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

• 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: Actelion
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		Macitentan
Arm/Group Description		Macitentan tablet, dose of 10 mg, once daily
Overall Number of Baseline Participants		284
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.

Outcome Measures

1. Primary Outcome

Title	Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT)
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)

Outcome Measure Data

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
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.
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.

Outcome Measure Data

Analysis Population Description

Per Protocol Set of 278 patients.

Arm/Group Title	Macitentan
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.
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.

Outcome Measure Data

Analysis Population Description

Per protocol set of 278.

Arm/Group Title	Macitentan
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)
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).

Outcome Measure Data

Analysis Population Description

Safety set of 284 subjects.

Arm/Group Title	Macitentan
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.
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).

Outcome Measure Data

Analysis Population Description

Per Protocol Set of 278 subjects.

Arm/Group Title	Macitentan
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)

Adverse Events

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
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
All-Cause Mortality
	Macitentan
	Affected / at Risk (%)
Total	1/284 (0.35%)
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
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

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Scott Tsurutani / Associate Director, Clinical Operations
• Organization: Actelion Pharmaceuticals US, Inc.
• Phone: 6508086586
• EMail: scott.tsurutani@actelion.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Chin KM, Gomberg-Maitland M, Channick RN, Cuttica MJ, Fischer A, Frantz RP, Hunsche E, Kleinman L, McConnell JW, McLaughlin VV, Miller CE, Zamanian RT, Zastrow MS, Badesch DB. Psychometric Validation of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Questionnaire: Results of the SYMPHONY Trial. Chest. 2018 Oct;154(4):848-861. doi: 10.1016/j.chest.2018.04.027. Epub 2018 Apr 26.

• 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