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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Macitentan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent prior to initiation of any study mandated procedure Patients with symptomatic PAH in World Health Organization (WHO) Functional Class (FC) II to IV Patients with PAH belonging to one of the following subgroups of the Dana Point Clinical Classification Group 1: Idiopathic, or Heritable, or Drug or toxin induced, or 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 Documented hemodynamic diagnosis of PAH by right heart catheterization - performed at any time prior to Screening showing: Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and Resting pulmonary vascular resistance (PVR) > 240 dyn•s•cm-5 and Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg 6-minute walk distance (6MWD) ≥ 150 m at Screening Able to fluently speak and read English 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 For patients on oral diuretics, stable doses for at least 4 weeks prior to Visit 2 Men or women aged 18 or older 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) 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: 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 Moderate to severe restrictive lung disease: total lung capacity < 60% of predicted value Hemoglobin < 75% of the lower limit of the normal range at screening Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of normal (ULN) at screening Estimated creatinine clearance < 30 mL/min at screening Systolic blood pressure (SBP) < 90 mmHg at screening Body weight < 40 kg at screening Known concomitant life-threatening diseases with a life expectancy of < 12 months Any condition that prevents compliance with the protocol or adherence to therapy 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 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 Treatment with riociguat within 3 months prior to Visit 2, or scheduled to receive riociguat during the trial Treatment with strong cytochrome P450 (CYP) 3A4 inducers or inhibitors within 4 weeks prior to Visit 2 Recently started (< 8 weeks prior to Visit 2) or planned cardio-pulmonary rehabilitation program based on exercise Females who are lactating or pregnant (positive Screening or Baseline pregnancy test) or plan to become pregnant during the study Known hypersensitivity to macitentan or its excipients or drugs of the same class Treatment with another investigational drug within 3 months prior to Visit 2 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Macitentan<br>Macitentan tablet, dose of 10 mg, once daily | Drug: Macitentan<br>* Macitentan tablet, dose of 10 mg, once daily<br>* Other names: Macitentan / ACT-064992;|

What is the study measuring?
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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). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAH-SYMPACT, Pulmonary Arterial Hypertension, psychometric instrument