Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

PORtopulmonary Hypertension Treatment wIth maCitentan - a randOmized Clinical Trial (PORTICO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02382016
Recruitment Status : Completed
First Posted : March 6, 2015
Results First Posted : November 23, 2018
Last Update Posted : November 5, 2019
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 Portopulmonary Hypertension
Interventions Drug: Macitentan
Other: Placebo
Enrollment 85
Recruitment Details Participants at 39 sites in 7 countries were screened and were randomized at 36 sites in these 7 countries (Brazil, Czech Republic, France, Germany, Spain, UK and US).
Pre-assignment Details A total of 119 participants were screened and 85 participants were randomized (43 to macitentan 10 mg once daily and 42 to matching placebo) and received double-blind (DB) study treatment. Overall, 80 participants who completed DB treatment period entered the open-label (OL) treatment period and 33 participants in open-label extension (OLE) period.
Arm/Group Title Macitentan 10 mg Placebo
Hide Arm/Group Description Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period . Participants (who were randomized at French sites) who completed the core phase of the study as scheduled and opted to continue receiving OL study treatment continued to receive macitentan 10 mg in OLE period. Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period were administered with macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period. Participants who were randomized at French sites who completed the core study as scheduled and opted to continue receiving OL study treatment continued to receive macitentan 10mg in OLE period.
Period Title: Double-blind (DB) Treatment Period
Started 43 42
Completed 39 41
Not Completed 4 1
Reason Not Completed
Physician Decision             3             0
Lack of Efficacy             1             0
Withdrawal by Subject             0             1
Period Title: Open-label (OL) Treatment Period
Started 80 0
Completed 71 0
Not Completed 9 0
Reason Not Completed
Physician Decision             3             0
Withdrawal by Subject             2             0
Death             4             0
Period Title: OL Extension Period
Started 33 [1] 0
Completed 27 0
Not Completed 6 0
Reason Not Completed
Physician Decision             3             0
Death             2             0
Withdrawal by Subject             1             0
[1]
Participants(French site) who completed DB,OL periods, consented receiving macitentan in OLE period.
Arm/Group Title Macitentan 10 mg Placebo Total
Hide Arm/Group Description Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Total of all reporting groups
Overall Number of Baseline Participants 43 42 85
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 42 participants 85 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
35
  81.4%
29
  69.0%
64
  75.3%
>=65 years
8
  18.6%
13
  31.0%
21
  24.7%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 43 participants 42 participants 85 participants
58.0  (8.7) 59.0  (9.5) 58.5  (9.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 42 participants 85 participants
Female
21
  48.8%
20
  47.6%
41
  48.2%
Male
22
  51.2%
22
  52.4%
44
  51.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 42 participants 85 participants
Hispanic or Latino
6
  14.0%
6
  14.3%
12
  14.1%
Not Hispanic or Latino
19
  44.2%
15
  35.7%
34
  40.0%
Unknown or Not Reported
18
  41.9%
21
  50.0%
39
  45.9%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 42 participants 85 participants
Asian
1
   2.3%
0
   0.0%
1
   1.2%
White
23
  53.5%
21
  50.0%
44
  51.8%
Other
1
   2.3%
0
   0.0%
1
   1.2%
Not Applicable
18
  41.9%
21
  50.0%
39
  45.9%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 42 participants 85 participants
United States
12
  27.9%
11
  26.2%
23
  27.1%
Brazil
2
   4.7%
3
   7.1%
5
   5.9%
Czech Republic
1
   2.3%
3
   7.1%
4
   4.7%
France
18
  41.9%
21
  50.0%
39
  45.9%
Germany
4
   9.3%
4
   9.5%
8
   9.4%
Spain
4
   9.3%
0
   0.0%
4
   4.7%
United Kingdom
2
   4.7%
0
   0.0%
2
   2.4%
Pulmonary arterial hypertension (PAH)-specific therapy   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 42 participants 85 participants
Yes
27
  62.8%
27
  64.3%
54
  63.5%
No
16
  37.2%
15
  35.7%
31
  36.5%
[1]
Measure Description: As per randomization stratification, 63.5% of patients were receiving a pulmonary arterial hypertension (PAH)-specific therapy at baseline.
Body Mass Index (BMI) at baseline  
Mean (Standard Deviation)
Unit of measure:  Kilogram per meter^2 (Kg/m^2)
Number Analyzed 43 participants 42 participants 85 participants
29.01  (4.79) 29.33  (4.04) 29.17  (4.41)
Time since portal hypertension diagnosis  
Median (Inter-Quartile Range)
Unit of measure:  Months
Number Analyzed 43 participants 42 participants 85 participants
23
(5 to 80)
31
(4 to 69)
25
(7 to 76)
Time since PAH diagnosis  
Median (Inter-Quartile Range)
Unit of measure:  Months
Number Analyzed 43 participants 42 participants 85 participants
7
(2 to 33)
12
(1 to 37)
10
(2 to 36)
Pulmonary vascular resistance (PVR) at baseline (calculated)  
Mean (Standard Deviation)
Unit of measure:  Dyn*sec/cm^5
Number Analyzed 43 participants 42 participants 85 participants
552.4  (192.8) 521.7  (163.3) 537.2  (178.4)
1.Primary Outcome
Title Relative Change From Baseline to Week 12 in Pulmonary Vascular Resistance (PVR).
Hide Description The relative change from baseline to Week 12 in PVR is expressed as a ratio of Week 12 to baseline PVR.
Time Frame From enrollment/baseline to Week 12 in the Double Blind (DB) treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Macitentan 10 mg Placebo
Hide Arm/Group Description:
Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Overall Number of Participants Analyzed 43 42
Geometric Mean (95% Confidence Interval)
Unit of Measure: ratio
0.63
(0.58 to 0.67)
0.98
(0.91 to 1.05)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan 10 mg, Placebo
Comments The null hypothesis (change of PVR at Week 12 as a ratio 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 ratio of PVR at Week 12 to baseline PVR.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model adjusted by treatment, background PAH-specific therapy at baseline and region as factors & log-transformed PVR at baseline as a covariate
Method of Estimation Estimation Parameter ratio of geometric means
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.59 to 0.72
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline to Week 12 in 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 enrollment/baseline to Week 12 in the DB treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Macitentan 10 mg Placebo
Hide Arm/Group Description:
Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Overall Number of Participants Analyzed 43 42
Mean (Standard Deviation)
Unit of Measure: meter
6MWD at baseline 385.8  (99.97) 383.2  (108.90)
6MWD at Week 12 392.2  (98.46) 380.8  (114.98)
Change of 6MWD from baseline to Week 12 6.4  (65.74) -2.4  (43.65)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan 10 mg, Placebo
Comments The main analysis on 6MWD was performed using a mixed-effect model repeated measure (MMRM) adjusted for treatment, visit, region, PAH-specific therapy at baseline, and treatment-by-visit interaction as factors, and baseline 6MWD and WHO functional class (FC) as covariates.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4264
Comments No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.
Method mixed-effect model repeated measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares (LS) mean difference
Estimated Value 9.73
Confidence Interval (2-Sided) 95%
-14.50 to 33.95
Estimation Comments The estimated value refers to a between-treatment analysis of change from baseline to Week 12 in 6MWD (LS mean difference macitentan 10 mg - placebo).
3.Secondary Outcome
Title Change From Baseline to Week 12 in WHO Functional Class (FC)
Hide Description Changes from baseline to Week 12 in WHO FC were dichotomized as worsening (i.e., change > 0) versus no change or improvement (i.e., change ≤ 0). 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.
Time Frame From enrollment/baseline to Week 12 in the DB treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Macitentan 10 mg Placebo
Hide Arm/Group Description:
Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Overall Number of Participants Analyzed 43 42
Measure Type: Count of Participants
Unit of Measure: Participants
WHO FC I at baseline
1
   2.3%
1
   2.4%
WHO FC II at baseline
27
  62.8%
23
  54.8%
WHO FC III at baseline
15
  34.9%
18
  42.9%
WHO FC IV at baseline
0
   0.0%
0
   0.0%
WHO FC I at Week 12
3
   7.0%
4
   9.5%
WHO FC II at Week 12
27
  62.8%
23
  54.8%
WHO FC III at Week 12
13
  30.2%
15
  35.7%
WHO FC IV at Week 12
0
   0.0%
0
   0.0%
Improved from baseline to Week 12
9
  20.9%
7
  16.7%
Worsened from baseline to Week 12
6
  14.0%
1
   2.4%
Unchanged from baseline to Week 12
28
  65.1%
34
  81.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan 10 mg, Placebo
Comments A logistic regression model (exact) adjusted for treatment, PAH-specific therapy at baseline, and region as covariates was used to analyze worsening in WHO FC.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1278
Comments No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 6.253
Confidence Interval (2-Sided) 95%
0.714 to 298.376
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline to Week 12 in the Biomarker N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
Hide Description NT-proBNP functions as a strong indicator of prognosis in patients with pulmonary hypertension (PH). The relative change from baseline to Week 12 in NT-proBNP is expressed as a ratio of Week 12 to baseline NT-proBNP.
Time Frame From enrollment/baseline to Week 12 in the DB treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set(FAS): All randomized participants who received at least one dose of study drug in DB treatment, have baseline value for PVR, evaluated As per assigned treatment. Here, 'N'(number of participants analyzed included population included participants with available baseline data.
Arm/Group Title Macitentan 10 mg Placebo
Hide Arm/Group Description:
Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Overall Number of Participants Analyzed 41 40
Geometric Mean (95% Confidence Interval)
Unit of Measure: ratio
0.86
(0.67 to 1.11)
1.04
(0.81 to 1.34)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan 10 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3951
Comments No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter ratio of geometric means
Estimated Value 0.874
Confidence Interval (2-Sided) 95%
0.639 to 1.196
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)
Hide Description mRAP is the mean blood pressure in the right atrium of the heart.
Time Frame From enrollment/baseline to Week 12 in the DB treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set(FAS): All randomized participants who received at least one dose of study drug in DB treatment, have baseline value for PVR, evaluated As per assigned treatment. Here, 'N'(number of participants analyzed included population included participants with available baseline data.
Arm/Group Title Macitentan 10 mg Placebo
Hide Arm/Group Description:
Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Overall Number of Participants Analyzed 42 42
Mean (Standard Deviation)
Unit of Measure: mmHg
mRAP at baseline 7.3  (3.74) 6.7  (3.60)
mRAP at Week 12 9.0  (5.32) 7.0  (2.93)
Change in mRAP from baseline to Week 12 1.6  (5.55) 0.3  (3.29)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan 10 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0637
Comments No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares (LS) mean difference
Estimated Value 1.67
Confidence Interval (2-Sided) 95%
-0.10 to 3.44
Estimation Comments The estimated value refers to a between-treatment analysis of change from baseline to Week 12 in mRAP (LS mean difference macitentan 10 mg - placebo).
6.Secondary Outcome
Title Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP)
Hide Description mPAP is the mean blood pressure inside the pulmonary artery which moves the blood from the heart to the lungs. Monitoring of mPAP can detect small changes in the function of the heart.
Time Frame From enrollment/baseline to Week 12 in the DB treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Macitentan 10 mg Placebo
Hide Arm/Group Description:
Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Overall Number of Participants Analyzed 43 42
Mean (Standard Deviation)
Unit of Measure: mmHg
mPAP at baseline 46.4  (7.89) 43.8  (8.52)
mPAP at Week 12 40.0  (7.61) 44.2  (8.26)
Change in mPAP at Week 12 -6.4  (4.94) 0.4  (7.04)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan 10 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares (LS) mean difference
Estimated Value -5.99
Confidence Interval (2-Sided) 95%
-8.40 to -3.57
Estimation Comments The estimated value refers to a between-treatment analysis of change from baseline to Week 12 in mPAP (LS mean difference macitentan 10 mg - placebo).
7.Secondary Outcome
Title Change From Baseline to Week 12 in Cardiac Index
Hide Description The cardiac index is an assessment of the function of the heart and relates the cardiac output to the patient's body size (the patient's body surface area).
Time Frame From enrollment/baseline to Week 12 in the DB treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Macitentan 10 mg Placebo
Hide Arm/Group Description:
Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Overall Number of Participants Analyzed 43 42
Mean (Standard Deviation)
Unit of Measure: L/min/m^2
Cardiac index at baseline 3.1  (0.83) 2.9  (0.76)
Cardiac index at Week 12 3.7  (1.04) 3.0  (0.82)
Change in cardiac index at Week 12 0.6  (0.8) 0.1  (0.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan 10 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0009
Comments No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares (LS) mean difference
Estimated Value 0.52
Confidence Interval (2-Sided) 95%
0.22 to 0.81
Estimation Comments The estimated value refers to a between-treatment analysis of change from baseline to Week 12 in cardiac index (LS mean difference macitentan 10 mg - placebo).
8.Secondary Outcome
Title Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR)
Hide Description TPR is the resistance the pulmonary circulation that must be overcome in order for the blood flow to occur. It takes into account the blood pressure in the pulmonary arteries and the cardiac output. It is an important measurement to monitor the function of the pulmonary circulation and detect disease progression or improvement.
Time Frame From enrollment/baseline to Week 12 in the DB treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Macitentan 10 mg Placebo
Hide Arm/Group Description:
Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Overall Number of Participants Analyzed 43 42
Mean (Standard Deviation)
Unit of Measure: dyn*sec/cm^5
TPR at baseline 689.3  (228.59) 671.5  (199.73)
TPR at Week 12 489.4  (157.13) 653.1  (197.88)
Change in TPR from baseline to Week 12 -199.8  (163.06) -18.3  (135.28)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan 10 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares (LS) mean difference
Estimated Value -171.48
Confidence Interval (2-Sided) 95%
-223.67 to -119.30
Estimation Comments The estimated value refers to a between-treatment analysis of change from baseline to Week 12 in TPR (LS mean difference macitentan 10 mg - placebo).
9.Secondary Outcome
Title Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2)
Hide Description SVO2 help assess tissue oxygen delivery. It describes the percentage of oxygen bound to hemoglobin in the blood which returns to the heart. This reflects the amount of residual oxygen in the blood after oxygen extraction by the tissues throughout the body.
Time Frame From enrollment/baseline to Week 12 in the DB treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set(FAS): All randomized participants who received at least one dose of study drug in DB treatment, have baseline value for PVR, evaluated As per assigned treatment. Here, 'N'(number of participants analyzed included population included participants with available baseline data.
Arm/Group Title Macitentan 10 mg Placebo
Hide Arm/Group Description:
Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
Overall Number of Participants Analyzed 41 41
Mean (Standard Deviation)
Unit of Measure: percent of oxygen bound to hemoglobin
SVO2 at baseline 69.2  (9.87) 69.9  (5.34)
SVO2 at Week 12 70.3  (7.07) 70.7  (8.58)
Change in SVO2 from baseline to Week 12 1.1  (6.70) 0.8  (7.81)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan 10 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9844
Comments No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares (LS) mean difference
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
-2.85 to 2.91
Estimation Comments The estimated value refers to a between-treatment analysis of change from baseline to Week 12 in SVO2 (LS mean difference macitentan 10 mg - placebo).
Time Frame Up to 3.4 years
Adverse Event Reporting Description The Safety Set (SS) included all participants who received at least one dose of study treatment.
 
Arm/Group Title Double-Blind (DB) Period: Macitentan 10 mg DB Period: Placebo Open-Label (OL) Period: Macitentan 10 mg OL Extension Period: Macitentan 10 mg
Hide Arm/Group Description Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks during DB treatment period. Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks during DB treatment period. Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period. Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period . Participants (who were randomized at French sites) who completed the core phase of the study as scheduled and opted to continue receiving OL study treatment continued to receive macitentan 10 mg in OLE period.
All-Cause Mortality
Double-Blind (DB) Period: Macitentan 10 mg DB Period: Placebo Open-Label (OL) Period: Macitentan 10 mg OL Extension Period: Macitentan 10 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/43 (0.00%)   0/42 (0.00%)   4/80 (5.00%)   2/33 (6.06%) 
Hide Serious Adverse Events
Double-Blind (DB) Period: Macitentan 10 mg DB Period: Placebo Open-Label (OL) Period: Macitentan 10 mg OL Extension Period: Macitentan 10 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   9/43 (20.93%)   6/42 (14.29%)   18/80 (22.50%)   11/33 (33.33%) 
Blood and lymphatic system disorders         
Anaemia * 1  0/43 (0.00%)  0/42 (0.00%)  2/80 (2.50%)  1/33 (3.03%) 
Iron Deficiency Anaemia * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Thrombocytopenia * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Cardiac disorders         
Atrial Fibrillation * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Left Ventricular Failure * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Right Ventricular Failure * 1  2/43 (4.65%)  1/42 (2.38%)  2/80 (2.50%)  2/33 (6.06%) 
Ear and labyrinth disorders         
Tinnitus * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Gastrointestinal disorders         
Abdominal Pain * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Ascites * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Duodenal Vascular Ectasia * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Gastrointestinal Angiodysplasia * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Gastrointestinal Haemorrhage * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Ileus * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Intestinal Obstruction * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Melaena * 1  0/43 (0.00%)  0/42 (0.00%)  2/80 (2.50%)  1/33 (3.03%) 
Portal Hypertensive Gastropathy * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
General disorders         
Death * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Localised Oedema * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Oedema Peripheral * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Hepatobiliary disorders         
Hepatic Failure * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Immune system disorders         
Hypersensitivity * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Infections and infestations         
Bronchitis * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Escherichia Pyelonephritis * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Gastroenteritis * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Lung Infection * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Pneumonia * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Staphylococcal Infection * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Urosepsis * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Localised Infection * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Injury, poisoning and procedural complications         
Fall * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Humerus Fracture * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Subdural Haematoma * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Vascular Procedure Complication * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Investigations         
Liver Function Test Increased * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Troponin I Increased * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Metabolism and nutrition disorders         
Diabetes Mellitus * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Fluid Overload * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Musculoskeletal and connective tissue disorders         
Intervertebral Disc Protrusion * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Osteitis * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Hepatocellular Carcinoma * 1  1/43 (2.33%)  2/42 (4.76%)  0/80 (0.00%)  0/33 (0.00%) 
Malignant Ascites * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Rectal Adenocarcinoma * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Testis Cancer * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Nervous system disorders         
Haemorrhagic Stroke * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Hepatic Encephalopathy * 1  1/43 (2.33%)  0/42 (0.00%)  2/80 (2.50%)  2/33 (6.06%) 
Presyncope * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Syncope * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Renal and urinary disorders         
Acute Kidney Injury * 1  1/43 (2.33%)  1/42 (2.38%)  1/80 (1.25%)  0/33 (0.00%) 
Chronic Kidney Disease * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Reproductive system and breast disorders         
Priapism * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Acute Pulmonary Oedema * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Alveolitis * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Asthma * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Haemoptysis * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Pulmonary Arterial Hypertension * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Pulmonary Toxicity * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Surgical and medical procedures         
Aneurysm Repair * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
1
Term from vocabulary, MedDRA Version 21.0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Double-Blind (DB) Period: Macitentan 10 mg DB Period: Placebo Open-Label (OL) Period: Macitentan 10 mg OL Extension Period: Macitentan 10 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   34/43 (79.07%)   32/42 (76.19%)   62/80 (77.50%)   30/33 (90.91%) 
Blood and lymphatic system disorders         
Anaemia * 1  2/43 (4.65%)  0/42 (0.00%)  9/80 (11.25%)  5/33 (15.15%) 
Increased Tendency to Bruise * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Iron Deficiency Anaemia * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Leukopenia * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Neutropenia * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Leukocytosis * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Pancytopenia * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Cardiac disorders         
Arrhythmia * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Atrial Fibrillation * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Bradycardia * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Cyanosis * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Palpitations * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  2/33 (6.06%) 
Pericarditis * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Right Ventricular Failure * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Tachycardia * 1  2/43 (4.65%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Ear and labyrinth disorders         
Ear Pain * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Tinnitus * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Vertigo * 1  0/43 (0.00%)  1/42 (2.38%)  1/80 (1.25%)  1/33 (3.03%) 
Eye disorders         
Cataract * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Conjunctival Hyperaemia * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Diabetic Retinopathy * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Diplopia * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Dry Eye * 1  0/43 (0.00%)  1/42 (2.38%)  2/80 (2.50%)  0/33 (0.00%) 
Eye Irritation * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Eye Oedema * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Eye Pruritus * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Eye Swelling * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Meibomian Gland Dysfunction * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Vision Blurred * 1  1/43 (2.33%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Conjunctival Haemorrhage * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Lacrimation Decreased * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Gastrointestinal disorders         
Abdominal Pain * 1  2/43 (4.65%)  1/42 (2.38%)  1/80 (1.25%)  0/33 (0.00%) 
Abdominal Pain Upper * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Anal Polyp * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Ascites * 1  0/43 (0.00%)  0/42 (0.00%)  2/80 (2.50%)  0/33 (0.00%) 
Constipation * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Diarrhoea * 1  1/43 (2.33%)  4/42 (9.52%)  1/80 (1.25%)  1/33 (3.03%) 
Dry Mouth * 1  1/43 (2.33%)  2/42 (4.76%)  0/80 (0.00%)  0/33 (0.00%) 
Duodenal Polyp * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Gastritis * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Gastritis Erosive * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Gastrooesophageal Reflux Disease * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Gingival Bleeding * 1  0/43 (0.00%)  1/42 (2.38%)  1/80 (1.25%)  0/33 (0.00%) 
Nausea * 1  1/43 (2.33%)  2/42 (4.76%)  3/80 (3.75%)  0/33 (0.00%) 
Pancreatic Cyst * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Portal Hypertensive Gastropathy * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Rectal Haemorrhage * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Varices Oesophageal * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Vomiting * 1  1/43 (2.33%)  0/42 (0.00%)  2/80 (2.50%)  1/33 (3.03%) 
Abdominal Discomfort * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Abdominal Distension * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Glossodynia * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
General disorders         
Asthenia * 1  0/43 (0.00%)  1/42 (2.38%)  4/80 (5.00%)  3/33 (9.09%) 
Chest Pain * 1  0/43 (0.00%)  1/42 (2.38%)  1/80 (1.25%)  1/33 (3.03%) 
Face Oedema * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Fatigue * 1  0/43 (0.00%)  1/42 (2.38%)  2/80 (2.50%)  0/33 (0.00%) 
Generalised Oedema * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Influenza Like Illness * 1  0/43 (0.00%)  0/42 (0.00%)  3/80 (3.75%)  2/33 (6.06%) 
Localised Oedema * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Malaise * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Non-Cardiac Chest Pain * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Oedema Peripheral * 1  10/43 (23.26%)  5/42 (11.90%)  13/80 (16.25%)  5/33 (15.15%) 
Pain * 1  0/43 (0.00%)  1/42 (2.38%)  1/80 (1.25%)  0/33 (0.00%) 
Peripheral Swelling * 1  2/43 (4.65%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Swelling * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Temperature Intolerance * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Hepatobiliary disorders         
Biliary Colic * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Cholelithiasis * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Hepatic Mass * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Jaundice * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Portal Vein Thrombosis * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Infections and infestations         
Bacterial Infection * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Bronchitis * 1  4/43 (9.30%)  0/42 (0.00%)  3/80 (3.75%)  13/33 (39.39%) 
Candida Infection * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Conjunctivitis * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Fungal Infection * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Furuncle * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Gastroenteritis * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Gastrointestinal Infection * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Herpes Virus Infection * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Herpes Zoster * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Influenza * 1  0/43 (0.00%)  1/42 (2.38%)  1/80 (1.25%)  0/33 (0.00%) 
Laryngitis * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Lower Respiratory Tract Infection * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Nasopharyngitis * 1  2/43 (4.65%)  2/42 (4.76%)  3/80 (3.75%)  2/33 (6.06%) 
Periodontitis * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Rhinitis * 1  2/43 (4.65%)  0/42 (0.00%)  4/80 (5.00%)  7/33 (21.21%) 
Sinusitis * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  2/33 (6.06%) 
Sinusitis Fungal * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Tonsillitis * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Tooth Abscess * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Upper Respiratory Tract Infection * 1  0/43 (0.00%)  1/42 (2.38%)  1/80 (1.25%)  0/33 (0.00%) 
Urinary Tract Infection * 1  2/43 (4.65%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Groin Abscess * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Onychomycosis * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Pharyngitis * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Injury, poisoning and procedural complications         
Anaemia Postoperative * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Contusion * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Eye Contusion * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Fall * 1  2/43 (4.65%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Foot Fracture * 1  1/43 (2.33%)  2/42 (4.76%)  0/80 (0.00%)  1/33 (3.03%) 
Head Injury * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Limb Injury * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Tooth Fracture * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Joint Dislocation * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Procedural Pain * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Investigations         
Ammonia Increased * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Aspartate Aminotransferase Increased * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Blood Bilirubin Increased * 1  0/43 (0.00%)  1/42 (2.38%)  1/80 (1.25%)  0/33 (0.00%) 
Blood Creatinine Increased * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Blood Glucose Increased * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Blood Potassium Decreased * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Blood Potassium Increased * 1  0/43 (0.00%)  1/42 (2.38%)  1/80 (1.25%)  0/33 (0.00%) 
Blood Sodium Decreased * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Blood Uric Acid Increased * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Blood Urine Present * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Brain Natriuretic Peptide Increased * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Coronavirus Test Positive * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Haematocrit Decreased * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Haemoglobin Decreased * 1  3/43 (6.98%)  0/42 (0.00%)  3/80 (3.75%)  0/33 (0.00%) 
Intestinal Transit Time Decreased * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Liver Function Test Abnormal * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Oxygen Saturation Decreased * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Platelet Count Decreased * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Total Bile Acids Increased * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Urine Output Decreased * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Intestinal Transit Time Abnormal * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Venous Pressure Jugular Increased * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Weight Increased * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Metabolism and nutrition disorders         
Decreased Appetite * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Fluid Retention * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  1/33 (3.03%) 
Folate Deficiency * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Gout * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Hypoglycaemia * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Hypokalaemia * 1  2/43 (4.65%)  6/42 (14.29%)  2/80 (2.50%)  2/33 (6.06%) 
Hypomagnesaemia * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Iron Deficiency * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Magnesium Deficiency * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Vitamin D Deficiency * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Musculoskeletal and connective tissue disorders         
Arthralgia * 1  1/43 (2.33%)  1/42 (2.38%)  2/80 (2.50%)  1/33 (3.03%) 
Back Pain * 1  2/43 (4.65%)  1/42 (2.38%)  1/80 (1.25%)  2/33 (6.06%) 
Bone Pain * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Dupuytren's Contracture * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Joint Swelling * 1  1/43 (2.33%)  1/42 (2.38%)  1/80 (1.25%)  0/33 (0.00%) 
Muscle Spasms * 1  0/43 (0.00%)  5/42 (11.90%)  3/80 (3.75%)  0/33 (0.00%) 
Musculoskeletal Chest Pain * 1  0/43 (0.00%)  0/42 (0.00%)  2/80 (2.50%)  0/33 (0.00%) 
Musculoskeletal Stiffness * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Myalgia * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Neck Pain * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Osteoarthritis * 1  0/43 (0.00%)  0/42 (0.00%)  2/80 (2.50%)  1/33 (3.03%) 
Pain in Extremity * 1  2/43 (4.65%)  3/42 (7.14%)  6/80 (7.50%)  1/33 (3.03%) 
Pain in Jaw * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Sebaceous Adenoma * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Nervous system disorders         
Balance Disorder * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Dizziness * 1  2/43 (4.65%)  2/42 (4.76%)  5/80 (6.25%)  1/33 (3.03%) 
Headache * 1  7/43 (16.28%)  7/42 (16.67%)  10/80 (12.50%)  1/33 (3.03%) 
Hepatic Encephalopathy * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Hypoaesthesia * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Intracranial Aneurysm * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Lethargy * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Neuralgia * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Presyncope * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Restless Legs Syndrome * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Sciatica * 1  1/43 (2.33%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Syncope * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Tremor * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Psychiatric disorders         
Alcohol Abuse * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Depression * 1  1/43 (2.33%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Insomnia * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  5/33 (15.15%) 
Sleep Disorder * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Renal and urinary disorders         
Acute Kidney Injury * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Oliguria * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Renal Failure * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Chromaturia * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Reproductive system and breast disorders         
Breast Mass * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Uterine Haemorrhage * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Gynaecomastia * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Bendopnoea * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Chronic Obstructive Pulmonary Disease * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Cough * 1  0/43 (0.00%)  3/42 (7.14%)  1/80 (1.25%)  0/33 (0.00%) 
Dry Throat * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Dyspnoea * 1  1/43 (2.33%)  2/42 (4.76%)  3/80 (3.75%)  3/33 (9.09%) 
Dyspnoea Exertional * 1  0/43 (0.00%)  0/42 (0.00%)  3/80 (3.75%)  0/33 (0.00%) 
Epistaxis * 1  0/43 (0.00%)  0/42 (0.00%)  2/80 (2.50%)  1/33 (3.03%) 
Hypoxia * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  2/33 (6.06%) 
Nasal Dryness * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Nasal Obstruction * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Oropharyngeal Pain * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  3/33 (9.09%) 
Portopulmonary Hypertension * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Pulmonary Arterial Hypertension * 1  1/43 (2.33%)  1/42 (2.38%)  1/80 (1.25%)  0/33 (0.00%) 
Sinus Congestion * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Sleep Apnoea Syndrome * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Sneezing * 1  1/43 (2.33%)  0/42 (0.00%)  0/80 (0.00%)  0/33 (0.00%) 
Haemoptysis * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Nasal Congestion * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Throat Irritation * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Skin and subcutaneous tissue disorders         
Blister * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Dermal Cyst * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Erythema * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Hyperkeratosis * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Pruritus * 1  0/43 (0.00%)  1/42 (2.38%)  3/80 (3.75%)  0/33 (0.00%) 
Psoriasis * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Rash * 1  1/43 (2.33%)  0/42 (0.00%)  2/80 (2.50%)  0/33 (0.00%) 
Umbilical Haemorrhage * 1  0/43 (0.00%)  0/42 (0.00%)  1/80 (1.25%)  0/33 (0.00%) 
Vitiligo * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Hyperhidrosis * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Social circumstances         
Alcohol Use * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Surgical and medical procedures         
Inguinal Hernia Repair * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Oesophageal Variceal Ligation * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  1/33 (3.03%) 
Injection * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Skin Neoplasm Excision * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Vascular disorders         
Flushing * 1  1/43 (2.33%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
Haematoma * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Hypotension * 1  2/43 (4.65%)  0/42 (0.00%)  3/80 (3.75%)  0/33 (0.00%) 
Peripheral Venous Disease * 1  0/43 (0.00%)  0/42 (0.00%)  0/80 (0.00%)  1/33 (3.03%) 
Orthostatic Hypotension * 1  0/43 (0.00%)  1/42 (2.38%)  0/80 (0.00%)  0/33 (0.00%) 
1
Term from vocabulary, MedDRA Version 21.0
*
Indicates events were collected by non-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 30 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.
Phone: +41 61 565 6565
EMail: clinical-trials-disclosure@its.jnj.com
Layout table for additonal information
Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT02382016    
Other Study ID Numbers: AC-055-404
First Submitted: March 3, 2015
First Posted: March 6, 2015
Results First Submitted: October 25, 2018
Results First Posted: November 23, 2018
Last Update Posted: November 5, 2019