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Clinical Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the PAH-SYMPACT Instrument

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ClinicalTrials.gov Identifier: NCT01841762
Recruitment Status : Completed
First Posted : April 29, 2013
Results First Posted : October 31, 2018
Last Update Posted : February 26, 2019
Sponsor:
Information provided by (Responsible Party):
Actelion

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Pulmonary Arterial Hypertension
Intervention Drug: Macitentan
Enrollment 284
Recruitment Details Seventy-nine sites recruited subjects to reach a total of 284 total enrolled, with 335 subjects entered screening. Institution-based and community clinic sites, with pulmonary arterial hypertension expertise, were included in the study. The first subject, first visit occurred on 25 APR 2013 and last subject, last visit occurred on 05 OCT 2015
Pre-assignment Details Screen failures total 51 subjects. Six subjects were removed from the full analysis set of 284 due to exclusion. The per protocol set includes 278 subjects total (97.9% of enrollment), utilized for all validation and exploratory ePRO analyses. The safety set, encompassing all enrolled subjects receiving study treatment, includes 284 subjects.
Arm/Group Title Macitentan
Hide Arm/Group Description Macitentan tablet, dose of 10 mg, once daily
Period Title: Screening Period
Started 335
Completed 284
Not Completed 51
Reason Not Completed
Other, 2 PAH-SYMPACT cycles not complete             51
Period Title: Treatment Period
Started 284
Completed 252
Not Completed 32
Reason Not Completed
Adverse Event             16
Death             1
Withdrawal by Subject             7
Lost to Follow-up             1
Physician Decision             2
Other, including non-compliance             5
Period Title: Post-Treatment Safety Follow-Up Period
Started 284
Completed 269
Not Completed 15
Reason Not Completed
Death             1
Withdrawal by Subject             7
Lost to Follow-up             6
Other, administrative error             1
Arm/Group Title Macitentan
Hide Arm/Group Description Macitentan tablet, dose of 10 mg, once daily
Overall Number of Baseline Participants 284
Hide Baseline Analysis Population Description
The number of subjects who dosed on macitentan in the trial was 284.
Age, Categorical   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 284 participants
<=18 years
0
   0.0%
Between 18 and 65 years
167
  58.8%
>=65 years
117
  41.2%
[1]
Measure Description: Age of patients reported.
Age, Continuous   [1] [2] 
Mean (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 284 participants
59.7
(52.0 to 69.0)
[1]
Measure Description: Full Analysis Set of 284 patients.
[2]
Measure Analysis Population Description: Each respective row population complies with overall number of patients.
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 284 participants
Female
223
  78.5%
Male
61
  21.5%
[1]
Measure Description: A total of 284 participants analyzed.
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 284 participants
Hispanic or Latino
27
   9.5%
Not Hispanic or Latino
257
  90.5%
Unknown or Not Reported
0
   0.0%
[1]
Measure Description: A total of 284 participants analyzed.
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 284 participants
American Indian or Alaska Native
2
   0.7%
Asian
8
   2.8%
Native Hawaiian or Other Pacific Islander
1
   0.4%
Black or African American
35
  12.3%
White
228
  80.3%
More than one race
10
   3.5%
Unknown or Not Reported
0
   0.0%
[1]
Measure Description: A total of 284 participants analyzed.
1.Primary Outcome
Title Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT)
Hide Description Content validity of the PAH-SYMPACT was assessed using item performance, exploratory and confirmatory factor analysis. The final item content and domain structure of PAH-SYMPACT was determined based on these analyses from the Steering Committee (expert clinicians) and findings from the qualitative research done with patients previously.
Time Frame From Screening Visit (Day -14) to End of Treatment (EOT) Visit (Visit 4, Week 16)
Hide Outcome Measure Data
Hide Analysis Population Description
Per Protocol Set (PPS) comprised all patients included in the Full Analysis Set (FAS) who had no major protocol violations.
Arm/Group Title Macitentan
Hide Arm/Group Description:
Macitentan tablet, dose of 10 mg, once daily
Overall Number of Participants Analyzed 278
Measure Type: Number
Unit of Measure: Items
Item number in symptoms part of baseline 16
Item number in symptoms part at Week 16 11
Item number in impacts part at baseline 25
Item number in impacts part at Week 16 11
2.Primary Outcome
Title Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability.
Hide Description The reliability of the PAH-SYMPACT is assessed by test-retest reliability. Intra-class correlation coefficients (ICCs) assess test-retest reliability for the symptom and impact part scores as well as domains. ICCs equal to or greater than 0.70 are considered to demonstrate good test-retest reliability for total and domain scores.
Time Frame From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.
Hide Outcome Measure Data
Hide Analysis Population Description
Per Protocol Set of 278 patients.
Arm/Group Title Macitentan
Hide Arm/Group Description:
Macitentan tablet, dose of 10 mg, once daily
Overall Number of Participants Analyzed 278
Measure Type: Number
Unit of Measure: Intra-class correlation coefficient
ICCs of Cardiopulmonary Symptoms domain 0.94
ICCs of Cardiovascular Symptoms domain 0.93
ICCs of Physical Impacts domain 0.91
ICCs of Cognitive/Emotional Impacts domain 0.84
3.Primary Outcome
Title Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability.
Hide Description The reliability of the PAH-SYMPACT is assessed by internal consistency reliability. This was determined using Cronbach's alpha-a value on an internal level scale from 0 to 1.0 with higher scores indicating a more-reliable (precise) instrument.
Time Frame From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol set of 278.
Arm/Group Title Macitentan
Hide Arm/Group Description:
Macitentan tablet, dose of 10 mg, once daily
Overall Number of Participants Analyzed 278
Measure Type: Number
Unit of Measure: Ratio of variance
Cronbach's Alpha for Cardiopulmonary Symptoms 0.81
Cronbach's Alpha for Cardiovascular Symptoms 0.88
Cronbach's Alpha for Physical Impacts Domain 0.92
Cronbach's Alpha for Cognitive/Emotional Impacts 0.87
4.Secondary Outcome
Title Number of Participants With Treatment-emergent Adverse Events, Serious Adverse Events, and Adverse Events Resulting in Patient Study Drug Discontinuation Between Time Periods, BL to End of Study Visit (EoS, Week 16+30 Days for Follow-up Safety Visits)
Hide Description Safety events are reported and documented as defined in study protocol.
Time Frame From Day 1 (Baseline Visit) to End of Study visit (EoS).
Hide Outcome Measure Data
Hide Analysis Population Description
Safety set of 284 subjects.
Arm/Group Title Macitentan
Hide Arm/Group Description:
Macitentan tablet, dose of 10 mg, once daily
Overall Number of Participants Analyzed 284
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with AEs
228
  80.3%
Participants with severe intensity AEs
36
  12.7%
Participants with SAEs
49
  17.3%
Participants prematurely discontinued study drug
17
   6.0%
5.Other Pre-specified Outcome
Title Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16.
Hide Description Sensitivity to change is an aspect of construct validity and represents the instrument's ability to detect underlying change. Sensitivity to change was examined to compare the difference in mean score in each domain of the PAH-SYMPACT. The symptoms and impacts domains consisted of 11 items each reported on a 7-point Likert Scale (from 0=no symptom/with no difficulty at all/not at all to 6=very severe symptoms/very much/extremely/not able at all). An average symptoms domain score is determined based on the daily scores of the containing items. An average impacts domain score is determined based on the items in the domain.
Time Frame From Screening period (Days -7 to -1) to Week 16 (7-day period prior to Week 16 visit).
Hide Outcome Measure Data
Hide Analysis Population Description
Per Protocol Set of 278 subjects.
Arm/Group Title Macitentan
Hide Arm/Group Description:
Macitentan tablet, dose of 10 mg, once daily
Overall Number of Participants Analyzed 278
Median (Inter-Quartile Range)
Unit of Measure: Score on a scale
Cardiopulmonary Symptoms domain score at baseline
1.0
(0.5 to 1.3)
Cardiopulmonary Symptoms domain score at Week 8
0.8
(0.4 to 1.2)
Cardiopulmonary Symptoms domain score at Week 16
0.7
(0.4 to 1.2)
Cardiovascular Symptoms domain score at baseline
0.4
(0.1 to 0.7)
Cardiovascular Symptoms domain score at Week 8
0.2
(0.0 to 0.5)
Cardiovascular Symptoms domain score at Week 16
0.2
(0.0 to 0.5)
Physical Impacts domain score at baseline
1.3
(0.6 to 2.0)
Physical Impacts domain score at Week 8
1.0
(0.4 to 1.7)
Physical Impacts domain score at Week 16
0.9
(0.4 to 1.6)
Cogn./Emotional Impacts domain score at baseline
0.8
(0.3 to 1.5)
Cogn./Emotional Impacts domain score at Week 8
0.8
(0.3 to 1.3)
Cogn./Emotional Impacts domain score at Week 16
0.5
(0.5 to 1.3)
Time Frame Treatment-emergent adverse events were collected from study drug initiation until Day 30 after study drug discontinuation.
Adverse Event Reporting Description Study sites were instructed to document any adverse change from the patient's baseline condition, i.e., any unfavorable and unintended sign, including an abnormal laboratory finding, symptom, or disease that occurs during the course of the study, whether or not considered related to the study drug. Counts and percentages of subjects who experienced adverse events were tabulated by system organ class and preferred term within each system organ class, as well as by individual preferred term.
 
Arm/Group Title Macitentan
Hide Arm/Group Description Macitentan tablet, dose of 10 mg, once daily
All-Cause Mortality
Macitentan
Affected / at Risk (%)
Total   1/284 (0.35%) 
Hide Serious Adverse Events
Macitentan
Affected / at Risk (%)
Total   49/284 (17.25%) 
Blood and lymphatic system disorders   
Anaemia  1  3/284 (1.06%) 
Hypoglycaemia  1  2/284 (0.70%) 
Angina Unstable  1  1/284 (0.35%) 
Cardiac disorders   
Cardiac Failure  1  3/284 (1.06%) 
Cardiac Failure Congestive  1  3/284 (1.06%) 
Atrial Fibrillation  1  1/284 (0.35%) 
Atrial Flutter  1  1/284 (0.35%) 
Gastrointestinal disorders   
Small Intestinal Obstruction  1  3/284 (1.06%) 
Diverticulitis  1  2/284 (0.70%) 
General disorders   
Chest Pain  1  4/284 (1.41%) 
Fluid Overload  1  3/284 (1.06%) 
Nervous system disorders   
Vertigo  1  2/284 (0.70%) 
Cerebrovascular Accident  1  1/284 (0.35%) 
Renal and urinary disorders   
Renal Failure Acute  1  3/284 (1.06%) 
Bladder Transitional Cell Carcinoma  1  1/284 (0.35%) 
Respiratory, thoracic and mediastinal disorders   
Dyspnoea  1  5/284 (1.76%) 
Pneumonia  1  4/284 (1.41%) 
Hypoxia  1  3/284 (1.06%) 
Acute Respiratory Disorder  1  2/284 (0.70%) 
Surgical and medical procedures   
Transfusion  1  2/284 (0.70%) 
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
Affected / at Risk (%)
Total   228/284 (80.28%) 
Blood and lymphatic system disorders   
Oedema peripheral  1  50/284 (17.61%) 
Anaemia  1  16/284 (5.63%) 
Ear and labyrinth disorders   
Dizziness  1  19/284 (6.69%) 
General disorders   
Fatigue  1  22/284 (7.75%) 
Nausea  1  17/284 (5.99%) 
Nervous system disorders   
Headache  1  36/284 (12.68%) 
Respiratory, thoracic and mediastinal disorders   
Dyspnoea  1  34/284 (11.97%) 
Cough  1  26/284 (9.15%) 
Nasal congestion  1  23/284 (8.10%) 
Upper Respiratory Tract Infection  1  19/284 (6.69%) 
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. Neither the institution nor the investigator should permit publication during such a review period.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Scott Tsurutani / Associate Director, Clinical Operations
Organization: Actelion Pharmaceuticals US, Inc.
Phone: 6508086586
EMail: scott.tsurutani@actelion.com
Layout table for additonal information
Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT01841762    
Other Study ID Numbers: AC-055-401
First Submitted: March 27, 2013
First Posted: April 29, 2013
Results First Submitted: May 30, 2017
Results First Posted: October 31, 2018
Last Update Posted: February 26, 2019