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Clinical Study to Assess the Efficacy, Safety and Tolerability of Macitentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (MERIT-1)

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: NCT02021292
Recruitment Status : Completed
First Posted : December 27, 2013
Results First Posted : January 23, 2018
Last Update Posted : July 26, 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 Chronic Thromboembolic Pulmonary Hypertension
Interventions Drug: Macitentan
Drug: Placebo
Enrollment 80
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 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.
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description Macitentan 10 mg, oral tablet, to be taken once daily. Matching placebo oral tablet, to be taken once daily.
Period Title: Overall Study
Started 40 40
Completed 40 37
Not Completed 0 3
Reason Not Completed
Physician Decision             0             1
Lost to Follow-up             0             1
Death             0             1
Arm/Group Title Macitentan Placebo Total
Hide Arm/Group Description Macitentan 10 mg, oral tablet, to be taken once daily. Matching placebo oral tablet, to be taken once daily. Total of all reporting groups
Overall Number of Baseline Participants 40 40 80
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 40 participants 80 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
26
  65.0%
26
  65.0%
52
  65.0%
>=65 years
14
  35.0%
14
  35.0%
28
  35.0%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 40 participants 40 participants 80 participants
60.0
(20 to 80)
58.0
(23 to 78)
59.0
(20 to 80)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 40 participants 80 participants
Female
26
  65.0%
25
  62.5%
51
  63.7%
Male
14
  35.0%
15
  37.5%
29
  36.3%
Region of Enrollment   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 40 participants 80 participants
Asia
15
  37.5%
14
  35.0%
29
  36.3%
Eastern Europe
17
  42.5%
19
  47.5%
36
  45.0%
Latin America
1
   2.5%
1
   2.5%
2
   2.5%
Western Europe
7
  17.5%
6
  15.0%
13
  16.3%
[1]
Measure Analysis Population Description: Asia includes: China, South Korea, Thailand; Eastern Europe: Czech Republic, Hungary, Lithuania, Poland, Russia, Ukraine; Latin America: Mexico; Western Europe: Belgium, France, Germany, Switzerland, Turkey and the United Kingdom.
Body Mass Index (BMI)  
Median (Full Range)
Unit of measure:  Kg/m^2
Number Analyzed 40 participants 40 participants 80 participants
25.7
(19.8 to 47.5)
26.0
(18.3 to 36.2)
25.7
(18.3 to 47.5)
Time since diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH)  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 40 participants 40 participants 80 participants
1.7  (2.36) 1.2  (1.95) 1.5  (2.16)
6-minute walk distance (6MWD)  
Mean (Standard Deviation)
Unit of measure:  Meter
Number Analyzed 40 participants 40 participants 80 participants
353.0  (87.90) 351.2  (73.79) 352.1  (80.64)
Pulmonary vascular resistance (PVR)  
Mean (Standard Deviation)
Unit of measure:  Dynes*sec/cm^5
Number Analyzed 40 participants 40 participants 80 participants
929.2  (379.65) 984.3  (487.06) 956.8  (434.78)
WHO functional class   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 40 participants 80 participants
class I
0
   0.0%
0
   0.0%
0
   0.0%
class II
12
  30.0%
6
  15.0%
18
  22.5%
class III
28
  70.0%
33
  82.5%
61
  76.3%
class IV
0
   0.0%
1
   2.5%
1
   1.3%
[1]
Measure Description: 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.
Use of pulmonary arterial hypertension (PAH) medication  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 40 participants 80 participants
NO
16
  40.0%
15
  37.5%
31
  38.8%
YES
24
  60.0%
25
  62.5%
49
  61.3%
1.Primary Outcome
Title Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest.
Hide Description The primary efficacy endpoint is defined as the PVR at rest at Week 16 expressed as percent of baseline PVR at rest.
Time Frame From baseline to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description:
Macitentan 10 mg, oral tablet, to be taken once daily
Matching placebo oral tablet, to be taken once daily
Overall Number of Participants Analyzed 40 40
Geometric Mean (95% Confidence Interval)
Unit of Measure: percent of baseline PVR
73.0
(63.6 to 83.8)
87.2
(78.5 to 96.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments 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.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0410
Comments To control for multiplicity across the primary and secondary endpoints, all secondary endpoints were analyzed hierarchically based on the order and significance as pre-specified in the protocol eliminating further adjustment for multiple comparisons.
Method ANCOVA
Comments 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.
Method of Estimation Estimation Parameter ratio of geometric means
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.70 to 0.99
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 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 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description:
Macitentan 10 mg, oral tablet, to be taken once daily.
Matching placebo oral tablet, to be taken once daily.
Overall Number of Participants Analyzed 40 40
Mean (Standard Deviation)
Unit of Measure: meter
6MWD (m) at baseline 353.0  (87.90) 351.2  (73.79)
6MWD (m) at Week 24 388.0  (83.31) 352.2  (121.29)
Change in 6MWD (m) from baseline to Week 24 35.0  (52.52) 1.0  (83.24)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline in 6MWD at Week 24 is the same in the placebo and the macitentan group. Statistical model is ANCOVA including 6MWD at baseline as a covariate, with treatment as factor in the model.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0326
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter least squares (LS) mean difference
Estimated Value 34.04
Confidence Interval (2-Sided) 95%
2.9 to 65.2
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT).
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 24 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 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description:
Macitentan 10 mg, oral tablet, to be taken once daily.
Matching placebo oral tablet, to be taken once daily.
Overall Number of Participants Analyzed 40 40
Mean (Standard Deviation)
Unit of Measure: Score on a scale
Borg dyspnea index score at baseline 4.2  (2.52) 4.2  (2.14)
Borg dyspnea index score at Week 24 4.1  (2.52) 4.4  (2.45)
Change from baseline to Week 24 -0.1  (1.86) 0.3  (2.04)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is that the mean change from baseline is the same in the placebo and the macitentan group. Statistical model is Analysis of Covariance including Borg dyspnea index at baseline as a covariate, with Treatment as factor in the model.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3492
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter least squares (LS) mean difference
Estimated Value -0.39
Confidence Interval (2-Sided) 95%
-1.21 to 0.43
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24
Hide 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'.

Time Frame From baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description:
Macitentan 10 mg, oral tablet, to be taken once daily.
Matching placebo oral tablet, to be taken once daily.
Overall Number of Participants Analyzed 40 40
Measure Type: Count of Participants
Unit of Measure: Participants
WHO functional class I at baseline
0
   0.0%
0
   0.0%
WHO functional class II at baseline
12
  30.0%
6
  15.0%
WHO functional class III at baseline
28
  70.0%
33
  82.5%
WHO functional class IV at baseline
0
   0.0%
1
   2.5%
WHO functional class I at Week 24
3
   7.5%
1
   2.5%
WHO functional class II at Week 24
15
  37.5%
10
  25.0%
WHO functional class III at Week 24
22
  55.0%
26
  65.0%
WHO functional class IV at Week 24
0
   0.0%
3
   7.5%
Worsened
0
   0.0%
3
   7.5%
Not worsened - total
40
 100.0%
37
  92.5%
Not Worsened - unchanged
31
  77.5%
29
  72.5%
Not worsened - improved
9
  22.5%
8
  20.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The null hypothesis is the odds of worsening are the same in the placebo and the macitentan group. Logistic regression is used for Treatment Group vs. Placebo comparison to generate odds ratio, confidence levels, and p-values with treatment and WHO functional class at baseline as factors in the model.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0962
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.212
Confidence Interval (2-Sided) 95%
0.001 to 1.464
Estimation Comments [Not Specified]
5.Post-Hoc Outcome
Title Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Including Subjects With Corrected Hemodynamic Values.
Hide Description The main analysis of the primary efficacy endpoint of PVR has been repeated using the corrected hemodynamic values reported after the clinical database closure for 4 subjects (3 macitentan, 1 placebo). The primary efficacy endpoint is defined as the PVR at rest at Week 16 expressed as percent of baseline PVR at rest.
Time Frame From baseline to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description:
Macitentan 10 mg, oral tablet, to be taken once daily.
Matching placebo oral tablet, to be taken once daily.
Overall Number of Participants Analyzed 40 40
Geometric Mean (95% Confidence Interval)
Unit of Measure: Percent of baseline PVR
70.8
(62.8 to 79.9)
87.6
(78.9 to 97.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The same statistical model as for the predefined analysis was applied using corrected hemodynamic values for the 4 subjects with data corrections. 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 efficacy endpoint by means of an analysis of covariance (ANCOVA) model on the log(e) transformed % of baseline PVR at rest at Week 16.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0084
Comments To control for multiplicity across the primary and secondary endpoints, all secondary endpoints were analyzed hierarchically based on the order and significance as pre-specified in the protocol eliminating further adjustment for multiple comparisons.
Method ANCOVA
Comments 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.
Method of Estimation Estimation Parameter ratio of geometric means
Estimated Value 0.81
Confidence Interval (2-Sided) 95%
0.69 to 0.95
Estimation Comments [Not Specified]
6.Post-Hoc Outcome
Title Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Incorrect Hemodynamic Values.
Hide Description The main analysis of the primary efficacy endpoint of PVR has been repeated excluding 4 subjects (3 macitentan, 1 placebo) with incorrect PVR values. The corrected hemodynamic values were reported after the clinical database closure (see post-hoc analysis 1 above). The primary efficacy endpoint is defined as the PVR at rest at Week 16 expressed as percent of baseline PVR at rest.
Time Frame From baseline to Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Modified full analysis set
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description:
Macitentan 10 mg, oral tablet, to be taken once daily.
Matching placebo oral tablet, to be taken once daily.
Overall Number of Participants Analyzed 37 39
Geometric Mean (95% Confidence Interval)
Unit of Measure: Percent of baseline PVR
69.7
(61.6 to 78.8)
87.7
(78.9 to 97.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Macitentan, Placebo
Comments The same statistical model as for the predefined analysis was applied excluding the 4 subjects with incorrect hemodynamic values. 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 efficacy endpoint by means of an analysis of covariance (ANCOVA) model on the log(e) transformed % of baseline PVR at rest at Week 16.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0045
Comments To control for multiplicity across the primary and secondary endpoints, all secondary endpoints were analyzed hierarchically based on the order and significance as pre-specified in the protocol eliminating further adjustment for multiple comparisons.
Method ANCOVA
Comments 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.
Method of Estimation Estimation Parameter ratio of geometric means
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.67 to 0.93
Estimation Comments [Not Specified]
Time Frame From double-blind study treatment initiation up to 30 days after study treatment discontinuation
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Macitentan Placebo
Hide Arm/Group Description Macitentan 10 mg, oral tablet, to be taken once daily. Matching placebo oral tablet, to be taken once daily.
All-Cause Mortality
Macitentan Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/40 (0.00%)      2/40 (5.00%)    
Hide Serious Adverse Events
Macitentan Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/40 (7.50%)      7/40 (17.50%)    
Cardiac disorders     
Acute right ventricular failure  1  1/40 (2.50%)  1 0/40 (0.00%)  0
Cardiac failure  1  0/40 (0.00%)  0 1/40 (2.50%)  2
Right ventricular failure  1  0/40 (0.00%)  0 2/40 (5.00%)  2
Supraventricular tachycardia  1  0/40 (0.00%)  0 1/40 (2.50%)  1
General disorders     
Oedema peripheral  1  1/40 (2.50%)  1 0/40 (0.00%)  0
Infections and infestations     
Sepsis  1  0/40 (0.00%)  0 1/40 (2.50%)  1
Investigations     
Weight increased  1  1/40 (2.50%)  1 0/40 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Back pain  1  0/40 (0.00%)  0 1/40 (2.50%)  1
Nervous system disorders     
Haemorrhagic stroke  1  0/40 (0.00%)  0 1/40 (2.50%)  1
Respiratory, thoracic and mediastinal disorders     
Dyspnoea  1  0/40 (0.00%)  0 1/40 (2.50%)  1
Pulmonary hypertension  1  0/40 (0.00%)  0 2/40 (5.00%)  2
Vascular disorders     
Embolism  1  0/40 (0.00%)  0 1/40 (2.50%)  1
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   22/40 (55.00%)      19/40 (47.50%)    
Cardiac disorders     
Ventricular extrasystoles  1  0/40 (0.00%)  0 2/40 (5.00%)  2
General disorders     
Fatigue  1  2/40 (5.00%)  2 0/40 (0.00%)  0
Oedema peripheral  1  8/40 (20.00%)  10 4/40 (10.00%)  4
Infections and infestations     
Nasopharyngitis  1  1/40 (2.50%)  1 4/40 (10.00%)  4
Pharyngitis  1  2/40 (5.00%)  3 0/40 (0.00%)  0
Respiratory tract infection  1  0/40 (0.00%)  0 2/40 (5.00%)  2
Upper respiratory tract infection  1  3/40 (7.50%)  4 0/40 (0.00%)  0
Urinary tract infection  1  2/40 (5.00%)  2 1/40 (2.50%)  1
Investigations     
Alanine aminotransferase increased  1  0/40 (0.00%)  0 3/40 (7.50%)  4
Aspartate aminotransferase increased  1  0/40 (0.00%)  0 3/40 (7.50%)  4
Haemoglobin decreased  1  6/40 (15.00%)  7 0/40 (0.00%)  0
Metabolism and nutrition disorders     
Hypomagnesaemia  1  0/40 (0.00%)  0 2/40 (5.00%)  2
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/40 (2.50%)  1 3/40 (7.50%)  3
Back pain  1  0/40 (0.00%)  0 2/40 (5.00%)  2
Bone pain  1  2/40 (5.00%)  3 0/40 (0.00%)  0
Pain in extremity  1  3/40 (7.50%)  3 0/40 (0.00%)  0
Nervous system disorders     
Dizziness  1  2/40 (5.00%)  2 1/40 (2.50%)  1
Syncope  1  0/40 (0.00%)  0 3/40 (7.50%)  3
Respiratory, thoracic and mediastinal disorders     
Cough  1  2/40 (5.00%)  2 3/40 (7.50%)  3
Dyspnoea  1  2/40 (5.00%)  2 1/40 (2.50%)  1
Epistaxis  1  1/40 (2.50%)  1 2/40 (5.00%)  2
Pulmonary hypertension  1  0/40 (0.00%)  0 2/40 (5.00%)  2
Vascular disorders     
Hypotension  1  0/40 (0.00%)  0 2/40 (5.00%)  2
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 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.
EMail: clinical-trials-disclosure@actelion.com
Layout table for additonal information
Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT02021292    
Other Study ID Numbers: AC-055E201
First Submitted: December 20, 2013
First Posted: December 27, 2013
Results First Submitted: September 26, 2017
Results First Posted: January 23, 2018
Last Update Posted: July 26, 2018