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Clinical Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome (MAESTRO)

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ClinicalTrials.gov Identifier: NCT01743001
Recruitment Status : Completed
First Posted : December 6, 2012
Results First Posted : January 30, 2018
Last Update Posted : February 23, 2018
Sponsor:
Information provided by (Responsible Party):
Actelion

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Pulmonary Arterial Hypertension
Interventions Drug: Macitentan 10 mg
Drug: Placebo
Enrollment 226
Recruitment Details The study was conducted at 71 sites in 26 countries (geographical regions: Asia-Pacific, Eastern Europe, Latin America, North America, Western Europe including Israel and Turkey, and South Africa), of which 55 sites in 21 countries randomized subjects.
Pre-assignment Details The screening period lasted a maximum of 30 days from Visit 1 up to Randomization (Visit 2). A total of 319 subjects were screened and 226 subjects were randomized to macitentan 10 mg and placebo.
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description Subjects receive macitentan 10 mg, oral tablet, to be taken once daily Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily
Period Title: Overall Study
Started 114 112
Completed 111 112
Not Completed 3 0
Reason Not Completed
Physician Decision             1             0
Pregnancy             1             0
Death             1             0
Arm/Group Title Macitentan Placebo Total
Hide Arm/Group Description Subjects receive macitentan 10 mg, oral tablet, to be taken once daily Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily Total of all reporting groups
Overall Number of Baseline Participants 114 112 226
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 114 participants 112 participants 226 participants
33.0
(12 to 82)
31.0
(13 to 62)
32.0
(12 to 82)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 114 participants 112 participants 226 participants
12 - 17 years
13
  11.4%
2
   1.8%
15
   6.6%
18 - 55 years
90
  78.9%
105
  93.8%
195
  86.3%
≥ 56 years
11
   9.6%
5
   4.5%
16
   7.1%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 114 participants 112 participants 226 participants
Female
82
  71.9%
68
  60.7%
150
  66.4%
Male
32
  28.1%
44
  39.3%
76
  33.6%
Region of Enrollment   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 114 participants 112 participants 226 participants
Asia-Pacific
47
  41.2%
44
  39.3%
91
  40.3%
Eastern Europe
25
  21.9%
27
  24.1%
52
  23.0%
Latin America
19
  16.7%
18
  16.1%
37
  16.4%
North America
2
   1.8%
5
   4.5%
7
   3.1%
Western Europe - Israel
21
  18.4%
18
  16.1%
39
  17.3%
[1]
Measure Description: Asia-Pacific includes: China, Malaysia, Philippines, Vietnam; Eastern Europe: Bulgaria, Poland, Romania, Russian Federation, Serbia; Latin America: Chile, Mexico; North America: United States; Western Europe - Israel: Austria, France, Germany, Greece, Israel, Portugal, Spain, Turkey, United Kingdom
Body Mass Index (BMI)  
Median (Full Range)
Unit of measure:  Kg/m^2
Number Analyzed 114 participants 112 participants 226 participants
21.15
(11.9 to 38.9)
21.55
(14.5 to 42.2)
21.35
(11.9 to 42.2)
WHO functional class   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 114 participants 112 participants 226 participants
class I
0
   0.0%
0
   0.0%
0
   0.0%
class II
69
  60.5%
66
  58.9%
135
  59.7%
class III
45
  39.5%
46
  41.1%
91
  40.3%
class IV
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Class I: no symptoms with exercise or at rest. No limitation of activity. 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). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure.
[2]
Measure Analysis Population Description: Per protocol patients in WHO functional class I were excluded.
1.Primary Outcome
Title Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD)
Hide 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.
Time Frame From baseline to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set: The analysis was performed on the full analysis set (FAS), i.e., all randomized subjects in the treatment group to which they were randomized and by imputing missing values at Week 16 according to pre-defined rules.
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description:
Subjects receive macitentan 10 mg, oral tablet, to be taken once daily
Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily
Overall Number of Participants Analyzed 114 112
Mean (Standard Deviation)
Unit of Measure: meter
6MWD at baseline 368.7  (74.5) 380.3  (76.3)
6MWD at Week 16 387.1  (101.8) 399.9  (79.5)
Change in 6MWD from baseline to Week 16 18.3  (84.4) 19.7  (53.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis was that there was no difference between macitentan and placebo for the mean change from baseline to Week 16 in 6MWD. Null hypothesis was tested by an analysis of covariance (ANCOVA).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6120
Comments To control for multiplicity across the primary and secondary endpoints, all secondary endpoints were analyzed hierarchically according to order and significance as pre-specified in the protocol eliminating further adjustment for multiple comparisons.
Method ANCOVA
Comments ANCOVA model included treatment group, presence of DS (yes/no), and WHO FC (II vs III/IV) as categorical factors, and baseline 6MWD value as covariate
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -4.7
Confidence Interval (2-Sided) 95%
-22.8 to 13.5
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline to Week 16 in WHO Functional Class
Hide Description A shift in WHO functional classes is considered an 'improvement' when shifting to a lower class (e.g. from class III to class II) or a 'worsening' when shifting to a higher class (e.g. from class III to class IV). Definition of functional classes as follows - Class I: no symptoms with exercise or at rest. Class II: No symptoms at rest but uncomfortable and short of breath with normal activity such as climbing a flight of stairs, grocery shopping, or making the bed. Class III: May not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting (e.g. doing normal chores around the house, have to take breaks while doing activities of daily living). Class IV: Symptoms at rest and severe symptoms with any activity. Most patients also have edema in the feet and ankles as result of right heart failure.
Time Frame From baseline to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set: The analysis was performed on the full analysis set (FAS), i.e., all randomized subjects in the treatment group to which they were randomized and by imputing missing values at Week 16 according to pre-defined rules.
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description:
Subjects receive macitentan 10 mg, oral tablet, to be taken once daily
Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily
Overall Number of Participants Analyzed 114 112
Measure Type: Count of Participants
Unit of Measure: Participants
WHO functional class 1 at Week 16
3
   2.6%
1
   0.9%
WHO functional class 2 at Week 16
72
  63.2%
79
  70.5%
WHO functional class 3 at Week 16
38
  33.3%
32
  28.6%
WHO functional class 4 at Week 16
1
   0.9%
0
   0.0%
Unchanged from baseline to Week 16
103
  90.4%
95
  84.8%
Improvement from baseline to Week 16
10
   8.8%
16
  14.3%
Worsening from baseline to Week 16
1
   0.9%
1
   0.9%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments For this secondary endpoint of WHO functional class, the improvement from baseline to Week 16 in WHO functional class was evaluated. The null hypothesis is the odds of improvement are the same in the placebo and the macitentan group.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1450
Comments The secondary efficacy endpoints were analyzed hierarchically as this approach eliminated the requirement for further adjustment for multiple comparisons.
Method Regression, Logistic
Comments Logistic regression model adjusted for randomized treatment group and location of cardiac defect (pre-tricupsid / post-tricupsid ) as factors.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.53
Confidence Interval (2-Sided) 95%
0.23 to 1.24
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index
Hide Description This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 16 compared to baseline. The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement.
Time Frame From baseline to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set: The analysis was performed on the full analysis set (FAS), i.e., all randomized subjects in the treatment group to which they were randomized and by imputing missing values at Week 16 according to pre-defined rules.
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description:
Subjects receive macitentan 10 mg, oral tablet, to be taken once daily
Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily
Overall Number of Participants Analyzed 114 112
Mean (Standard Deviation)
Unit of Measure: Score on a scale
Borg dyspnea index score at baseline 3.00  (1.95) 2.94  (1.88)
Borg dyspnea index score at Week 16 2.78  (2.10) 2.66  (1.64)
Change from baseline to Week 16 -0.22  (1.56) -0.29  (1.50)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis was that the mean change from baseline to Week 16 in the Borg dyspnea index is the same in the macitentan and in the placebo group.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6818
Comments The secondary efficacy endpoints were analyzed hierarchically as this approach eliminated the requirement for further adjustment for multiple comparisons.
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect(pre-tricupsid/post-tricupsid) as factors, baseline Borg dyspnea index as covariate
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value 0.08
Confidence Interval 95%
-0.29 to 0.44
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire
Hide Description

The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of the functional health and well-being scores (i.e., physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health), as well as psychometrically based physical and mental health summary measures and a preference-based health utility (health rated as much better now than one year ago to much worse now than one year ago). It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group.

For each of the domains and scores that the SF36 measures an aggregate percentage score is produced. The percentage scores range from 0% (lowest or worst possible level of functioning) to 100% (highest or best possible level of functioning). A higher score for the individual domains and summary component scores indicates a better condition of the subject.

Time Frame From baseline to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (excluding children <14 years of age and Down Syndrome subjects)
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description:
Subjects receive macitentan 10 mg, oral tablet, to be taken once daily
Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily
Overall Number of Participants Analyzed 101 99
Mean (Standard Deviation)
Unit of Measure: Score on a scale
Domain score: physical functioning at baseline 51.9  (21.8) 52.7  (22.4)
Domain score: physical functioning at Week 16 56.4  (21.9) 58.0  (19.7)
Change in physical functioning (domain score) 4.6  (16.5) 5.3  (15.4)
Domain score: role-physical at baseline 46.2  (25.5) 48.4  (27.9)
Domain score: role-physical at Week 16 52.8  (25.5) 55.9  (25.3)
Change in role-physical (domain score) 6.6  (20.1) 7.4  (22.1)
Domain score: pain index at baseline 61.7  (23.0) 64.6  (24.6)
Domain score: pain index at Week 16 65.2  (23.6) 66.2  (24.7)
Change in pain index (domain score) 3.5  (22.1) 1.6  (27.1)
Domain score:general health perceptions baseline 36.1  (21.0) 37.2  (19.8)
Domain score:general health perceptions at Week 16 40.3  (22.7) 37.6  (20.3)
Change in general health perceptions(domain score) 4.2  (16.4) 0.5  (15.5)
Domain score: vitality at baseline 49.0  (22.1) 51.9  (21.5)
Domain score: vitality at Week 16 56.1  (19.8) 56.3  (17.5)
Change in vitality (domain score) 7.1  (18.3) 4.4  (18.2)
Domain score: social functioning at baseline 64.7  (26.8) 66.9  (25.0)
Domain score: social functioning at Week 16 66.6  (25.8) 69.2  (23.5)
Change in social functioning (domain score) 1.9  (23.0) 2.3  (24.5)
Domain score: role-emotional at baseline 61.6  (27.4) 61.3  (28.8)
Domain score: role-emotional at Week 16 63.3  (26.8) 66.0  (25.6)
Change in role-emotional (domain score) 1.7  (22.8) 4.7  (25.0)
Domain score: mental health index at baseline 63.8  (21.1) 64.0  (20.5)
Domain score: mental health index at Week 16 65.7  (18.9) 67.7  (20.6)
Change in mental health index (domain score) 1.9  (16.1) 3.7  (16.6)
Norm-based: physical functioning at baseline 36.8  (9.2) 37.1  (9.4)
Norm-based: physical functioning at Week 16 38.7  (9.2) 39.3  (8.3)
Change in physical functioning (norm-based) 1.9  (6.9) 2.2  (6.5)
Norm-based: role-physical at baseline 35.8  (10.0) 36.6  (10.9)
Norm-based: role-physical at Week 16 38.4  (10.0) 39.6  (9.9)
Change in role-physical (norm-based) 2.6  (7.9) 2.9  (8.7)
Norm-based: pain index at baseline 45.9  (9.7) 47.2  (10.4)
Norm-based: pain index at Week 16 47.4  (10.0) 47.8  (10.4)
Change in pain index (norm-based) 1.5  (9.3) 0.7  (11.5)
Norm-based: general health perceptions at baseline 33.4  (10.0) 33.9  (9.4)
Norm-based: general health perceptions at Week 16 35.4  (10.8) 34.2  (9.7)
Change in general health perceptions (norm-based) 2.0  (7.8) 0.2  (7.4)
Norm-based: vitality at baseline 45.4  (11.1) 46.8  (10.7)
Norm-based: vitality at Week 16 48.9  (9.9) 49.0  (8.7)
Change in vitality (norm-based) 3.6  (9.1) 2.2  (9.1)
Norm-based: social functioning at baseline 41.5  (11.7) 42.4  (10.9)
Norm-based: social functioning at Week 16 42.3  (11.3) 43.4  (10.3)
Change in social functioning (norm-based) 0.8  (10.0) 1.0  (10.7)
Norm-based: role-emotional at baseline 37.9  (12.8) 37.8  (13.4)
Norm-based: role-emotional at Week 16 38.8  (12.5) 40.0  (11.9)
Change in role-emotional (norm-based) 0.8  (10.6) 2.2  (11.7)
Norm-based: mental health index at baseline 43.7  (11.9) 43.8  (11.6)
Norm-based: mental health index at Week 16 44.8  (10.6) 45.9  (11.6)
Change in mental health index (norm-based) 1.1  (9.1) 2.1  (9.3)
Physical component summary score at baseline 37.6  (7.5) 38.6  (8.7)
Physical component summary score at Week 16 40.0  (8.4) 40.0  (7.7)
Change in physical component summary score 2.4  (6.4) 1.4  (6.5)
Mental component summary score at baseline 43.8  (12.4) 44.1  (12.1)
Mental component summary score at Week 16 44.7  (11.7) 45.9  (10.9)
Change in mental component summary score 1.0  (9.3) 1.8  (9.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Physical Functioning.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6431
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -1.0
Confidence Interval (2-Sided) 95%
-5.0 to 3.1
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Role-Physical.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5988
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -1.4
Confidence Interval (2-Sided) 95%
-6.7 to 3.9
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Pain Index.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9642
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-5.9 to 6.2
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of General Health Perceptions.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1542
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value 3.1
Confidence Interval (2-Sided) 95%
-1.2 to 7.3
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Vitality.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6020
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value 1.1
Confidence Interval (2-Sided) 95%
-3.1 to 5.3
Estimation Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Social Functioning.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6340
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -1.4
Confidence Interval (2-Sided) 95%
-7.2 to 4.4
Estimation Comments [Not Specified]
Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Role-Emotional.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3384
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -2.8
Confidence Interval (2-Sided) 95%
-8.7 to 3.0
Estimation Comments [Not Specified]
Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Mental Health Index.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2704
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -2.3
Confidence Interval (2-Sided) 95%
-6.4 to 1.8
Estimation Comments [Not Specified]
Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Physical Functioning (norm-based).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6431
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -0.4
Confidence Interval (2-Sided) 95%
-2.1 to 1.3
Estimation Comments [Not Specified]
Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Role-Physical (norm-based).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5988
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -0.6
Confidence Interval (2-Sided) 95%
-2.6 to 1.5
Estimation Comments [Not Specified]
Hide Statistical Analysis 11
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Pain Index (norm-based).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9642
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-2.5 to 2.6
Estimation Comments [Not Specified]
Hide Statistical Analysis 12
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of General Health Perceptions (norm-based).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1542
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value 1.5
Confidence Interval (2-Sided) 95%
-0.6 to 3.5
Estimation Comments [Not Specified]
Hide Statistical Analysis 13
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Vitality (norm-based).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6020
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value 0.6
Confidence Interval (2-Sided) 95%
-1.5 to 2.6
Estimation Comments [Not Specified]
Hide Statistical Analysis 14
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Social Functioning (norm-based).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6340
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -0.6
Confidence Interval (2-Sided) 95%
-3.1 to 1.9
Estimation Comments [Not Specified]
Hide Statistical Analysis 15
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Role-Emotional (norm-based).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3384
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -1.3
Confidence Interval (2-Sided) 95%
-4.1 to 1.4
Estimation Comments [Not Specified]
Hide Statistical Analysis 16
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Mental Health Index.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2704
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -1.3
Confidence Interval (2-Sided) 95%
-3.6 to 1.0
Estimation Comments [Not Specified]
Hide Statistical Analysis 17
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the Physical Component Summary Score.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4332
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value 0.7
Confidence Interval (2-Sided) 95%
-1.0 to 2.3
Estimation Comments [Not Specified]
Hide Statistical Analysis 18
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the Mental Component Summary Score.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3416
Comments [Not Specified]
Method ANCOVA
Comments Adjusted for randomized treatment group, location of cardiac defect (pre-tricupsid/post-tricupsid) as factors and baseline scores as covariates.
Method of Estimation Estimation Parameter least-square (LS) mean difference
Estimated Value -1.1
Confidence Interval (2-Sided) 95%
-3.4 to 1.2
Estimation Comments [Not Specified]
Time Frame A safety follow-up visit was required 30 days after end of treatment period at Week 16. Subjects who prematurely discontinued treatment prior to Week 16 were required to perform a premature end-of-treatment visit no later than 7 days after last dose of study treatment and then followed by the 30 day safety follow-up visit.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description Subjects receive macitentan 10 mg orally to be taken once daily. 114 subjects were exposed to Macitentan 10 mg for 15.93 weeks on average. Subjects receive macitentan-matching placebo orally to be taken once daily. 112 subjects were exposed to placebo for 15.96 weeks on average.
All-Cause Mortality
Macitentan Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   1/114 (0.88%)      0/112 (0.00%)    
Hide Serious Adverse Events
Macitentan Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/114 (6.14%)      2/112 (1.79%)    
Cardiac disorders     
Atrial fibrillation  1  1/114 (0.88%)  1 1/112 (0.89%)  2
Cardiac failure chronic  1  0/114 (0.00%)  0 1/112 (0.89%)  1
Right ventricular failure  1  3/114 (2.63%)  4 0/112 (0.00%)  0
Infections and infestations     
Endocarditis  1  1/114 (0.88%)  1 0/112 (0.00%)  0
Pneumonia  1  2/114 (1.75%)  2 0/112 (0.00%)  0
Septic shock  1  1/114 (0.88%)  1 0/112 (0.00%)  0
Nervous system disorders     
Dizziness  1  1/114 (0.88%)  1 0/112 (0.00%)  0
Transient ischaemic attack  1  1/114 (0.88%)  1 0/112 (0.00%)  0
Renal and urinary disorders     
Acute kidney injury  1  1/114 (0.88%)  1 0/112 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Respiratory failure  1  1/114 (0.88%)  1 0/112 (0.00%)  0
1
Term from vocabulary, MedDRA
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Macitentan Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   31/114 (27.19%)      30/112 (26.79%)    
Infections and infestations     
Bronchitis  1  6/114 (5.26%)  6 3/112 (2.68%)  3
Nasopharyngitis  1  3/114 (2.63%)  4 14/112 (12.50%)  16
Upper respiratory tract infection  1  11/114 (9.65%)  12 7/112 (6.25%)  10
Nervous system disorders     
Headache  1  13/114 (11.40%)  15 5/112 (4.46%)  5
Respiratory, thoracic and mediastinal disorders     
Haemoptysis  1  0/114 (0.00%)  0 6/112 (5.36%)  8
1
Term from vocabulary, MedDRA
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Any study-related publication written independently by investigators must be submitted to Actelion for review at least 60 days prior to submission for publication or presentation. Upon review, Actelion may provide comments, and may also request alterations and/or deletions for the sole purpose of protecting its confidential information and/or patent rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Trial Disclosure Desk
Organization: Actelion Pharmaceuticals Ltd
EMail: clinical-trials-disclosure@actelion.com
Layout table for additonal information
Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT01743001    
Other Study ID Numbers: AC-055-305
First Submitted: November 29, 2012
First Posted: December 6, 2012
Results First Submitted: November 28, 2017
Results First Posted: January 30, 2018
Last Update Posted: February 23, 2018