Clinical trial NCT01841762: Clinical Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the PAH-SYMPACT Instrument
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Keywords: PAH-SYMPACT
Pulmonary Arterial Hypertension
psychometric instrument
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2013-04-29
Enrollment: 284
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT)
timeFrame: From Screening Visit (Day -14) to End of Treatment (EOT) Visit (Visit 4, Week 16)
measure: Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability.
timeFrame: From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.
measure: Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability.
timeFrame: From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.
Secondary outcomes:
measure: 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)
timeFrame: From Day 1 (Baseline Visit) to End of Study visit (EoS).
Other outcomes:
measure: Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16.
timeFrame: From Screening period (Days -7 to -1) to Week 16 (7-day period prior to Week 16 visit).
Locations:
city: Birmingham
country: United States
facility: Cardiovascular Associates of the Southeast, LLC
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Pulmonary Associates, PA
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Beverly Hills
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Fresno
country: United States
facility: UCSF Fresno
state: California
city: La Jolla
country: United States
facility: UCSD Medical Center, Pulmonary Department
state: California
city: Los Angeles
country: United States
facility: VAGLAHS, VA Greater LA Healthcare System
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Torrance
country: United States
facility: Los Angeles Biomedical Research Institute
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Washington
country: United States
facility: Medstar Washington Hospital Center
state: District of Columbia
city: Brandon
country: United States
facility: Bay Area Cardiology Associates, P.A.
state: Florida
city: Gainesville
country: United States
facility: University of Florida Academic Health Center
state: Florida
city: Jacksonville
country: United States
facility: University of Florida College of Medicine, Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Augusta
country: United States
facility: Georgia Regents University
state: Georgia
city: Austell
country: United States
facility: Georgia Clinical Research
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical
state: Illinois
city: Oakbrook Terrace
country: United States
facility: Advocate Health and Hospitals Corporation
state: Illinois
city: Des Moines
country: United States
facility: Chest Infectious Diseases and Critical Care Associates, PC
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Iowa City
country: United States
facility: Iowa City Heart Center
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Topeka
country: United States
facility: Veritas Clinical Specialties
state: Kansas
city: Louisville
country: United States
facility: Kentuckiana Pulmonary Associates
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Troy
country: United States
facility: Beaumont Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Midwest Pulmonary Consultants
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Clinic Pulmonology
state: Missouri
city: Saint Louis
country: United States
facility: Clayton Sleep Institute
state: Missouri
city: Springfield
country: United States
facility: Ferrell-Duncan Clinic
state: Missouri
city: Lincoln
country: United States
facility: Nebraska Pulmonary Specialties
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Union
country: United States
facility: Pulmonary and Critical Care Associates
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center, Weiler Division
state: New York
city: Buffalo
country: United States
facility: Buffalo General Medical Center
state: New York
city: Mineola
country: United States
facility: Winthrop University Hospital
state: New York
city: New Hyde Park
country: United States
facility: North Shore-LIJ/Advance Lung Disease Clinic
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Matthews
country: United States
facility: Novant Health Pulmonary and Critical Care
state: North Carolina
city: Cincinnati
country: United States
facility: The Christ Hospital
state: Ohio
city: Cincinnati
country: United States
facility: UC Health/University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Davis Heart & Lung Research Institute
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: The Oregon Clinic
state: Oregon
city: Portland
country: United States
facility: CDA for Oregon Pulmonary Associate
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University, Division on Pulmonary and Critical Care
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple Lung Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Wyomissing
country: United States
facility: Berks Schuylkill Respiratory Specialists, Ltd.
state: Pennsylvania
city: York
country: United States
facility: Wellspan Lung, Sleep and Critical Care
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sioux Falls Cardiovascular, PC
state: South Dakota
city: Dallas
country: United States
facility: Baylor Research Institute (BRI)
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
city: Temple
country: United States
facility: Scott & White Memorial Hospital
state: Texas
city: Falls Church
country: United States
facility: Inova Heart and Vascular Institue / Inova Fairfax Hospital
state: Virginia
city: Norfolk
country: United States
facility: Sentara Norfolk General Hospital
state: Virginia
city: Spokane
country: United States
facility: Pulmonary & Sleep Research
state: Washington
city: Madison
country: United States
facility: University of Wisconsin School of Medicine and Public Health
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora Cardiovascular Services
state: Wisconsin
Study officials:
affiliation: Actelion Pharmaceuticals US, Inc
name: Alain Romero, PharmD, PhD
role: STUDY_CHAIR
affiliation: Actelion Pharmaceuticals US, Inc.
name: Gary Palmer, MD, MBA
role: STUDY_CHAIR
References:
citation: 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.