Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
Conditions
Keywords
Pulmonary Arterial Hypertension, PAH, macitentan, tadalafil, fixed dose combination therapy
Brief summary
Combination therapy in pulmonary arterial hypertension (PAH) has been the subject of active investigation for more than a decade, with the benefit of targeting different pathways known to be involved in the pathogenesis of the disease. Adherence to prescribed therapy has an impact on clinical outcomes. Reducing the pill/tablet count and frequency has a major impact on patients' adherence to therapies and therefore the observed clinical outcomes. One way to simplify treatment is to use fixed-dose combination (FDC) products that combine multiple treatments targeting different pathways into a single tablet. This study aims to demonstrate that the FDC of macitentan and tadalafil is more effective than therapy with 10 mg of macitentan alone or 40 mg of tadalafil alone. This phase 3 study will evaluate the efficacy and safety at 16 weeks of an FDC (macitentan 10 mg and tadalafil 40 mg) against these two PAH-approved therapies given as monotherapy to further confirm the added value of the FDC.
Detailed description
PAH is characterized by a progressive increase in pulmonary arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading to right heart failure and death. Current PAH-specific therapeutic options include treatments that target the three pathways (endothelin, nitric oxide, and prostacyclin pathways). While combination treatment is common, FDC pills or tablets that combine two or more PAH-specific therapies are not available, thereby requiring participants to take multiple pills/tablets daily. An FDC is an attractive option for PAH participants because it simplifies the treatment regimen by combining two therapies (which would otherwise involve a total of three tablets: one macitentan 10 mg tablet and two tadalafil 20 mg tablets) into a single tablet. Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B antagonist. Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). This study comprises the following consecutive periods: Screening period (lasts up to 30 days), Double-blind treatment period (consists of the titration phase \[the first 2 weeks\] and the maintenance phase \[Week 3 through Week 16\]), Open-label treatment period, End-of-Treatment (EOT), Safety follow-up (S-FU) period, and End of Study (EOS). The total study duration for a participant will be up to 30 months. Study assessments like physical examinations, vital signs, right heart catheterization, 6-minute walk test will be performed. Safety will be assessed throughout the study.
Interventions
DRUGFDC macitentan/tadalafil
Film-coated tablet with 10 mg macitentan and 40 mg tadalafil, to be administered orally once daily.
DRUGMacitentan 10 mg
Film-coated tablet with 10 mg macitentan, to be administered orally once daily.
DRUGTadalafil 40 mg
Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily.
DRUGPlacebo FDC
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
DRUGPlacebo macitentan
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
DRUGPlacebo tadalafil
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
In total, approximately 170 subjects are planned to be randomized into study to receive either FDC macitentan/tadalafil or macitentan 10 mg or tadalafil 40 mg given once daily and will also receive matching placebos for two other study treatments. Treatment allocation will be stratified based on prior PAH therapy (i.e., treatment-naïve or treated by an Endothelin receptor antagonist or a Phosphodiesterase type-5 inhibitor as a monotherapy) at baseline. Sample size will be re-estimated at interim analysis if study is not terminated early for efficacy/futility up to sample size of 150-250. After completion of double-blind treatment period, subjects will continue study in an open-label treatment (OLT) period for 24 months, which may be prolonged beyond 24 months until macitentan and tadalafil are accessible at required doses, through other options according to local regulations. All assessments at end of double-blind treatment must be completed before subject enters OLT period.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated informed consent form (ICF) * Confirmed diagnosis of symptomatic PAH in WHO FC II or III * Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary hypertension: * Idiopathic * Heritable * Drug- or toxin-induced * Associated with connective tissue disease, HIV infection, portal hypertension or congenital heart disease with simple systemic-to-pulmonary shunt with persistent pulmonary hypertension documented by a right heart catheterization (RHC) ≥ 1 year after surgical repair * PAH diagnosis confirmed by hemodynamic evaluation at rest (through central reading), evaluated within 5 weeks prior to randomization: * Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, AND * Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg, AND * Pulmonary vascular resistance (PVR) ≥ 3 WU (i.e., ≥ 240 dyn∙sec∙cm-5) * Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH. (Participants for whom no vasoreactivity test was performed at diagnosis can be eligible if currently treated with PAH therapy for more than 3 months and PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after introduction of their PAH therapy). * Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the prespecified doses in the study protocol or no history of PAH-specific treatment * Participant able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at Screening * A woman of childbearing potential must: * have negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization * agree to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation * agree to follow the contraception scheme from Screening up to at least 30 days after study treatment discontinuation
Exclusion criteria
* Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period prior to start of treatment * Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior to start of treatment or history of intolerance to ERA and PDE-5i combination therapy * Hypersensitivity to any of the study treatments or any excipient of their formulations * Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer in the 1-month period prior to start of treatment * Treatment with a strong CYP3A4 inhibitor or a moderate dual CYP3A4/CYP2C9 inhibitor or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period prior to start of treatment * Treatment with doxazosin * Treatment with any form of organic nitrate, either regularly or intermittently * Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of treatment * Treatment with another investigational drug in the 3-month period prior to start of treatment * Body mass index (BMI) \> 40 kg/m2 at Screening * Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening: * BMI \> 30 kg/m2 * Diabetes mellitus of any type * Essential hypertension (even if well controlled) * Coronary artery disease, i.e. history of stable angina or known more than 50% stenosis in a coronary artery or history of myocardial infarction or history of or planned coronary artery bypass grafting and/or coronary artery stenting * Known presence of moderate or severe obstructive lung disease any time prior to Screening as specified in study protocol * Known presence of moderate or severe restrictive lung disease any time prior to Screening as specified in study protocol * Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction, in the opinion of the investigator * Known permanent atrial fibrillation, in the opinion of the investigator * Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism) * Documented pulmonary veno-occlusive disease * Hemoglobin \< 100 g/L (\<10 g/dL) at Screening * Known severe hepatic impairment as specified in study protocol * Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 1.5 × upper limit of normal (ULN) at Screening * Severe renal impairment at Screening as specified in study protocol * Systemic hypotension at Screening or Randomization and systemic hypertension at Screening as specified in study protocol * Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening * Known bleeding disorder, in the opinion of the investigator * Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic neuropathy * Hereditary degenerative retinal disorders, including retinitis pigmentosa * History of priapism, conditions that predispose to priapism (example, sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (example, angulation, cavernosal fibrosis, or Peyronie's disease) * Difficulty swallowing large pills/tablets that would interfere with the ability to comply with study treatment regimen * Any planned surgical intervention (including organ transplant) during the double-blind treatment period, except minor interventions * Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to start of treatment, or planned to be started during the double-blind period of the study * Pregnant, planning to become pregnant or lactating * Any known factor or disease that might interfere with treatment adherence, full participation in the study or interpretation of the results as judged by the investigator (e.g., drug or alcohol dependence etc.) * Known concomitant life-threatening disease with a life expectancy less than (\<) 12 months * Calcium channel blocker treatment initiated, or dose changed within 3 months prior to right heart catheterization (RHC) at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline | Baseline, EDBT (up to 16 weeks) | Change in PVR expressed as the ratio of geometric means of EDBT to baseline were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD) | Baseline, EDBT (Week 16) | Change from baseline to EDBT in 6MWD were reported. 6MWD was measured by 6-minute walk test (6MWT). The test measured the distance an individual was able to walk over a total of six minutes on a hard, flat surface with no obstacles. The goal was for the individual to walk as far as possible in 6 minutes. |
| Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT | Baseline, EDBT (Week 16) | Change from baseline in PAH-SYMPACT in cardiopulmonary symptom domain scores to EDBT were reported. PAH-SYMPACT was a pulmonary arterial hypertension (PAH)-specific patient-reported outcomes questionnaire that consists of 11 symptoms items, 11 impacts items and 1 item on oxygen use. The symptom items were divided into cardiopulmonary and cardiovascular domains, and the impact items were divided into physical and emotional/cognitive domains. Cardiopulmonary symptoms contain 6 items; shortness of breath, fatigue, lack of energy, swelling in ankles or legs, swelling in stomach area, and cough. Scores for the individual items were reported on a 5-point Likert scale, ranging from 0 (no symptom at all) to 4 (very severe symptoms), with higher scores indicated greater symptom severity. |
| Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT | Baseline, EDBT (Week 16) | Change from baseline in PAH-SYMPACT in cardiovascular symptom domain scores to EDBT were reported. PAH-SYMPACT is a PAH-specific patient-reported outcomes questionnaire that consists of 11 symptoms items, 11 impacts items and 1 item on oxygen use. The symptom items were divided into cardiopulmonary and cardiovascular domains, and the impact items were divided into physical and emotional/cognitive domains. Cardiovascular symptoms contain 5 items; heart palpitations (heart fluttering), rapid heartbeat, chest pain, chest tightness, and lightheadedness. Scores for the individual items were reported on a 5-point Likert scale, ranging from 0 (no symptom at all) to 4 (very severe symptom), with higher scores indicated greater symptom severity. |
| Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | At Week 16 (EDBT) | Percentage of participants with absence of worsening in FC from baseline to EDBT were reported. The study was adaptive with two stages: Stage 1 and Stage 2. WHO functional classification (FC), PAH range from Class I (no limitation in physical activity, no dyspnea or fatigue, chest pain, or near syncope with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity), Class IV (cannot perform a physical activity without any symptoms, dyspnea and/or fatigue at rest). |
Countries
Australia, Brazil, Bulgaria, Canada, China, Czechia, Germany, Hungary, Italy, Japan, Malaysia, Mexico, Poland, Russia, South Africa, Spain, Taiwan, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
In open label period, safety was presented using the combination safety set. Combination safety set included all participants randomized to macitentan/tadalafil fixed-dose combination (M/T FDC) in DB period and who received at least 1 dose of M/T FDC in DB treatment and all participants who received at least 1 dose of M/T FDC treatment in OL period.
Participants by arm
| Arm | Count |
|---|---|
| DB: Treatment-naive and Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) During double-blind (DB) treatment period, participants who were either treatment-naive or on a predefined stable dose of endothelin receptor antagonist (ERA), received one tablet of macitentan 10 mg along with two tablets of placebo matching to tadalafil 20 mg, orally, once daily at Weeks 1 and 2 (titration phase). From Week 3 to 16 (maintenance phase), participants continued to receive one tablet of macitentan 10 mg and two tablets placebo tablet matching to tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), orally, once daily. | 35 |
| DB: Treatment-naive and Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) During DB treatment period, participants who were either treatment-naive or on a predefined stable dose of phosphodiesterase type-5 inhibitor (PDE-5i), received one tablet (two tablets if already on allowable dose at baseline) of tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg and one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (titration phase). Participants further received two tablets of tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg, orally, once daily at Week 2 (titration phase). From Week 3 to 16 (maintenance phase), participants received two tablets of tadalafil 20 mg along with one tablet of placebo matching to macitentan 10 mg and one tablet of placebo matching to M/T FDC, orally, once daily. | 44 |
| DB: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC During DB treatment period, participants who were either treatment-naive or on a predefined stable dose of ERA or PDE-5i, received one tablet of macitentan 10 mg along with one tablet of tadalafil 20 mg and one tablet of placebo matching to tadalafil 20 mg, orally, once daily at Week 1 (uptitration phase). Participants further received one tablet of macitentan 10 mg along with two tablets of tadalafil 20 mg, orally, once daily at Week 2 (uptitration phase). From Week 3 to 16 (maintenance phase), participants received one tablet of placebo matching to macitentan 10 mg along with two tablets of placebo matching to tadalafil 20 mg and one tablet of macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC), orally, once daily. | 107 |
| Total | 186 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| DB Treatment Period (Week 1 to Week 16) | Death | 0 | 0 | 3 | 0 | 0 | 0 |
| DB Treatment Period (Week 1 to Week 16) | Physician Decision | 0 | 0 | 2 | 0 | 0 | 0 |
| DB Treatment Period (Week 1 to Week 16) | Withdrawal by Subject | 0 | 1 | 4 | 0 | 0 | 0 |
| OL Treatment Period (Week 17 to Week189) | Adverse Event | 0 | 0 | 0 | 2 | 0 | 0 |
| OL Treatment Period (Week 17 to Week189) | Death | 0 | 0 | 0 | 0 | 0 | 5 |
| OL Treatment Period (Week 17 to Week189) | Family problems | 0 | 0 | 0 | 0 | 0 | 1 |
| OL Treatment Period (Week 17 to Week189) | Initiated prohibited medication | 0 | 0 | 0 | 1 | 0 | 0 |
| OL Treatment Period (Week 17 to Week189) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 |
| OL Treatment Period (Week 17 to Week189) | Non-compliance with study drug | 0 | 0 | 0 | 0 | 1 | 0 |
| OL Treatment Period (Week 17 to Week189) | Technical problems | 0 | 0 | 0 | 0 | 0 | 1 |
| OL Treatment Period (Week 17 to Week189) | Withdrawal by Subject | 0 | 0 | 0 | 2 | 4 | 7 |
Baseline characteristics
| Characteristic | DB: Treatment-naive and Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | DB: Treatment-naive and Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | DB: Treatment-naive and Prior ERA/ PDE-5i Strata: M/T FDC | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 10 Participants | 20 Participants | 38 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 34 Participants | 87 Participants | 148 Participants |
| Age, Continuous | 51.3 years STANDARD_DEVIATION 15.85 | 53.1 years STANDARD_DEVIATION 13.66 | 48.7 years STANDARD_DEVIATION 15.78 | 50.2 years STANDARD_DEVIATION 15.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 8 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 39 Participants | 95 Participants | 164 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 11 Participants | 36 Participants | 59 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) White | 20 Participants | 29 Participants | 66 Participants | 115 Participants |
| Region of Enrollment BRAZIL | 5 Participants | 3 Participants | 4 Participants | 12 Participants |
| Region of Enrollment BULGARIA | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment CANADA | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment CHINA | 5 Participants | 5 Participants | 13 Participants | 23 Participants |
| Region of Enrollment GERMANY | 2 Participants | 4 Participants | 7 Participants | 13 Participants |
| Region of Enrollment ITALY | 1 Participants | 1 Participants | 4 Participants | 6 Participants |
| Region of Enrollment JAPAN | 1 Participants | 1 Participants | 6 Participants | 8 Participants |
| Region of Enrollment MALAYSIA | 1 Participants | 2 Participants | 10 Participants | 13 Participants |
| Region of Enrollment MEXICO | 2 Participants | 2 Participants | 6 Participants | 10 Participants |
| Region of Enrollment POLAND | 3 Participants | 2 Participants | 7 Participants | 12 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 1 Participants | 0 Participants | 10 Participants | 11 Participants |
| Region of Enrollment SOUTH AFRICA | 3 Participants | 2 Participants | 1 Participants | 6 Participants |
| Region of Enrollment SPAIN | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Region of Enrollment TAIWAN | 3 Participants | 2 Participants | 6 Participants | 11 Participants |
| Region of Enrollment TURKEY | 1 Participants | 2 Participants | 14 Participants | 17 Participants |
| Region of Enrollment UNITED STATES | 4 Participants | 13 Participants | 13 Participants | 30 Participants |
| Sex: Female, Male Female | 29 Participants | 34 Participants | 82 Participants | 145 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 25 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 2 / 71 | 0 / 44 | 2 / 87 | 3 / 108 | 0 / 35 | 2 / 43 | 9 / 107 |
| other Total, other adverse events | 16 / 35 | 49 / 70 | 31 / 44 | 58 / 86 | 72 / 107 | 28 / 35 | 38 / 43 | 89 / 107 |
| serious Total, serious adverse events | 3 / 35 | 11 / 70 | 4 / 44 | 12 / 86 | 15 / 107 | 10 / 35 | 13 / 43 | 39 / 107 |
Outcome results
Primary
Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline
Change in PVR expressed as the ratio of geometric means of EDBT to baseline were reported.
Time frame: Baseline, EDBT (up to 16 weeks)
Population: The full analysis set (FAS) included all randomized participants who received at least one dose of study treatment (for participants on FDC, at least one dose of either macitentan or tadalafil). Treatment-naive participants randomized to both M/T FDC arms (ERA and PDE-5i strata) are counted twice as per planned analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline | 0.77 Ratio |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline | 0.55 Ratio |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline | 0.78 Ratio |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline | 0.56 Ratio |
p-value: <0.000195% CI: [0.61, 0.82]ANCOVA
p-value: <0.000195% CI: [0.64, 0.8]ANCOVA
Secondary
Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT
Change from baseline in PAH-SYMPACT in cardiopulmonary symptom domain scores to EDBT were reported. PAH-SYMPACT was a pulmonary arterial hypertension (PAH)-specific patient-reported outcomes questionnaire that consists of 11 symptoms items, 11 impacts items and 1 item on oxygen use. The symptom items were divided into cardiopulmonary and cardiovascular domains, and the impact items were divided into physical and emotional/cognitive domains. Cardiopulmonary symptoms contain 6 items; shortness of breath, fatigue, lack of energy, swelling in ankles or legs, swelling in stomach area, and cough. Scores for the individual items were reported on a 5-point Likert scale, ranging from 0 (no symptom at all) to 4 (very severe symptoms), with higher scores indicated greater symptom severity.
Time frame: Baseline, EDBT (Week 16)
Population: The PAH-SYMPACT symptoms analysis set included all participants included in the FAS for whom at least one baseline value of symptoms domain was provided. Treatment-naive participants randomized to both M/T FDC arms (ERA and PDE-5i strata) were counted twice as per planned analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT | -0.14 Score on a scale | Standard Deviation 0.478 |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT | -0.20 Score on a scale | Standard Deviation 0.394 |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT | -0.13 Score on a scale | Standard Deviation 0.554 |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT | -0.15 Score on a scale | Standard Deviation 0.404 |
Secondary
Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT
Change from baseline in PAH-SYMPACT in cardiovascular symptom domain scores to EDBT were reported. PAH-SYMPACT is a PAH-specific patient-reported outcomes questionnaire that consists of 11 symptoms items, 11 impacts items and 1 item on oxygen use. The symptom items were divided into cardiopulmonary and cardiovascular domains, and the impact items were divided into physical and emotional/cognitive domains. Cardiovascular symptoms contain 5 items; heart palpitations (heart fluttering), rapid heartbeat, chest pain, chest tightness, and lightheadedness. Scores for the individual items were reported on a 5-point Likert scale, ranging from 0 (no symptom at all) to 4 (very severe symptom), with higher scores indicated greater symptom severity.
Time frame: Baseline, EDBT (Week 16)
Population: The PAH-SYMPACT symptoms analysis set included all participants included in the FAS for whom at least one baseline value of symptoms domain was provided. Treatment-naive participants randomized to both M/T FDC arms (ERA and PDE-5i strata) were counted twice as per planned analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT | -0.14 Score on a scale | Standard Deviation 0.473 |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT | -0.15 Score on a scale | Standard Deviation 0.349 |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT | -0.18 Score on a scale | Standard Deviation 0.612 |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT | -0.10 Score on a scale | Standard Deviation 0.318 |
Secondary
Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD)
Change from baseline to EDBT in 6MWD were reported. 6MWD was measured by 6-minute walk test (6MWT). The test measured the distance an individual was able to walk over a total of six minutes on a hard, flat surface with no obstacles. The goal was for the individual to walk as far as possible in 6 minutes.
Time frame: Baseline, EDBT (Week 16)
Population: The FAS included all randomized participants who received at least one dose of study treatment (for participants on FDC, at least one dose of either macitentan or tadalafil). Treatment-naive participants randomized to both macitentan 10 mg and tadalafil 40 mg fixed-dose combination (M/T FDC) arms (ERA and PDE-5i strata) are counted twice as per planned analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD) | 38.5 Meters | Standard Deviation 70.42 |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD) | 52.9 Meters | Standard Deviation 88.23 |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD) | 15.9 Meters | Standard Deviation 45.04 |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD) | 43.4 Meters | Standard Deviation 78.03 |
p-value: =0.380295% CI: [-17, 49.08]ANCOVA
p-value: =0.059195% CI: [-0.93, 51.59]ANCOVA
Secondary
Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT
Percentage of participants with absence of worsening in FC from baseline to EDBT were reported. The study was adaptive with two stages: Stage 1 and Stage 2. WHO functional classification (FC), PAH range from Class I (no limitation in physical activity, no dyspnea or fatigue, chest pain, or near syncope with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity), Class IV (cannot perform a physical activity without any symptoms, dyspnea and/or fatigue at rest).
Time frame: At Week 16 (EDBT)
Population: The FAS included all randomized participants who received at least one dose of study treatment (for participants on FDC, at least one dose of either macitentan or tadalafil). Treatment-naive participants randomized to both M/T FDC arms (ERA and PDE-5i strata) are counted twice as per planned analysis. Here, 'N' overall (number of participants analyzed) signifies the number of participants evaluable, n (number analyzed) =number of participants evaluable for specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class IV | 0 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Missing | 0 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class III | 38.9 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class II | 55.6 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Missing | 0 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class I | 5.6 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class IV | 0 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class I | 11.8 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class II | 52.9 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: Macitentan Monotherapy 10 Milligrams (mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2: Class III | 35.3 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2: Class III | 15.6 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class I | 9.4 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Missing | 0 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class IV | 0 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class I | 5.3 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class II | 57.9 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class II | 75.0 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class IV | 0 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Missing | 13.2 Percentage of participants |
| DB: Treatment-naive And Prior ERA Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class III | 23.7 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class IV | 0 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class I | 4.5 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class IV | 0 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Missing | 0 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class II | 54.5 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2: Class III | 36.4 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Missing | 0 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class II | 63.6 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class III | 31.8 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: Tadalafil Monotherapy 20 mg (2 Tablets*20 mg) | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class I | 9.1 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class IV | 0 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class IV | 0 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class III | 25.5 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2: Class III | 25.6 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class II | 61.5 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Class I | 7.7 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class II | 59.6 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Class I | 12.8 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 1 : Missing | 2.1 Percentage of participants |
| DB: Treatment-naive And Prior PDE-5i Strata: M/T FDC | Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT | Stage: 2 : Missing | 5.1 Percentage of participants |