Pulmonary Arterial Hypertension
Conditions
Keywords
PAH-SYMPACT, Pulmonary Arterial Hypertension, psychometric 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.
Interventions
DRUGMacitentan
Macitentan tablet, dose of 10 mg, once daily
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT) | 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. | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | From Day 1 (Baseline Visit) to End of Study visit (EoS). | Safety events are reported and documented as defined in study protocol. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | 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. |
Countries
United States
Participant flow
Recruitment details
Seventy-nine sites recruited subjects to reach a total of 284 total enrolled, with 335 subjects entered screening. Institution-based and community clinic sites, with pulmonary arterial hypertension expertise, were included in the study. The first subject, first visit occurred on 25 APR 2013 and last subject, last visit occurred on 05 OCT 2015
Pre-assignment details
Screen failures total 51 subjects. Six subjects were removed from the full analysis set of 284 due to exclusion. The per protocol set includes 278 subjects total (97.9% of enrollment), utilized for all validation and exploratory ePRO analyses. The safety set, encompassing all enrolled subjects receiving study treatment, includes 284 subjects.
Participants by arm
| Arm | Count |
|---|---|
| Macitentan Macitentan tablet, dose of 10 mg, once daily | 284 |
| Total | 284 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Post-Treatment Safety Follow-Up Period | Death | 1 |
| Post-Treatment Safety Follow-Up Period | Lost to Follow-up | 6 |
| Post-Treatment Safety Follow-Up Period | Other, administrative error | 1 |
| Post-Treatment Safety Follow-Up Period | Withdrawal by Subject | 7 |
| Screening Period | Other, 2 PAH-SYMPACT cycles not complete | 51 |
| Treatment Period | Adverse Event | 16 |
| Treatment Period | Death | 1 |
| Treatment Period | Lost to Follow-up | 1 |
| Treatment Period | Other, including non-compliance | 5 |
| Treatment Period | Physician Decision | 2 |
| Treatment Period | Withdrawal by Subject | 7 |
Baseline characteristics
| Characteristic | Macitentan |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 117 Participants |
| Age, Categorical Between 18 and 65 years | 167 Participants |
| Age, Continuous | 59.7 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 257 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 8 Participants |
| Race (NIH/OMB) Black or African American | 35 Participants |
| Race (NIH/OMB) More than one race | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 228 Participants |
| Sex: Female, Male Female | 223 Participants |
| Sex: Female, Male Male | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 284 |
| other Total, other adverse events | 228 / 284 |
| serious Total, serious adverse events | 49 / 284 |
Outcome results
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.
Time frame: From Screening Visit (Day -14) to End of Treatment (EOT) Visit (Visit 4, Week 16)
Population: Per Protocol Set (PPS) comprised all patients included in the Full Analysis Set (FAS) who had no major protocol violations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Macitentan | Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT) | Item number in symptoms part of baseline | 16 Items |
| Macitentan | Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT) | Item number in symptoms part at Week 16 | 11 Items |
| Macitentan | Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT) | Item number in impacts part at baseline | 25 Items |
| Macitentan | Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT) | Item number in impacts part at Week 16 | 11 Items |
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.
Time frame: From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.
Population: Per protocol set of 278.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Macitentan | Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability. | Cronbach's Alpha for Cardiopulmonary Symptoms | 0.81 Ratio of variance |
| Macitentan | Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability. | Cronbach's Alpha for Cardiovascular Symptoms | 0.88 Ratio of variance |
| Macitentan | Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability. | Cronbach's Alpha for Physical Impacts Domain | 0.92 Ratio of variance |
| Macitentan | Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability. | Cronbach's Alpha for Cognitive/Emotional Impacts | 0.87 Ratio of variance |
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.
Time frame: From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.
Population: Per Protocol Set of 278 patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Macitentan | Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability. | ICCs of Cardiopulmonary Symptoms domain | 0.94 Intra-class correlation coefficient |
| Macitentan | Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability. | ICCs of Cardiovascular Symptoms domain | 0.93 Intra-class correlation coefficient |
| Macitentan | Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability. | ICCs of Physical Impacts domain | 0.91 Intra-class correlation coefficient |
| Macitentan | Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability. | ICCs of Cognitive/Emotional Impacts domain | 0.84 Intra-class correlation coefficient |
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.
Time frame: From Day 1 (Baseline Visit) to End of Study visit (EoS).
Population: Safety set of 284 subjects.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan | 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) | Participants with AEs | 228 Participants |
| Macitentan | 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) | Participants with severe intensity AEs | 36 Participants |
| Macitentan | 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) | Participants with SAEs | 49 Participants |
| Macitentan | 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) | Participants prematurely discontinued study drug | 17 Participants |
Other Pre-specified
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.
Time frame: From Screening period (Days -7 to -1) to Week 16 (7-day period prior to Week 16 visit).
Population: Per Protocol Set of 278 subjects.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Cardiopulmonary Symptoms domain score at baseline | 1.0 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Cardiopulmonary Symptoms domain score at Week 8 | 0.8 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Cardiopulmonary Symptoms domain score at Week 16 | 0.7 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Cardiovascular Symptoms domain score at baseline | 0.4 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Cardiovascular Symptoms domain score at Week 8 | 0.2 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Cardiovascular Symptoms domain score at Week 16 | 0.2 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Physical Impacts domain score at baseline | 1.3 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Physical Impacts domain score at Week 8 | 1.0 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Physical Impacts domain score at Week 16 | 0.9 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Cogn./Emotional Impacts domain score at baseline | 0.8 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Cogn./Emotional Impacts domain score at Week 8 | 0.8 Score on a scale |
| Macitentan | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. | Cogn./Emotional Impacts domain score at Week 16 | 0.5 Score on a scale |