
Point estimate |
0.85
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.73 | ||||||||||||
upper limit |
0.99 | ||||||||||||
Notes [9] - ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate. [10] - This is the post-hoc analysis and p-value is an exploratory p-value. |
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End point title |
Post-hoc Analysis of Change from baseline to Week 24 in exercise capacity, as measured by the 6-minute walk distance (6MWD) Excluding subjects with Implausible Hemodynamic Findings | ||||||||||||
End point description |
The same analysis for the secondary endpoint, 6MWD, is repeated on the full analysis set excluding 14 subject with implausible hemodynamic findings. Full analysis set excluding subjects with implausible hemodynamic findings.
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End point type |
Post-hoc
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End point timeframe |
From baseline to Week 24
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Statistical analysis title |
Post-hoc statistical analysis 1 | ||||||||||||
Statistical analysis description |
Statistical model is ANCOVA including 6MWD at baseline as a covariate, with treatment as factor in the model.
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Comparison groups |
Macitentan v Placebo
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Number of subjects included in analysis |
66
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Analysis specification |
Post-hoc
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0468 [11] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
least squares (LS) mean difference | ||||||||||||
Point estimate |
37.19
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.54 | ||||||||||||
upper limit |
73.83 | ||||||||||||
Notes [11] - This is the post-hoc analysis and p-value is an exploratory p-value. |
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Adverse events information
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Timeframe for reporting adverse events |
From double-blind study treatment initiation up to 30 days after study treatment discontinuation
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19
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Reporting groups
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Reporting group title |
Macitentan
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Reporting group description |
Macitentan 10 mg, oral tablet, to be taken once daily. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Matching placebo oral tablet, to be taken once daily. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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25 Mar 2015 |
Global amendment 1 resulting in Protocol version 2. Changes included: - Number of study countries screening period was prolonged to improve the rate of recruitment. - Modification of the required qualifications for country-specific adjudication committees (CSAC). - Further clarification of guidelines on oxygen use during the 6MWT. - Clarification of use of the PAH-SYMPACT questionnaire. - Update of ICF to reflect changes in country numbers and of clarifications of study procedures in clinical protocol. |
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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 | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/28919201 |