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

Pulmonary Arterial Hypertension Clinical Trial

Official title:

A Multi-center, Open-label, Single-arm, Phase 3b Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the PAH-SYMPACT Instrument

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01841762
• Other study ID #: AC-055-401
• Status: Completed
• Phase: Phase 3
• Start date: April 1, 2013
• Est. completion date: November 1, 2015

Study information

• Verified date: February 2019
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

SYMPHONY is prospective, multi-center, open-label, single-arm, Phase 3b psychometric validation study of the PAH-SYMPACT, a new quality of life questionnaire for patients with pulmonary arterial hypertension. Patients will be in the study for 5 1/2 months, 4 months of which they will receive macitentan, 10 mg, once daily.

The primary objectives are to demonstrate the final content validity of the PAH SYMPACT instrument, to demonstrate the psychometric characteristics of reliability and construct validity of the PAH-SYMPACT instrument, and to demonstrate the ability of the PAH SYMPACT instrument to detect change. The secondary objective is to assess the safety of macitentan in patients with pulmonary arterial hypertension. The exploratory objective is to explore the effects of macitentan on PAH symptoms and their impact (as measured by the PAH-SYMPACT) in patients with pulmonary arterial hypertension.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 284
• Est. completion date: November 1, 2015
• Est. primary completion date: November 1, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Signed informed consent prior to initiation of any study mandated procedure

2. Patients with symptomatic PAH in World Health Organization (WHO) Functional Class (FC) II to IV

3. Patients with PAH belonging to one of the following subgroups of the Dana Point Clinical Classification Group 1:

1. Idiopathic, or

2. Heritable, or

3. Drug or toxin induced, or

4. Associated with one of the following:

i. Connective tissue disease ii. Congenital heart disease with simple systemic-to-pulmonary shunt at least one year after surgical repair iii. HIV infection

4. Documented hemodynamic diagnosis of PAH by right heart catheterization - performed at any time prior to Screening showing:

1. Resting mean pulmonary arterial pressure (mPAP) = 25 mmHg and

2. Resting pulmonary vascular resistance (PVR) > 240 dyn•s•cm-5 and

3. Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) = 15 mmHg

5. 6-minute walk distance (6MWD) = 150 m at Screening

6. Able to fluently speak and read English

7. For patients on phosphodiesterase type-5 inhibitors (PDE5i), inhaled prostacyclin analogues, or calcium channel blockers, stable doses for at least 3 months prior to Visit 2

8. For patients on oral diuretics, stable doses for at least 4 weeks prior to Visit 2

9. Men or women aged 18 or older

1. A woman is considered to be of childbearing potential unless she:

• Has not yet entered puberty, or

• Does not have a uterus, or

• Has gone through menopause (has not had a period for at least 12 months for natural reasons, or who has had their ovaries removed)

2. A women of childbearing potential is eligible only if she meets both criteria below:

• Has a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline and agree to perform monthly urine pregnancy tests, and

• Agrees to use two methods of contraception (one method for patients with a progesterone implant or an intrauterine device or tubal sterilization) from the Screening Visit 1 until one month after study drug discontinuation

Exclusion Criteria:

1. Moderate to severe obstructive lung disease: forced expiratory volume in one second (FEV1) / forced vital capacity < 70% and FEV1 < 65% of predicted value after bronchodilator administration

2. Moderate to severe restrictive lung disease: total lung capacity < 60% of predicted value

3. Hemoglobin < 75% of the lower limit of the normal range at screening

4. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of normal (ULN) at screening

5. Estimated creatinine clearance < 30 mL/min at screening

6. Systolic blood pressure (SBP) < 90 mmHg at screening

7. Body weight < 40 kg at screening

8. Known concomitant life-threatening diseases with a life expectancy of < 12 months

9. Any condition that prevents compliance with the protocol or adherence to therapy

10. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to Visit 2, or scheduled to receive any of these compounds, other than macitentan, during the trial

11. Treatment with intravenous or subcutaneous prostacyclin or prostacyclin analogs within 3 months prior to Visit 2, or scheduled to receive any of these compounds during the trial

12. Treatment with riociguat within 3 months prior to Visit 2, or scheduled to receive riociguat during the trial

13. Treatment with strong cytochrome P450 (CYP) 3A4 inducers or inhibitors within 4 weeks prior to Visit 2

14. Recently started (< 8 weeks prior to Visit 2) or planned cardio-pulmonary rehabilitation program based on exercise

15. Females who are lactating or pregnant (positive Screening or Baseline pregnancy test) or plan to become pregnant during the study

16. Known hypersensitivity to macitentan or its excipients or drugs of the same class

17. Treatment with another investigational drug within 3 months prior to Visit 2

18. Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Macitentan
Macitentan tablet, dose of 10 mg, once daily

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Georgia Regents University	Augusta	Georgia
United States	University of Colorado	Aurora	Colorado
United States	Georgia Clinical Research	Austell	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Cedars-Sinai Medical Center	Beverly Hills	California
United States	Cardiovascular Associates of the Southeast, LLC	Birmingham	Alabama
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston University Medical Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Bay Area Cardiology Associates, P.A.	Brandon	Florida
United States	Montefiore Medical Center, Weiler Division	Bronx	New York
United States	Buffalo General Medical Center	Buffalo	New York
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Medical	Chicago	Illinois
United States	The Christ Hospital	Cincinnati	Ohio
United States	UC Health/University of Cincinnati	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Davis Heart & Lung Research Institute	Columbus	Ohio
United States	The Ohio State University	Columbus	Ohio
United States	Baylor Research Institute (BRI)	Dallas	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Chest Infectious Diseases and Critical Care Associates, PC	Des Moines	Iowa
United States	Inova Heart and Vascular Institue / Inova Fairfax Hospital	Falls Church	Virginia
United States	UCSF Fresno	Fresno	California
United States	University of Florida Academic Health Center	Gainesville	Florida
United States	Baylor College of Medicine	Houston	Texas
United States	The University of Texas Health Science Center at Houston	Houston	Texas
United States	Iowa City Heart Center	Iowa City	Iowa
United States	University of Iowa Hospitals & Clinics	Iowa City	Iowa
United States	Mayo Clinic	Jacksonville	Florida
United States	University of Florida College of Medicine, Jacksonville	Jacksonville	Florida
United States	Midwest Pulmonary Consultants	Kansas City	Missouri
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	UCSD Medical Center, Pulmonary Department	La Jolla	California
United States	Nebraska Pulmonary Specialties	Lincoln	Nebraska
United States	University of California Los Angeles	Los Angeles	California
United States	VAGLAHS, VA Greater LA Healthcare System	Los Angeles	California
United States	Kentuckiana Pulmonary Associates	Louisville	Kentucky
United States	University of Louisville	Louisville	Kentucky
United States	University of Wisconsin School of Medicine and Public Health	Madison	Wisconsin
United States	Novant Health Pulmonary and Critical Care	Matthews	North Carolina
United States	Aurora Cardiovascular Services	Milwaukee	Wisconsin
United States	Winthrop University Hospital	Mineola	New York
United States	North Shore-LIJ/Advance Lung Disease Clinic	New Hyde Park	New York
United States	Beth Israel Medical Center	New York	New York
United States	Columbia University Medical Center	New York	New York
United States	Sentara Norfolk General Hospital	Norfolk	Virginia
United States	Advocate Health and Hospitals Corporation	Oakbrook Terrace	Illinois
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Temple Lung Center	Philadelphia	Pennsylvania
United States	Thomas Jefferson University, Division on Pulmonary and Critical Care	Philadelphia	Pennsylvania
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	Pulmonary Associates, PA	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	UPMC	Pittsburgh	Pennsylvania
United States	CDA for Oregon Pulmonary Associate	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	The Oregon Clinic	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Clayton Sleep Institute	Saint Louis	Missouri
United States	Mercy Clinic Pulmonology	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California San Francisco Medical Center	San Francisco	California
United States	Sioux Falls Cardiovascular, PC	Sioux Falls	South Dakota
United States	Pulmonary & Sleep Research	Spokane	Washington
United States	Ferrell-Duncan Clinic	Springfield	Missouri
United States	Stanford University	Stanford	California
United States	Scott & White Memorial Hospital	Temple	Texas
United States	Veritas Clinical Specialties	Topeka	Kansas
United States	Los Angeles Biomedical Research Institute	Torrance	California
United States	Beaumont Hospital	Troy	Michigan
United States	Pulmonary and Critical Care Associates	Union	New Jersey
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Medstar Washington Hospital Center	Washington	District of Columbia
United States	Cleveland Clinic Florida	Weston	Florida
United States	Berks Schuylkill Respiratory Specialists, Ltd.	Wyomissing	Pennsylvania
United States	Wellspan Lung, Sleep and Critical Care	York	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16.	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.	From Screening period (Days -7 to -1) to Week 16 (7-day period prior to Week 16 visit).
Primary	Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT)	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.	From Screening Visit (Day -14) to End of Treatment (EOT) Visit (Visit 4, Week 16)
Primary	Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability.	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.	From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.
Primary	Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability.	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.	From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.
Secondary	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)	Safety events are reported and documented as defined in study protocol.	From Day 1 (Baseline Visit) to End of Study visit (EoS).