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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

Tracking Information
First Submitted Date  ICMJE March 27, 2013
First Posted Date  ICMJE April 29, 2013
Results First Submitted Date  ICMJE May 30, 2017
Results First Posted Date  ICMJE October 31, 2018
Last Update Posted Date February 26, 2019
Actual Study Start Date  ICMJE April 1, 2013
Actual Primary Completion Date November 1, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 5, 2018)
  • Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT) [ Time Frame: From Screening Visit (Day -14) to End of Treatment (EOT) Visit (Visit 4, Week 16) ]
    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.
  • Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability. [ Time Frame: From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period. ]
    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.
  • Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability. [ Time Frame: From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period. ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 24, 2013)
Development of patient-reported outcome measure of symptoms and their impact in PAH (the PAH-SYMPACT) [ Time Frame: From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16) ]
Assessed through item analyses, factor analyses, and Rasch analyses.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 5, 2018)
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) [ Time Frame: From Day 1 (Baseline Visit) to End of Study visit (EoS). ]
Safety events are reported and documented as defined in study protocol.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 24, 2013)
To assess the frequency of treatment-emergent adverse events, serious adverse events, and adverse events leading to study drug discontinuation from Baseline to Week 16. [ Time Frame: From Baseline Visit (Visit 2, Day 1) to End of Treatment (EOT) Visit (Visit 4, Week 16) ]
Current Other Pre-specified Outcome Measures
 (submitted: October 5, 2018)
Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. [ Time Frame: From Screening period (Days -7 to -1) to Week 16 (7-day period prior to Week 16 visit). ]
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.
Original Other Pre-specified Outcome Measures
 (submitted: April 24, 2013)
Change from Baseline to Week 16 in the symptom and impact scales of the PAH-SYMPACT. [ Time Frame: From Baseline Visit (Visit 2, Day 1) to End of Treatment (EOT) Visit (Visit 4, Week 16) ]
Assessed by the PAH-SYMPACT questionnaire.
 
Descriptive Information
Brief Title  ICMJE Clinical Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the PAH-SYMPACT Instrument
Official Title  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Arterial Hypertension
Intervention  ICMJE Drug: Macitentan
Macitentan tablet, dose of 10 mg, once daily
Other Name: Macitentan / ACT-064992
Study Arms  ICMJE Experimental: Macitentan
Macitentan tablet, dose of 10 mg, once daily
Intervention: Drug: Macitentan
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 1, 2016)
284
Original Estimated Enrollment  ICMJE
 (submitted: April 24, 2013)
275
Actual Study Completion Date  ICMJE November 1, 2015
Actual Primary Completion Date November 1, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01841762
Other Study ID Numbers  ICMJE AC-055-401
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Actelion
Study Sponsor  ICMJE Actelion
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Alain Romero, PharmD, PhD Actelion Pharmaceuticals US, Inc
Study Chair: Gary Palmer, MD, MBA Actelion Pharmaceuticals US, Inc.
PRS Account Actelion
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP