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

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Macitentan

• Study Type: Interventional
• Enrollment (Actual): 284
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35243
      • Cardiovascular Associates of the Southeast, LLC
  • Arizona
    • Phoenix, Arizona, United States, 85006-2611
      • Pulmonary Associates, PA
    • Phoenix, Arizona, United States, 85054-4502
      • Mayo Clinic Arizona
  • California
    • Beverly Hills, California, United States, 90211
      • Cedars-Sinai Medical Center
    • Fresno, California, United States, 93701
      • UCSF Fresno
    • La Jolla, California, United States, 92093
      • UCSD Medical Center, Pulmonary Department
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Los Angeles, California, United States, 90073
      • VAGLAHS, VA Greater LA Healthcare System
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center
    • Stanford, California, United States, 94305-2200
      • Stanford University
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Research Institute
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Medstar Washington Hospital Center
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Brandon, Florida, United States, 33511
      • Bay Area Cardiology Associates, P.A.
    • Gainesville, Florida, United States, 32610
      • University of Florida Academic Health Center
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine, Jacksonville
    • Jacksonville, Florida, United States, 32224-1865
      • Mayo Clinic
    • Weston, Florida, United States, 33331-3609
      • Cleveland Clinic Florida
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Regents University
    • Austell, Georgia, United States, 30106
      • Georgia Clinical Research
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical
    • Oakbrook Terrace, Illinois, United States, 60181
      • Advocate Health and Hospitals Corporation
  • Iowa
    • Des Moines, Iowa, United States, 50325-7046
      • Chest Infectious Diseases and Critical Care Associates, PC
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics
    • Iowa City, Iowa, United States, 52245
      • Iowa City Heart Center
  • Kansas
    • Kansas City, Kansas, United States, 66160-0001
      • University of Kansas Medical Center
    • Topeka, Kansas, United States, 66606
      • Veritas Clinical Specialties
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University Of Louisville
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Pulmonary Associates
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston University Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5644
      • University of Michigan
    • Troy, Michigan, United States, 48085
      • Beaumont Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Midwest Pulmonary Consultants
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63143
      • Clayton Sleep Institute
    • Saint Louis, Missouri, United States, 63141
      • Mercy Clinic Pulmonology
    • Springfield, Missouri, United States, 65807
      • Ferrell-Duncan Clinic
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Nebraska Pulmonary Specialties
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Jersey
    • Union, New Jersey, United States, 07083
      • Pulmonary and Critical Care Associates
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center, Weiler Division
    • Buffalo, New York, United States, 14203
      • Buffalo General Medical Center
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New Hyde Park, New York, United States, 11040
      • North Shore-LIJ/Advance Lung Disease Clinic
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
    • Matthews, North Carolina, United States, 28105
      • Novant Health Pulmonary and Critical Care
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Christ Hospital
    • Cincinnati, Ohio, United States, 45267
      • UC Health/University of Cincinnati
    • Cleveland, Ohio, United States, 45219
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43221
      • The Ohio State University
    • Columbus, Ohio, United States, 43210-1252
      • Davis Heart & Lung Research Institute
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97220
      • The Oregon Clinic
    • Portland, Oregon, United States, 97225
      • CDA for Oregon Pulmonary Associate
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple Lung Center
    • Philadelphia, Pennsylvania, United States, 19107-5109
      • Thomas Jefferson University, Division on Pulmonary and Critical Care
    • Pittsburgh, Pennsylvania, United States, 15123
      • UPMC
    • Pittsburgh, Pennsylvania, United States, 15212-4756
      • Allegheny General Hospital
    • Wyomissing, Pennsylvania, United States, 19610
      • Berks Schuylkill Respiratory Specialists, Ltd.
    • York, Pennsylvania, United States, 17402-8200
      • Wellspan Lung, Sleep and Critical Care
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57108
      • Sioux Falls Cardiovascular, PC
  • Texas
    • Dallas, Texas, United States, 75390-8550
      • UT Southwestern Medical Center
    • Dallas, Texas, United States, 75204
      • Baylor Research Institute (BRI)
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston
    • Houston, Texas, United States, 77030-2348
      • Baylor College of Medicine
    • Temple, Texas, United States, 76508
      • Scott & White Memorial Hospital
  • Virginia
    • Falls Church, Virginia, United States, 22042-3307
      • Inova Heart and Vascular Institue / Inova Fairfax Hospital
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk General Hospital
  • Washington
    • Spokane, Washington, United States, 99204
      • Pulmonary & Sleep Research
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin School of Medicine and Public Health
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora Cardiovascular Services

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Macitentan; Macitentan tablet, dose of 10 mg, once daily	Drug: Macitentan; Macitentan tablet, dose of 10 mg, once daily; Other Names: Macitentan / ACT-064992

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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.
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).

Collaborators and Investigators

• Sponsor: Actelion
• Investigators: Study Chair: Alain Romero, PharmD, PhD, Actelion Pharmaceuticals US, Inc

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2013
• Primary Completion (ACTUAL): November 1, 2015
• Study Completion (ACTUAL): November 1, 2015

Study Registration Dates

• First Submitted: March 27, 2013
• First Submitted That Met QC Criteria: April 24, 2013
• First Posted (ESTIMATE): April 29, 2013

Study Record Updates

• Last Update Posted (ACTUAL): February 26, 2019
• Last Update Submitted That Met QC Criteria: February 5, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Pulmonary Arterial Hypertension; PAH-SYMPACT; psychometric instrument
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Molecular Mechanisms of Pharmacological Action; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Macitentan
• Other Study ID Numbers: AC-055-401