| Trial | Phase | Enrollment | Study Type | Start Date | Status |
|---|
| Long-term Single-arm Open-label Extension Study of the SERAPHIN Study, to Assess the Safety and Tolerability of ACT 064992 in Patients With Symptomatic Pulmonary Arterial Hypertension [NCT00667823] | Phase 3 | 550 participants (Actual) | Interventional | 2008-10-17 | Completed |
| A Multicenter, Open-label, Single-arm Study to Assess the Pharmacokinetics and Safety of Macitentan in Children Aged 1 Month to <2 Years With Pulmonary Arterial Hypertension [NCT05731492] | Phase 1 | 10 participants (Anticipated) | Interventional | 2023-12-08 | Recruiting |
| A Prospective, Open-label, Platform Study for Long-term Follow-up of Participants Using Study Intervention in Pulmonary Hypertension Parent Studies [NCT05179876] | Phase 3 | 230 participants (Anticipated) | Interventional | 2022-05-04 | Recruiting |
| A Multicenter, Open-label, Phase III Study to Assess the Efficacy, Safety, and Pharmacokinetics of Macitentan in Japanese Pediatric Patients (>=3 Months to <15 Years) With Pulmonary Arterial Hypertension [NCT05167825] | Phase 3 | 6 participants (Anticipated) | Interventional | 2022-11-14 | Recruiting |
| A Phase 3, Prospective, Multicenter, Double-blind, Double-dummy, Randomized, Active-controlled, Parallel-group, Group-sequential, Adaptive, Event-driven Study to Compare Efficacy, Safety, and Tolerability of Macitentan 75 mg Versus Macitentan 10 mg in Pat [NCT04273945] | Phase 3 | 900 participants (Anticipated) | Interventional | 2020-06-30 | Recruiting |
| A Prospective, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel Group, Adaptive Phase 3 Study With Open-label Extension to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pul [NCT04271475] | Phase 3 | 127 participants (Actual) | Interventional | 2020-07-07 | Active, not recruiting |
| CompRehensive Phenotypic Characterization of Patients With Scleroderma-Associated Interstitial Lung DiseasE and Pulmonary Hypertension (PH): The CRuSADE PH Study [NCT03726398] | Phase 2/Phase 3 | 26 participants (Anticipated) | Interventional | 2018-09-01 | Recruiting |
| Raising the Bars in the Treatment of Pulmonary Arterial Hypertension: Goal Oriented Strategy to Preserve Ejection Fraction Trial [NCT03236818] | Phase 4 | 30 participants (Anticipated) | Interventional | 2013-05-31 | Active, not recruiting |
| A Double-blind, Randomized, Placebo-controlled, Four-way Crossover Phase 1 Study Including an Open-label Positive Control (Moxifloxacin) to Assess the Effect of Repeated Daily Doses of 10 mg and 30 mg Macitentan on the QT/QTc Interval of the ECG in Health [NCT02050802] | Phase 1 | 64 participants (Actual) | Interventional | 2011-08-31 | Completed |
| Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Adult and Adolescent Subjects [NCT03153137] | Phase 3 | 142 participants (Actual) | Interventional | 2017-08-14 | Completed |
| A Single-center, Open-label, Single-dose, Randomized, 2-way Crossover Phase 1 Study in Healthy Adult Participants to Assess the Relative Oral Bioavailability of the Combination of Macitentan/Tadalafil (10 mg/20 mg) Administered a Fixed-dose Combination Fo [NCT04540744] | Phase 1 | 18 participants (Actual) | Interventional | 2021-04-30 | Completed |
| Prospective, Multi-center, Double-blind, Randomized, Active-controlled, Triple-dummy, Parallel-group, Group-sequential, Adaptive Phase 3 Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fix [NCT03904693] | Phase 3 | 187 participants (Actual) | Interventional | 2019-07-29 | Active, not recruiting |
| mUlticenter, Single-arM, Open-laBel, Long-teRm Safety Study With macitEntan in Patients With puLmonary Arterial Hypertension previousLy Treated With mAcitentan in Clinical Studies [NCT03422328] | Phase 3 | 147 participants (Actual) | Interventional | 2018-04-05 | Active, not recruiting |
| A Multicenter, Open-label, Randomized, Study With Single-arm Extension Period to Assess the Pharmacokinetics, Safety and Efficacy of Macitentan Versus Standard of Care in Children With Pulmonary Arterial Hypertension [NCT02932410] | Phase 3 | 300 participants (Anticipated) | Interventional | 2017-10-24 | Recruiting |
| US-based, Observational, Drug Registry of Opsumit® (Macitentan) New Users in Clinical Practice [NCT02126943] | | 2,686 participants (Actual) | Observational | 2014-04-30 | Completed |
| Long Term, Single-arm, Open-label Extension Study of the MUSIC Study to Assess the Safety and Tolerability of Macitentan in Patients With Idiopathic Pulmonary Fibrosis [NCT01346930] | Phase 2 | 0 participants (Actual) | Interventional | 2011-07-31 | Withdrawn(stopped due to Due to Protocol AC-055B201 (MUSIC) not meeting it's primary end point) |
| A Single-center, Open-label, Single-sequence, 2-part Study to Investigate the Effect of 75 mg Macitentan Once Daily at Steady State on the Pharmacokinetics of Riociguat, Sildenafil, Rosuvastatin and Tadalafil in Healthy Male Subjects [NCT04211272] | Phase 1 | 47 participants (Actual) | Interventional | 2020-01-14 | Completed |
| A Double-blind, Randomized, Placebo-controlled, Multiple-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Macitentan and an Open-label, Randomized, Crossover, Single-dose Study to Evaluate the Effect of Food on Ma [NCT04500808] | Phase 1 | 24 participants (Actual) | Interventional | 2020-07-21 | Completed |
| Single-center, Open-label, Randomized, Two-treatment, Single-dose, Crossover Study in Healthy Subjects to Investigate the Biocomparison of the Adult and Pediatric Formulation of Macitentan [NCT02476864] | Phase 1 | 12 participants (Actual) | Interventional | 2015-08-31 | Completed |
| Initial Dual Oral coMbination Therapy Versus Standard-of-care Initial Oral Monotherapy Prior to Balloon Pulmonary Angioplasty in Patients With Inoperable Chronic Thromboembolic Pulmonary hyperTension [NCT04780932] | Phase 2/Phase 3 | 96 participants (Anticipated) | Interventional | 2021-06-14 | Recruiting |
| An Extension of AC-055-310, a Multi-center, Open-label, Single-arm, Phase 3b Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the French, Italian and Spanish Versions of the PAH-SYMPACT™ [NCT02112487] | Phase 3 | 88 participants (Actual) | Interventional | 2014-06-23 | Completed |
| A Randomized, Double-blind, Placebo-controlled, Prospective, Multicenter, Parallel Group Study to Assess the Safety and Efficacy of Macitentan in Patients With Portopulmonary Hypertension [NCT02382016] | Phase 4 | 85 participants (Actual) | Interventional | 2015-06-23 | Completed |
| A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group, Event-driven, Phase III Study to Assess the Effects of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension [NCT00660179] | Phase 3 | 742 participants (Actual) | Interventional | 2008-05-31 | Completed |
| Single-center, Open-label, Single-dose, 2-period, Randomized, Crossover Phase 1 Study to Demonstrate Bioequivalence of Tadalafil Administered as a Fixed Dose Combination Formulation of Macitentan/Tadalafil (10 mg/40 mg) and as the Free Combination of 10 m [NCT04235270] | Phase 1 | 62 participants (Actual) | Interventional | 2020-01-17 | Completed |
| A Long-term, Multicenter, Single-arm, Open-label Extension of the SERENADE Study, to Assess the Safety and Efficacy of Macitentan in Subjects With Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease [NCT03714815] | Phase 2 | 91 participants (Actual) | Interventional | 2018-12-07 | Terminated(stopped due to the absence of a positive trend in all efficacy parameters indicates that macitentan 10 mg does not have a beneficial effect in patients with HFpEF and PVD.) |
| A Single-center, Open-label, Phase 1 Study of Macitentan, Radiotherapy and Temozolomide Concurrent Therapy Followed by Maintenance Therapy With Macitentan and Temozolomide in Subjects With Newly Diagnosed Glioblastoma [NCT02254954] | Phase 1 | 30 participants (Actual) | Interventional | 2015-01-08 | Terminated(stopped due to Sponsor decision due to low recruitment) |
| Pulmonary Arterial Hypertension Quality Enhancement Research Initiative Extension Program [NCT01389206] | | 797 participants (Actual) | Observational [Patient Registry] | 2011-06-01 | Completed |
| Prospective, Multi-center, Single-arm, Open-label Long-term Study Assessing the Safety, Tolerability, and Effectiveness of Macitentan in Fontan-palliated Adult and Adolescent Subjects [NCT03775421] | Phase 3 | 112 participants (Actual) | Interventional | 2019-04-11 | Terminated(stopped due to As The RUBATO DB study (NCT03153137) did not show any benefit of treatment with macitentan in Fontan-palliated participants, the sponsor has decided to terminate the RUBATO OL study (NCT03775421). No new safety observations were made.) |
| MERIT-2 : Long Term, Multicenter, Single-arm, Open-label Extension Study of the MERIT-1 Study, to Assess the Safety, Tolerabilty and Efficacy of Macitentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH) [NCT02060721] | Phase 2 | 76 participants (Actual) | Interventional | 2015-02-03 | Completed |
| Potential Therapy With MACITENTAN in the Treatment of Chronic Lung Allograft Dysfunction (CLAD) After Lung Transplantation [NCT02893176] | Phase 4 | 0 participants (Actual) | Interventional | 2016-09-30 | Withdrawn |
| A Double-blind, Randomized, Placebo-controlled, Multicenter, Parallel Group Study to Evaluate the Efficacy, Safety, and Tolerability of Macitentan in Patients With Idiopathic Pulmonary Fibrosis [NCT00903331] | Phase 2 | 178 participants (Actual) | Interventional | 2009-05-31 | Completed |
| Impact of Endothelin-1 on the Development of Cardiac Allograft Vasculopathy in Heart Transplant Recipients: Endothelin Receptor Antagonism and Vasomotor Function [NCT05373108] | Phase 4 | 20 participants (Actual) | Interventional | 2022-05-19 | Completed |
| Prospective, Randomized, Placebo-controlled, Double-blind, Multicenter, Parallel Group Study to Assess the Efficacy, Safety and Tolerability of Macitentan in Patients With Ischemic Digital Ulcers Associated With Systemic Sclerosis [NCT01474122] | Phase 3 | 265 participants (Actual) | Interventional | 2011-12-31 | Terminated(stopped due to company decision) |
| A Single-center, Open-label, Single-dose, Randomized, 2-way Crossover Phase 1 Study in Healthy Adult Participants to Assess the Bioequivalence of the Dispersible Final Market Image (FMI) Macitentan Tablet (4 x 2.5 mg) and the Opsumit Tablet (10 mg) in Fas [NCT05433675] | Phase 1 | 28 participants (Actual) | Interventional | 2022-06-22 | Completed |
| Prospective, Multicenter, Open-label Study Evaluating the Effects of First-line Oral Combination Therapy of Macitentan and Tadalafil in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (OPTIMA). [NCT02968901] | Phase 4 | 46 participants (Actual) | Interventional | 2015-09-01 | Terminated |
| A Prospective, Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group, 12-week Study to Evaluate the Safety and Tolerability of Macitentan in Subjects With Combined Pre- and Post-capillary Pulmonary Hypertension (CpcPH) Due to Left Vent [NCT02070991] | Phase 2 | 63 participants (Actual) | Interventional | 2014-07-01 | Completed |
| A Phase 1/1b, Open-label Study in Patients With Recurrent Glioblastoma to Assess the Safety and Tolerability of Macitentan in Combination With Dose-dense Temozolomide [NCT01499251] | Phase 1 | 75 participants (Anticipated) | Interventional | 2012-01-31 | Terminated(stopped due to Results did not clearly support continuing development in recurrent GBM) |
| Untersuchung Des Einflusses PAH-spezifischer Medikation Auf Die rechtsventrikuläre Funktion Bei Patienten Mit Pulmonaler Arterieller Hypertonie (PAH) Unter Basalen Bedingungen [NCT03362047] | Phase 2 | 30 participants (Anticipated) | Interventional | 2018-03-01 | Recruiting |
| 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 [NCT01841762] | Phase 3 | 284 participants (Actual) | Interventional | 2013-04-01 | Completed |
| Effects of Combination Medical Therapy Followed by Balloon Pulmonary Angioplasty on Right Ventricular-PA Coupling and Hemodynamics in Chronic Thromboembolic Pulmonary Hypertension [NCT05140525] | Phase 3 | 15 participants (Anticipated) | Interventional | 2024-01-31 | Not yet recruiting |
| A Single-center, Open-label, One-sequence, Two-treatment Study to Investigate the Effect of Macitentan at Steady State on the Pharmacokinetics of Riociguat in Healthy Male Subjects [NCT03389321] | Phase 1 | 20 participants (Actual) | Interventional | 2018-01-09 | Completed |
| A Prospective, Multicenter, Single-arm, Open-label, Phase 4 Study to Evaluate the Effects of Macitentan on Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension Assessed by Cardiac Magnetic Resonance Imaging [NCT02310672] | Phase 4 | 89 participants (Actual) | Interventional | 2015-06-01 | Completed |
| A Multi-center, Open-label, Single-arm, Phase 3b Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the French, Italian and Spanish Versions of the PAH-SYMPACT™ [NCT02081690] | Phase 3 | 160 participants (Actual) | Interventional | 2014-03-01 | Terminated(stopped due to Slow recruitment) |
| The Role of MACitentan on the Prevention of Residual Pulmonary vasculaR Occlusion [NCT05946811] | Phase 3 | 128 participants (Anticipated) | Interventional | 2024-05-01 | Not yet recruiting |
| Single-center, Open-label, Single-dose, Two-period, Randomized, Crossover, Phase I Study to Demonstrate Bioequivalence Between a Fixed Dose Combination Product Formulation of Macitentan/Tadalafil (10 mg/40 mg) and the Free Combination of 10 mg Macitentan [NCT03215966] | Phase 1 | 38 participants (Actual) | Interventional | 2017-08-07 | Completed |
| A Multi-center, Double-blind, Placebo-controlled Phase 2b Study to Evaluate the Efficacy and Safety of Macitentan in Subjects With Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease [NCT03153111] | Phase 2 | 143 participants (Actual) | Interventional | 2017-07-11 | Completed |
| The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension: A Multi-center, Double-blind, Placebo-controlled, Phase 3b Study [NCT02558231] | Phase 3 | 247 participants (Actual) | Interventional | 2016-05-01 | Completed |
| Prospective, Randomized, Placebo-controlled, Double-blind, Multicenter, Parallel-group, 24-week Study to Assess the Efficacy, Safety and Tolerability of Macitentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension [NCT02021292] | Phase 2 | 80 participants (Actual) | Interventional | 2014-08-20 | Completed |
| A Single-center, Open-label, Single-dose, Randomized, 2-way Crossover Phase 1 Study in Healthy Adult Participants to Assess the Relative Oral Bioavailability of Two Macitentan Pediatric Formulations [NCT04963439] | Phase 1 | 16 participants (Actual) | Interventional | 2021-07-08 | Completed |
| A Single-center, Open-label, Single-dose, Randomized, 3-way Crossover Phase 1 Study in Healthy Adult Participants to Assess the Relative Oral Bioavailability of Macitentan 75 mg as Two Different Test Formulations Compared to the Reference Formulation [NCT05392530] | Phase 1 | 23 participants (Actual) | Interventional | 2022-05-25 | Completed |
| A Prospective, Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation [NCT02554903] | Phase 2 | 57 participants (Actual) | Interventional | 2016-03-28 | Completed |
| A Prospective, Multicenter, Open-label, Single Arm, Phase III Study to Assess the Efficacy and Safety of Macitentan (ACT-064992) in Subjects With Chronic Thromboembolic Pulmonary Hypertension (CTEPH) [NCT03809650] | Phase 3 | 9 participants (Actual) | Interventional | 2019-01-08 | Terminated(stopped due to Due to a change in the development strategy) |
| A Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase 3 Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome [NCT01743001] | Phase 3 | 226 participants (Actual) | Interventional | 2013-05-21 | Completed |
| Prospective, Randomized, Placebo-controlled, Double-blind, Multicenter, Parallel Group Study to Assess the Efficacy, Safety and Tolerability of Macitentan in Patients With Ischemic Digital Ulcers Associated With Systemic Sclerosis [NCT01474109] | Phase 3 | 289 participants (Actual) | Interventional | 2011-12-31 | Completed |
| AC-055-402: An Extension of AC-055-401, 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 [NCT01847014] | Phase 3 | 4 participants (Actual) | Interventional | 2013-09-01 | Terminated(stopped due to Protocol-defined criterion of macitentan availability achieved.) |
| Long Term, Single-arm, Open-label Extension Study of Protocol AC-055-305 to Assess the Safety, Tolerability and Efficacy of Macitentan in Subjects With Eisenmenger Syndrome [NCT01739400] | Phase 3 | 217 participants (Actual) | Interventional | 2013-09-10 | Terminated(stopped due to Primary endpoint of parent study AC-055-305/MAESTRO (NCT01743001) not met.) |
| A Single-center, Open-label, Single-dose, Randomized, 3-way Crossover Phase 1 Study in Healthy Adult Participants to Assess the Bioequivalence of the Combination of Macitentan/Tadalafil (10 mg/20 mg) Administered as a Fixed Dose Combination Formulation Co [NCT05236231] | Phase 1 | 40 participants (Actual) | Interventional | 2022-02-04 | Completed |
| A Single-center, Open-label, One-sequence, Two-treatment Study to Investigate the Effect of Macitentan at Steady State on the Pharmacokinetics of Rosuvastatin in Healthy Male Subjects. [NCT03359291] | Phase 1 | 20 participants (Actual) | Interventional | 2017-11-03 | Completed |
| The Safety and Efficacy of Macitentan for Treatment of Pulmonary Hypertension in Sickle Cell Disease [NCT02651272] | Phase 2 | 4 participants (Actual) | Interventional | 2015-07-31 | Terminated(stopped due to Unable to enroll IRB approved sample of participants.) |
| [information is prepared from clinicaltrials.gov, extracted Sep-2024] |
| Trial | Outcome |
|---|
| NCT00660179 (9) [back to overview] | Pulmonary Vascular Resistance at Baseline and Month 6 |
| NCT00660179 (9) [back to overview] | Cardiac Index at Baseline and Month 6 |
| NCT00660179 (9) [back to overview] | Change From Baseline to Month 6 in 6-minute Walk Distance |
| NCT00660179 (9) [back to overview] | Summary of the First Causes of Morbidity or Mortality |
| NCT00660179 (9) [back to overview] | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) |
| NCT00660179 (9) [back to overview] | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) |
| NCT00660179 (9) [back to overview] | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) |
| NCT00660179 (9) [back to overview] | Time to First Confirmed Morbidity or Mortality Event up to the End of Treatment (Kaplan-Meier Estimate of Patients Without a Morbidity or Mortality Event) |
| NCT00660179 (9) [back to overview] | Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6 |
| NCT00667823 (6) [back to overview] | Number of Participants With Death up to 28 Days After Study Treatment Discontinuation |
| NCT00667823 (6) [back to overview] | Number of Participants With Treatment Emergent Adverse Events (TEAEs) up to 28 Days After Study Treatment Discontinuation |
| NCT00667823 (6) [back to overview] | Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) up to 28 Days After Study Treatment Discontinuation |
| NCT00667823 (6) [back to overview] | Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation |
| NCT00667823 (6) [back to overview] | Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation |
| NCT00667823 (6) [back to overview] | Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment |
| NCT00903331 (2) [back to overview] | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study |
| NCT00903331 (2) [back to overview] | Forced Vital Capacity (FVC) at Baseline and End of Period 1 |
| NCT01474109 (6) [back to overview] | Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16 |
| NCT01474109 (6) [back to overview] | Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16 |
| NCT01474109 (6) [back to overview] | Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16 |
| NCT01474109 (6) [back to overview] | Percentage of Participants Without a New DU Up To Week 16 |
| NCT01474109 (6) [back to overview] | Percentage of Participants With at Least One DU Complication |
| NCT01474109 (6) [back to overview] | Incidence Rate of New Digital Ulcers (DUs) up to Week 16 |
| NCT01474122 (6) [back to overview] | Percentage of Participants Without a New DU up to Week 16 |
| NCT01474122 (6) [back to overview] | Percentage of Participants With at Least One DU Complication |
| NCT01474122 (6) [back to overview] | Incidence Rate of New Digital Ulcers (DUs) up to Week 16 |
| NCT01474122 (6) [back to overview] | Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16 |
| NCT01474122 (6) [back to overview] | Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16 |
| NCT01474122 (6) [back to overview] | Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16 |
| NCT01739400 (4) [back to overview] | Change in WHO Functional Class (FC) at Month 6 and 12 |
| NCT01739400 (4) [back to overview] | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 |
| NCT01739400 (4) [back to overview] | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 |
| NCT01739400 (4) [back to overview] | Change in Borg Dyspnea Score at Month 6 and 12 |
| NCT01743001 (4) [back to overview] | Change From Baseline to Week 16 in WHO Functional Class |
| NCT01743001 (4) [back to overview] | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire |
| NCT01743001 (4) [back to overview] | Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index |
| NCT01743001 (4) [back to overview] | Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD) |
| NCT01841762 (5) [back to overview] | Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), With Reliability Assessed Via Test-retest Reliability. |
| NCT01841762 (5) [back to overview] | Validation of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT), Assessing Internal Consistency Reliability. |
| NCT01841762 (5) [back to overview] | 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) |
| NCT01841762 (5) [back to overview] | Development and Refinement of the Patient-reported Outcome Measure of Symptoms and Their Impact in PAH (the PAH-SYMPACT) |
| NCT01841762 (5) [back to overview] | Assessment of the Sensitivity to Detect Change in the Symptoms and Impacts Domain Scores of the PAH-SYMPACT From Baseline to Week 16. |
| NCT02021292 (8) [back to overview] | Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Corrected Hemodynamic Values |
| NCT02021292 (8) [back to overview] | Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest. |
| NCT02021292 (8) [back to overview] | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 |
| NCT02021292 (8) [back to overview] | Post-hoc Analysis of Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD) Excluding Subjects With Implausible Hemodynamic Findings |
| NCT02021292 (8) [back to overview] | Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Implausible Hemodynamic Findings |
| NCT02021292 (8) [back to overview] | Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD). |
| NCT02021292 (8) [back to overview] | Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT). |
| NCT02021292 (8) [back to overview] | Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Including Subjects With Corrected Hemodynamic Values |
| NCT02060721 (8) [back to overview] | Number of Participants With Hemoglobin Abnormalities |
| NCT02060721 (8) [back to overview] | Number of Participants With Liver Tests Abnormalities |
| NCT02060721 (8) [back to overview] | Change From Baseline in Body Weight at Month 6 |
| NCT02060721 (8) [back to overview] | Change From Baseline in Pulse Rate at Month 6 |
| NCT02060721 (8) [back to overview] | Number of Participants With AEs Leading to Study Drug Discontinuation |
| NCT02060721 (8) [back to overview] | Number of Participants With Treatment-emergent Adverse Events (TEAEs) |
| NCT02060721 (8) [back to overview] | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) |
| NCT02060721 (8) [back to overview] | Change From Baseline in Blood Pressure at Month 6 |
| NCT02070991 (8) [back to overview] | PVR at Rest at Week 12 Expressed as Percent of Baseline PVR at Rest |
| NCT02070991 (8) [back to overview] | NT-proBNP at Week 12 Expressed as Percent of Baseline NT-proBNP at Rest |
| NCT02070991 (8) [back to overview] | Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP) |
| NCT02070991 (8) [back to overview] | Change From Baseline to Week 12 in Cardiac Index (CI) |
| NCT02070991 (8) [back to overview] | Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG) |
| NCT02070991 (8) [back to overview] | Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) |
| NCT02070991 (8) [back to overview] | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) |
| NCT02070991 (8) [back to overview] | Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment |
| NCT02081690 (4) [back to overview] | Evaluation of the Reliability and the Construct Validity of the Cognitive/Emotional Impacts Domain of the PAH-SYMPACT |
| NCT02081690 (4) [back to overview] | Evaluation of the Reliability and the Construct Validity of the Cardiovascular Symptoms Domain of the PAH-SYMPACT |
| NCT02081690 (4) [back to overview] | Evaluation of the Reliability and the Construct Validity of the Cardiopulmonary Symptoms Domain of the PAH-SYMPACT |
| NCT02081690 (4) [back to overview] | Evaluation of the Reliability and the Construct Validity of the Physical Impacts Domain of the PAH-SYMPACT |
| NCT02310672 (7) [back to overview] | Change From Baseline in Right Ventricular End Diastolic Volume (RVEDV) to Week 26 |
| NCT02310672 (7) [back to overview] | Change From Baseline in Right Ventricular Ejection Fraction (RVEF) to Week 26 (% Blood Volume) |
| NCT02310672 (7) [back to overview] | Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR) |
| NCT02310672 (7) [back to overview] | Change From Baseline in Six-minutes Walk Distance (6MWD) to Week 26 |
| NCT02310672 (7) [back to overview] | Change From Baseline in Right Ventricular Stroke Volume (RVSV) to Week 26 |
| NCT02310672 (7) [back to overview] | Change From Baseline in Right Ventricular End Systolic Volume (RVESV) to Week 26 |
| NCT02310672 (7) [back to overview] | Change From Baseline in Right Ventricle (RV) Mass to Week 26 |
| NCT02382016 (9) [back to overview] | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) |
| NCT02382016 (9) [back to overview] | Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2) |
| NCT02382016 (9) [back to overview] | Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) |
| NCT02382016 (9) [back to overview] | Change From Baseline to Week 12 in WHO Functional Class (FC) |
| NCT02382016 (9) [back to overview] | Relative Change From Baseline to Week 12 in Pulmonary Vascular Resistance (PVR). |
| NCT02382016 (9) [back to overview] | Change From Baseline to Week 12 in the Biomarker N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) |
| NCT02382016 (9) [back to overview] | Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD) |
| NCT02382016 (9) [back to overview] | Change From Baseline to Week 12 in Cardiac Index |
| NCT02382016 (9) [back to overview] | Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP) |
| NCT02554903 (9) [back to overview] | Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC) |
| NCT02554903 (9) [back to overview] | Change From Baseline to Week 12 in Pulmonary Arterial Wedge Pressure (PAWP) |
| NCT02554903 (9) [back to overview] | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) |
| NCT02554903 (9) [back to overview] | Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) |
| NCT02554903 (9) [back to overview] | Change From Baseline to Week 12 in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels |
| NCT02554903 (9) [back to overview] | Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SvO2) |
| NCT02554903 (9) [back to overview] | Pulmonary Vascular Resistance (PVR) Ratio of Week 12 to Baseline |
| NCT02554903 (9) [back to overview] | Change From Baseline to Week 12 in Cardiac Index (CI) |
| NCT02554903 (9) [back to overview] | Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) |
| NCT02558231 (10) [back to overview] | Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP) |
| NCT02558231 (10) [back to overview] | Change From Baseline to Week 26 in Total Pulmonary Resistance |
| NCT02558231 (10) [back to overview] | Number of Participants With Disease Progression Event |
| NCT02558231 (10) [back to overview] | Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC) |
| NCT02558231 (10) [back to overview] | Change From Baseline to Week 26 in Venous Oxygen Saturation (%) |
| NCT02558231 (10) [back to overview] | Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels |
| NCT02558231 (10) [back to overview] | Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP) |
| NCT02558231 (10) [back to overview] | Change From Baseline to Week 26 in Cardiac Index |
| NCT02558231 (10) [back to overview] | Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) |
| NCT02558231 (10) [back to overview] | Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR) |
| NCT02651272 (12) [back to overview] | Change in NT-proB-type Natriuretic Peptide (NT-pro-BNP) |
| NCT02651272 (12) [back to overview] | Change in Right Arterial Pressure (RAP) |
| NCT02651272 (12) [back to overview] | Change in Systemic Vascular Resistance Index (SVR) |
| NCT02651272 (12) [back to overview] | Change in Systolic Pulmonary Artery Pressure (SPAP) |
| NCT02651272 (12) [back to overview] | Change in Systolic Right Ventricular Pressure (RVSP) |
| NCT02651272 (12) [back to overview] | Number of Participants With Treatment-emergent Adverse Events |
| NCT02651272 (12) [back to overview] | World Health Organization (WHO) Functional Classification |
| NCT02651272 (12) [back to overview] | Assess Change of Borg Dyspnea Index |
| NCT02651272 (12) [back to overview] | Change in 6 Minute Walk Distance (6MWD) |
| NCT02651272 (12) [back to overview] | Change in Cardiac Index (CI) |
| NCT02651272 (12) [back to overview] | Change in Cardiac Output (CO) |
| NCT02651272 (12) [back to overview] | Change in Diastolic Pulmonary Artery Pressure (PADP) |
| NCT03153111 (4) [back to overview] | Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks |
| NCT03153111 (4) [back to overview] | Percent of Baseline N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Assessed at Week 24 |
| NCT03153111 (4) [back to overview] | Change From Baseline to Week 24 in the Clinical Summary Score Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) Score |
| NCT03153111 (4) [back to overview] | Change From Baseline to Week 24 in Accelerometer-assessed Proportion of Time Spent in Light to Vigourous Physical Activity |
| NCT03153137 (27) [back to overview] | Change From Baseline in Peak VO2 Up to Week 52 |
| NCT03153137 (27) [back to overview] | Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment |
| NCT03153137 (27) [back to overview] | Number of Participants With Treatment-emergent Adverse Events (AEs) |
| NCT03153137 (27) [back to overview] | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) |
| NCT03153137 (27) [back to overview] | Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP) |
| NCT03153137 (27) [back to overview] | Change From Baseline in Albumin and Protein |
| NCT03153137 (27) [back to overview] | Change From Baseline in Alpha Fetoprotein |
| NCT03153137 (27) [back to overview] | Change From Baseline in Bilirubin and Direct Bilirubin |
| NCT03153137 (27) [back to overview] | Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) Up to Week 16 |
| NCT03153137 (27) [back to overview] | Change From Baseline in Creatinine |
| NCT03153137 (27) [back to overview] | Change From Baseline in Cystatin C |
| NCT03153137 (27) [back to overview] | Change From Baseline in Erythrocytes and Reticulocytes |
| NCT03153137 (27) [back to overview] | Change From Baseline in Gamma Glutamyl Transferase |
| NCT03153137 (27) [back to overview] | Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium |
| NCT03153137 (27) [back to overview] | Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets |
| NCT03153137 (27) [back to overview] | Change From Baseline in Oxygen Saturation (SpO2) |
| NCT03153137 (27) [back to overview] | Change From Baseline in Prothrombin International Normalized Ratio |
| NCT03153137 (27) [back to overview] | Change From Baseline in Body Weight |
| NCT03153137 (27) [back to overview] | Change From Baseline in Urea Nitrogen |
| NCT03153137 (27) [back to overview] | Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) Up to Week 16 |
| NCT03153137 (27) [back to overview] | Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values |
| NCT03153137 (27) [back to overview] | Change From Baseline in Prothrombin Time |
| NCT03153137 (27) [back to overview] | Change From Baseline in Hematocrit |
| NCT03153137 (27) [back to overview] | Change From Baseline in Pulse Rate |
| NCT03153137 (27) [back to overview] | Change From Baseline in Hemoglobin |
| NCT03153137 (27) [back to overview] | Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) |
| NCT03153137 (27) [back to overview] | Change From Baseline in Urate |
| NCT03714815 (21) [back to overview] | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) up to 30 Days After Study Treatment Discontinuation |
| NCT03714815 (21) [back to overview] | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Body Weight at Week 52 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Bilirubin at Week 52 |
| NCT03714815 (21) [back to overview] | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation |
| NCT03714815 (21) [back to overview] | Change From Baseline in Body Weight at Week 24 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Bilirubin at Week 24 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 52 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 24 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Leukocytes and Platelets at Week 52 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Leukocytes and Platelets at Week 24 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 52 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 24 |
| NCT03714815 (21) [back to overview] | Number of Participants With TEAEs Leading to Premature Discontinuation of Study Treatment |
| NCT03714815 (21) [back to overview] | Number of Participants With All-cause Hospital Admissions up to 30 Days After Study Treatment Discontinuation |
| NCT03714815 (21) [back to overview] | Number of Participants With All-cause Deaths up to 30 Days After Study Treatment Discontinuation |
| NCT03714815 (21) [back to overview] | Change From Baseline in Pulse Rate at Week 24 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Hemoglobin at Week 52 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Hemoglobin at Week 24 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52 |
| NCT03714815 (21) [back to overview] | Change From Baseline in Pulse Rate at Week 52 |
| NCT03775421 (19) [back to overview] | Change From Baseline in Prothrombin Time Over Time |
| NCT03775421 (19) [back to overview] | Number of Participants With TEAEs Leading to Death |
| NCT03775421 (19) [back to overview] | Number of Participants With TEAEs Leading to Premature Discontinuation of Study Treatment |
| NCT03775421 (19) [back to overview] | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities up to 30 Days After Study Treatment Discontinuation |
| NCT03775421 (19) [back to overview] | Change From Baseline in Body Weight Over Time |
| NCT03775421 (19) [back to overview] | Number of Participants With Treatment-emergent Adverse Events (TEAEs) |
| NCT03775421 (19) [back to overview] | Number of Participants With Treatment-emergent Serious AEs (TESAEs) |
| NCT03775421 (19) [back to overview] | Change From Baseline in Glomerular Filtration Rate (GFR) Over Time |
| NCT03775421 (19) [back to overview] | Change From Baseline in Hematocrit Over Time |
| NCT03775421 (19) [back to overview] | Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP), and Gamma Glutamyl Transferase (GGT) Over Time |
| NCT03775421 (19) [back to overview] | Change From Baseline in Bilirubin, Direct Bilirubin, and Creatinine Over Time |
| NCT03775421 (19) [back to overview] | Change From Baseline in Leukocytes, Neutrophils, Lymphocytes, and Platelets Over Time |
| NCT03775421 (19) [back to overview] | Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) |
| NCT03775421 (19) [back to overview] | Change From Baseline in Peripheral Oxygen Saturation (SpO2) Over Time |
| NCT03775421 (19) [back to overview] | Change From Baseline in Prothrombin International Normalized Ratio Over Time |
| NCT03775421 (19) [back to overview] | Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) |
| NCT03775421 (19) [back to overview] | Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) Over Time |
| NCT03775421 (19) [back to overview] | Change From Baseline in Pulse Rate Over Time |
| NCT03775421 (19) [back to overview] | Change From Baseline in Hemoglobin Over Time |
| NCT03904693 (1) [back to overview] | Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline |
Pulmonary Vascular Resistance at Baseline and Month 6
In a sub-study, hemodynamic variables were assessed at baseline and Month 6. If the patient had undergone a right heart catheterization during the 3 months prior to randomization, these results were to be used as baseline values, if the background therapy had not changed during the intervening period. (NCT00660179)
Timeframe: Baseline to month 6
| Intervention | (dyn*sec/cm^5) (Mean) |
|---|
| Baseline | Month 6 |
|---|
| ACT-064992 10 mg | 907 | 680 |
,| ACT-064992 3 mg | 945 | 736 |
,| Placebo | 886 | 1042 |
Cardiac Index at Baseline and Month 6
In a sub-study, hemodynamic variables were assessed at baseline and Month 6. If the patient had undergone a right heart catheterization during the 3 months prior to randomization, these results were to be used as baseline values, if the background therapy had not changed during the intervening period. (NCT00660179)
Timeframe: Baseline to month 6
| Intervention | L/min/m^2 (Mean) |
|---|
| Baseline | Month 6 | Change from Baseline to Month 6 |
|---|
| ACT-064992 10 mg | 2.63 | 2.93 | 0.30 |
,| ACT-064992 3 mg | 2.34 | 2.69 | 0.36 |
,| Placebo | 2.54 | 2.21 | -0.33 |
Change From Baseline to Month 6 in 6-minute Walk Distance
The 6-minute walk test (6MWT) is a non-encouraged test, performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. These guidelines were provided to all sites. For patients who had never performed a 6MWT previously, a training test was required before the qualifying tests for inclusion were performed. (NCT00660179)
Timeframe: Baseline to month 6
| Intervention | metres (Mean) |
|---|
| Baseline | Change from baseline at Month 6 |
|---|
| ACT-064992 10 mg | 363 | 12.5 |
,| ACT-064992 3 mg | 364 | 7.4 |
,| Placebo | 352 | -9.4 |
Summary of the First Causes of Morbidity or Mortality
"Morbidity or mortality events were defined as: a) Death; b) Atrial septostomy; c) Lung transplantation; d) Initiation of intravenous (i.v.) or subcutaneous prostanoids, or; e) Other worsening of pulmonary arterial hypertension (PAH).~Other worsening of PAH was defined by the combined occurrence of all the following 3 events:~At least 15% decrease in the 6 minute walk distance from baseline, confirmed by 2 tests performed on separate days, within 2 weeks.~AND worsening of PAH symptoms including at least one of the following:~a) Increase in WHO Functional Class (WHO FC), or no change in patients in WHO FC IV at baseline; b) Appearance or worsening of signs of right heart failure that did not respond to optimized oral diuretic therapy~AND need for new treatment(s) for PAH that included the following: a) Oral or inhaled prostanoids; b) Oral phosphodiesterase inhibitors; c) Endothelin receptor antagonists (only after discontinuation of study treatment; d) i.v. diuretics" (NCT00660179)
Timeframe: Up to end of treatment (Up to 36 months)
| Intervention | participants (Number) |
|---|
| Other worsening of PAH | Death | Prostanoid initiation (i.v. or s.c.) | Lung transplantation |
|---|
| ACT-064992 10 mg | 59 | 16 | 1 | 0 |
,| ACT-064992 3 mg | 72 | 21 | 1 | 1 |
,| Placebo | 93 | 17 | 6 | 0 |
Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event)
Events of death due to any cause up to the end of study (EOS). The initiation of EOS procedure occurred when the target of 285 events was expected to have been achieved (30 January 2012). (NCT00660179)
Timeframe: Up to end of study (data presented up to month 36)
| Intervention | percentage of participants-Kaplan Meier (Number) |
|---|
| Kaplan-Meier Estimate at Month 6 | Kaplan-Meier Estimate at Month 12 | Kaplan-Meier Estimate at Month 18 | Kaplan-Meier Estimate at Month 24 | Kaplan-Meier Estimate at Month 30 | Kaplan-Meier Estimate at Month 36 |
|---|
| ACT-064992 10 mg | 96.3 | 95.0 | 93.3 | 89.1 | 86.9 | 82.9 |
,| ACT-064992 3 mg | 96.4 | 93.9 | 91.4 | 87.3 | 83.4 | 80.0 |
,| Placebo | 94.7 | 91.4 | 89.3 | 87.2 | 82.6 | 80.7 |
Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event)
Events of death due to any cause up to the end of treatment (plus 7 days) (NCT00660179)
Timeframe: Up to end of treatment (data presented up to month 36)
| Intervention | percentage of participants-Kaplan Meier (Number) |
|---|
| Kaplan-Meier Estimate at Month 6 | Kaplan-Meier Estimate at Month 12 | Kaplan-Meier Estimate at Month 18 | Kaplan-Meier Estimate at Month 24 | Kaplan-Meier Estimate at Month 30 | Kaplan-Meier Estimate at Month 36 |
|---|
| ACT-064992 10 mg | 97.4 | 96.4 | 94.8 | 94.8 | 93.3 | 93.3 |
,| ACT-064992 3 mg | 97.1 | 95.6 | 94.6 | 91.7 | 89.9 | 87.3 |
,| Placebo | 95.2 | 93.6 | 92.4 | 91.7 | 89.8 | 89.8 |
Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event)
Events of PAH or hospitalization for PAH up to the end of treatment included: death due to PAH, or onset of a treatment-emergent adverse event with a fatal outcome due to PAH occurring up to 4 weeks after the end of treatment, or hospitalisation for PAH up to the end of treatment. (NCT00660179)
Timeframe: Up to end of treatment (data presented up to month 36)
| Intervention | percentage of participants-Kaplan Meier (Number) |
|---|
| Kaplan-Meier Estimate at Month 6 | Kaplan-Meier Estimate at Month 12 | Kaplan-Meier Estimate at Month 18 | Kaplan-Meier Estimate at Month 24 | Kaplan-Meier Estimate at Month 30 | Kaplan-Meier Estimate at Month 36 |
|---|
| ACT-064992 10 mg | 94.6 | 89.8 | 84.8 | 81.7 | 77.9 | 70.6 |
,| ACT-064992 3 mg | 90.8 | 84.9 | 78.1 | 75.1 | 70.3 | 67.1 |
,| Placebo | 84.8 | 76.7 | 69.0 | 67.9 | 62.0 | 55.4 |
Time to First Confirmed Morbidity or Mortality Event up to the End of Treatment (Kaplan-Meier Estimate of Patients Without a Morbidity or Mortality Event)
"Morbidity or mortality events were defined as: a) Death; b) Atrial septostomy; c) Lung transplantation; d) Initiation of intravenous (i.v.) or subcutaneous prostanoids, or; e) Other worsening of pulmonary arterial hypertension (PAH).~Other worsening of PAH was defined by the combined occurrence of all the following 3 events:~At least 15% decrease in the 6 minute walk distance from baseline, confirmed by 2 tests performed on separate days, within 2 weeks.~AND worsening of PAH symptoms including at least one of the following:~a) Increase in WHO Functional Class (WHO FC), or no change in patients in WHO FC IV at baseline; b) Appearance or worsening of signs of right heart failure that did not respond to optimized oral diuretic therapy~AND need for new treatment(s) for PAH that included the following: a) Oral or inhaled prostanoids; b) Oral phosphodiesterase inhibitors; c) Endothelin receptor antagonists (only after discontinuation of study treatment; d) i.v. diuretics" (NCT00660179)
Timeframe: Up to end of treatment (data presented up to month 36)
| Intervention | percentage of participants-Kaplan Meier (Number) |
|---|
| Kaplan-Meier estimate at Month 6 | Kaplan-Meier estimate at Month 12 | Kaplan-Meier estimate at Month 18 | Kaplan-Meier estimate at Month 24 | Kaplan-Meier estimate at Month 30 | Kaplan-Meier estimate at Month 36 |
|---|
| ACT-064992 10 mg | 92.7 | 85.5 | 79.9 | 74.3 | 70.0 | 63.2 |
,| ACT-064992 3 mg | 89.3 | 81.6 | 72.5 | 65.5 | 61.9 | 55.0 |
,| Placebo | 80.1 | 71.4 | 61.5 | 57.3 | 50.2 | 47.0 |
Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6
"Class I: no limitation of usual physical activity (PA) which does not increase dyspnea, fatigue, chest pain, or presyncope.~Class II: mild limitation of PA. No discomfort at rest. Normal PA increases dyspnea, fatigue, chest pain, or presyncope.~Class III: marked limitation of PA. No discomfort at rest. Less than ordinary activity increases dyspnea, fatigue, chest pain, or presyncope.~Class IV: unable to perform any PA and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any PA." (NCT00660179)
Timeframe: Baseline to month 6
| Intervention | participants (Number) |
|---|
| Placebo | 32 |
| ACT-064992 3 mg | 49 |
| ACT-064992 10 mg | 54 |
Number of Participants With Death up to 28 Days After Study Treatment Discontinuation
Number of participants with deaths up to 28 days after study treatment discontinuation were reported. (NCT00667823)
Timeframe: Up to 28 days after study treatment discontinuation (Up to 12 years)
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 175 |
Number of Participants With Treatment Emergent Adverse Events (TEAEs) up to 28 Days After Study Treatment Discontinuation
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. (NCT00667823)
Timeframe: Up to 28 days after study treatment discontinuation (Up to 12 years)
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 527 |
Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) up to 28 Days After Study Treatment Discontinuation
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically significant, or requires intervention to prevent at least one of the outcomes listed above. (NCT00667823)
Timeframe: Up to 28 days after study treatment discontinuation (Up to 12 years)
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 354 |
Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation
Number of participants with treatment-emergent abnormal liver tests: Alanine aminotransferase (ALT) greater than (>) 3*upper limit of normal (ULN) or aspartate aminotransferase (AST) >3* ULN, ALT >5* ULN or AST >5*ULN, ALT >8*ULN or AST >8*ULN, total bilirubin (TBIL) >2*ULN, ALT >3*ULN or AST >3*ULN and TBIL >2*ULN at any time were reported. (NCT00667823)
Timeframe: Up to 28 days after study treatment discontinuation (Up to12 years)
| Intervention | Participants (Count of Participants) |
|---|
| ALT or AST >3*ULN | ALT or AST >5*ULN | ALT or AST >8*ULN | TBIL >2*ULN | ALT or AST >3*ULN and (TBIL>2*ULN at any time) |
|---|
| Macitentan 10 mg | 45 | 20 | 11 | 75 | 8 |
Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation
Number of participants with treatment-emergent hemoglobin (HGB) abnormality up to 28 days after study treatment discontinuation were reported. Participants assessed for different categories of HGB were <=80 grams/Liter (g/L), <=100g/L, decrease from baseline >=20 g/L, and decrease from baseline >=50 g/L. (NCT00667823)
Timeframe: Up to 28 days after treatment discontinuation (Up to 12 years)
| Intervention | Participants (Count of Participants) |
|---|
| HGB <= 80 gram/Liter (g/L) | HGB <= 100 g/L | HGB decrease from baseline >= 20 g/L | HGB decrease from baseline >= 50 g/L |
|---|
| Macitentan 10 mg | 33 | 98 | 188 | 29 |
Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment
Number of participants with AEs leading to permanent discontinuation of study treatment were reported. An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. (NCT00667823)
Timeframe: Up to 28 days after study treatment discontinuation (Up to12 years)
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 62 |
Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study
"Disease worsening was indicated by pulmonary function test/idiopathic pulmonary fibrosis worsening (PFT/IPF) or acute respiratory decompensation of IPF.~PFT/IPF worsening was indicated by the occurrence of both of the following: confirmed by two tests at least 4 weeks apart, as defined by the occurrence of both of the following: decrease from baseline ≥ 10% in forced vital capacity and decrease from baseline ≥ 15% in corrected diffusing capacity of the lung for carbon monoxide.~Acute respiratory decompensation of IPF was defined as an unexplained rapid deterioration (over a period of less than 4 weeks) of the patient's condition with increasing shortness of breath requiring oxygen supplementation ≥ 5 L/min to maintain a resting oxygen saturation ≥ 90% or arterial oxygen pressure ≥ 55 mmHg (sea level) or 50 mmHg (high altitude)." (NCT00903331)
Timeframe: Up to end of study (Up to 24 months)
| Intervention | participants (Number) |
|---|
| Patients at Risk of Event at Month 4 | Patients at Risk of Event at Month 8 | Patients at Risk of Event at Month 12 | Patients at Risk of Event at Month 16 | Patients at Risk of Event at Month 20 | Patients at Risk of Event at Month 24 |
|---|
| ACT-064922 | 112 | 103 | 81 | 43 | 14 | 1 |
,| Placebo | 59 | 57 | 44 | 22 | 8 | 2 |
Forced Vital Capacity (FVC) at Baseline and End of Period 1
FVC was measured at baseline and at the end of Period 1. The same equipment and tester were used during the course of the study. The equipment was calibrated and the calibration documented prior to each patient's measurement. The person responsible for conducting the pulmonary function tests was required to comply with the study guidelines and the American Thoracic Society/European Respiratory Society joint criteria on lung function testing. (NCT00903331)
Timeframe: 12 months
| Intervention | litres (Median) |
|---|
| Baseline | End of Period 1 |
|---|
| ACT-064922 | 2.83 | 2.57 |
,| Placebo | 2.74 | 2.40 |
Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16
HAQ-DI assesses functional ability regarding fine movements of the upper extremities, locomotor activities in the lower extremities, and movements of the upper and lower limbs. Responses were extracted from the Scleroderma Health Assessment Questionnaire covering 8 domains of functional disability (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other daily activities). A mean score ranging from 0-3 was calculated for each domain, and a composite score by dividing the summed domain scores by the number of domains. The composite score was interpreted as 0 (no impairment in function) to 3 (maximal impairment of function). (NCT01474109)
Timeframe: Baseline to week 16
| Intervention | units on a scale (Mean) |
|---|
| Baseline | Week 16 |
|---|
| Macitentan 10mg | 1.2 | 1.1 |
,| Macitentan 3mg | 1.1 | 1.1 |
,| Placebo | 1.1 | 1.1 |
Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16
HAQ-DI assesses functional ability regarding fine movements of the upper extremities, locomotor activities in the lower extremities, and movements of the upper and lower limbs. Responses were extracted from the Scleroderma Health Assessment Questionnaire covering 8 domains of functional disability (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other daily activities). A mean score ranging from 0-3 was calculated for each domain, and a composite score by dividing the summed domain scores by the number of domains. The composite score was interpreted as 0 (no impairment in function) to 3 (maximal impairment of function). Hand functionality was assessed using a composite of 4 domains (dressing and grooming, grip, hygiene, and eating). (NCT01474109)
Timeframe: Baseline to week 16
| Intervention | units on a scale (Mean) |
|---|
| Baseline | Week 16 |
|---|
| Macitentan 10mg | 1.4 | 1.2 |
,| Macitentan 3mg | 1.3 | 1.2 |
,| Placebo | 1.3 | 1.2 |
Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16
Patients were asked to answer 24 questions on the use of the hand(s) affected by DUs over the past 7 days on a 6-point scale from 0 (yes without difficulty) to 5 (impossible). The HDISS-DU score is the arithmetic mean of the valid non-missing items. The scores are interpreted as 1 (better ability in completing activities) to 6 (worst ability in completing activities) (NCT01474109)
Timeframe: Baseline to week 16
| Intervention | units on a scale (Mean) |
|---|
| Baseline | Week 16 |
|---|
| Macitentan 10mg | 3.0 | 2.6 |
,| Macitentan 3mg | 3.0 | 2.7 |
,| Placebo | 3.0 | 2.7 |
Percentage of Participants Without a New DU Up To Week 16
DUs were assessed at each visit starting with the screening visit. Only DUs from the proximal interphalangeal joint (PIP) distally (both on the dorsal and volar surface of the hand, including the digital tip) were recorded. The location of each DU was noted. At each subsequent visit the location of each new DU was noted. DUs that occurred and healed between visits and were reported by patients were not recorded as new DUs. The evaluation was performed by an experienced physician or a trained rater with expertise in the assessment of DUs in systemic sclerosis (SSc). For a given patient, DUs were assessed by the same rater at each visit, whenever possible. Any DU that developed over a previously healed ulcer was recorded as a new DU. Numbers of patients with no new DU at Week 16 are imputed using the last observation carried forward method. (NCT01474109)
Timeframe: Baseline to week 16
| Intervention | Percentage of participants (Number) |
|---|
| Macitentan 3mg | 64.1 |
| Macitentan 10mg | 63.0 |
| Placebo | 67.0 |
Percentage of Participants With at Least One DU Complication
DU complications were defined as any one of the following, resulting from DU worsening: critical ischemic crisis necessitating hospitalization; gangrene, (auto)amputation; failure of conservative management; surgical and chemical sympathectomy, vascular reconstructions, or any unplanned surgery in the management of hand SSc manifestations; use of parenteral prostanoids; use of endothelin-receptor antagonists; class II, III, or IV narcotics or a > 50% increase in the existing dose compared with baseline; initiation of systemic antibiotics for the treatment of infection attributed to DUs. (NCT01474109)
Timeframe: Up to approximately 90 weeks
| Intervention | percentage of participants (Number) |
|---|
| Macitentan 3mg | 14.1 |
| Macitentan 10mg | 19.6 |
| Placebo | 19.1 |
Incidence Rate of New Digital Ulcers (DUs) up to Week 16
DUs were assessed at each visit starting with the screening visit. Only DUs from the proximal interphalangeal joint (PIP) distally (both on the dorsal and volar surface of the hand, including the digital tip) were recorded. The location of each DU was noted. At each subsequent visit the location of each new DU was noted. DUs that occurred and healed between visits and were reported by patients were not recorded as new DUs. The evaluation was performed by an experienced physician or a trained rater with expertise in the assessment of DUs in systemic sclerosis (SSc). For a given patient, DUs were assessed by the same rater at each visit, whenever possible. Any DU that developed over a previously healed ulcer was recorded as a new DU. Incidence rate is adjusted for 16 weeks of observation, hence is calculated as the number of new DUs/total number of observation days. (NCT01474109)
Timeframe: Baseline to week 16
| Intervention | number of new DUs/observation days (Number) |
|---|
| Macitentan 3mg | 0.9082 |
| Macitentan 10mg | 0.9567 |
| Placebo | 0.8115 |
Percentage of Participants Without a New DU up to Week 16
DUs were assessed at each visit starting with the screening visit. Only DUs from the proximal interphalangeal joint (PIP) distally (both on the dorsal and volar surface of the hand, including the digital tip) were recorded. The location of each DU was noted. At each subsequent visit the location of each new DU was noted. DUs that occurred and healed between visits and were reported by patients were not recorded as new DUs. The evaluation was performed by an experienced physician or a trained rater with expertise in the assessment of DUs in systemic sclerosis (SSc). For a given patient, DUs were assessed by the same rater at each visit, whenever possible. Any DU that developed over a previously healed ulcer was recorded as a new DU. Numbers of patients with no new DU at Week 16 are imputed using the last observation carried forward method. (NCT01474122)
Timeframe: Baseline to Week 16
| Intervention | Percentage of participants (Number) |
|---|
| Macitentan 3mg | 56.0 |
| Macitentan 10mg | 54.8 |
| Placebo | 59.8 |
Percentage of Participants With at Least One DU Complication
"DU complications were defined as any one of the following:~resulting from DU worsening: critical ischemic crisis necessitating hospitalization; gangrene, (auto)amputation; failure of conservative management; surgical and chemical sympathectomy, vascular reconstructions, or any unplanned surgery in the management of hand SSc manifestations; use of parenteral prostanoids; use of endothelin-receptor antagonists; class II, III, or IV narcotics or a > 50% increase in the existing dose compared with baseline; initiation of systemic antibiotics for the treatment of infection attributed to DUs." (NCT01474122)
Timeframe: Up to 95 weeks
| Intervention | Percentage of participants (Number) |
|---|
| Macitentan 3mg | 21.4 |
| Macitentan 10mg | 19.0 |
| Placebo | 18.4 |
Incidence Rate of New Digital Ulcers (DUs) up to Week 16
DUs were assessed at each visit starting with the screening visit. Only DUs from the proximal interphalangeal joint (PIP) distally (both on the dorsal and volar surface of the hand, including the digital tip) were recorded. The location of each DU was noted. At each subsequent visit the location of each new DU was noted. DUs that occurred and healed between visits and were reported by patients were not recorded as new DUs. The evaluation was performed by an experienced physician or a trained rater with expertise in the assessment of DUs in systemic sclerosis (SSc). For a given patient, DUs were assessed by the same rater at each visit, whenever possible. Any DU that developed over a previously healed ulcer was recorded as a new DU. Incidence rate is adjusted for 16 weeks of observation, hence is calculated as the number of new DUs/total number of observation days. (NCT01474122)
Timeframe: Baseline to Week 16
| Intervention | new DUs/16 weeks (Number) |
|---|
| Macitentan 3mg | 1.4413 |
| Macitentan 10mg | 1.3636 |
| Placebo | 1.1049 |
Health Assessment Questionnaire - Disability Index (HAQ-DI) Overall Score From Baseline to Week 16
HAQ-DI assesses functional ability regarding fine movements of the upper extremities, locomotor activities in the lower extremities, and movements of the upper and lower limbs. Responses were extracted from the Scleroderma Health Assessment Questionnaire covering 8 domains of functional disability (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other daily activities). A mean score ranging from 0-3 was calculated for each domain, and a composite score by dividing the summed domain scores by the number of domains. The composite score was interpreted as 0 (no impairment in function) to 3 (maximal impairment of function). (NCT01474122)
Timeframe: Baseline to Week 16
| Intervention | Units on a scale (Mean) |
|---|
| Baseline | Week 16 |
|---|
| Macitentan 10mg | 1.1 | 1.0 |
,| Macitentan 3mg | 1.2 | 1.1 |
,| Placebo | 1.2 | 1.2 |
Change in Hand Functionality Health Assessment Questionnaire - Disability Index (HAQ-DI) Hand Component From Baseline to Week 16
HAQ-DI assesses functional ability regarding fine movements of the upper extremities, locomotor activities in the lower extremities, and movements of the upper and lower limbs. Responses were extracted from the Scleroderma Health Assessment Questionnaire covering 8 domains of functional disability (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other daily activities). A mean score ranging from 0-3 was calculated for each domain, and a composite score by dividing the summed domain scores by the number of domains. The composite score was interpreted as 0 (no impairment in function) to 3 (maximal impairment of function). Hand functionality was assessed using a composite of 4 domains (dressing and grooming, grip, hygiene, and eating). (NCT01474122)
Timeframe: Baseline to Week 16
| Intervention | Units on a scale (Mean) |
|---|
| Baseline | Week 16 |
|---|
| Macitentan 10mg | 1.3 | 1.1 |
,| Macitentan 3mg | 1.4 | 1.2 |
,| Placebo | 1.4 | 1.3 |
Change in Hand Functionality - Hand Disability in Systemic Sclerosis - Digital Ulcers (HDISS-DU) Score From Baseline to Week 16
Patients were asked to answer 24 questions on the use of the hand(s) affected by DUs over the past 7 days on a 6-point scale from 0 (yes without difficulty) to 5 (impossible). The HDISS-DU score is the arithmetic mean of the valid non-missing items. The scores are interpreted as 1 (better ability in completing activities) to 6 (worst ability in completing activities) (NCT01474122)
Timeframe: Baseline to Week 16
| Intervention | Units on a scale (Mean) |
|---|
| Baseline | Week 16 |
|---|
| Macitentan 10mg | 2.9 | 2.7 |
,| Macitentan 3mg | 3.0 | 2.8 |
,| Placebo | 2.9 | 2.9 |
Change in WHO Functional Class (FC) at Month 6 and 12
Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing stairs). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure. For missing WHO FC values in the OL study, the following imputation rules were applied: If the reason for missing data was death, class IV was imputed for all WHO visits from the date of death. For any other reasons, the last available value was carried forward. (NCT01739400)
Timeframe: From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.
| Intervention | Participants (Count of Participants) |
|---|
| WHO functional class I at DB study baseline | WHO functional class II at DB study baseline | WHO functional class III at DB study baseline | WHO functional class IV at DB study baseline | WHO functional class I at Week 16 in DB study | WHO functional class II at Week 16 in DB study | WHO functional class III at Week 16 in DB study | WHO functional class IV at Week 16 in DB study | Improvement from DB study baseline to Week 16 | Worsening from DB study baseline to Week 16 | WHO functional class I at Month 6 in OL study | WHO functional class II at Month 6 in OL study | WHO functional class III at Month 6 in OL study | WHO functional class IV at Month 6 in OL study | Improvement from DB study baseline to Month 6 | Worsening from DB study baseline to Month 6 | WHO functional class I at Month 12 in OL study | WHO functional class II at Month 12 in OL study | WHO functional class III at Month 12 in OL study | WHO functional class IV at Month 12 in OL study | Improvement from DB study baseline to Month 12 | Worsening from DB study baseline to Month 12 |
|---|
| DB-macitentan | 0 | 66 | 43 | 0 | 3 | 70 | 36 | 0 | 10 | 0 | 5 | 74 | 28 | 2 | 19 | 3 | 5 | 74 | 28 | 2 | 20 | 4 |
,| DB-placebo | 0 | 65 | 43 | 0 | 1 | 77 | 30 | 0 | 15 | 1 | 7 | 79 | 22 | 0 | 27 | 1 | 7 | 79 | 22 | 0 | 31 | 3 |
Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12
No imputation of missing data for SpO2 was applied. Oxygen saturation assessed by pulse oximetry: peripheral oxygen saturation (SpO2) at rest before the 6-minute walk test (6MWT) (NCT01739400)
Timeframe: From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.
| Intervention | % of oxygen saturation at rest (Mean) |
|---|
| SpO2 at DB study baseline | SpO2 at Week 16 in DB study | Change in SpO2 from DB study baseline to Week 16 | SpO2 at Month 6 in OL study | Change in SpO2 from DB study baseline to Month 6 | SpO2 at Month 12 in OL study | Change in SpO2 from DB study baseline to Month 12 |
|---|
| DB-macitentan | 84.2 | 85.3 | 1.1 | 85.9 | 1.5 | 86.4 | 2.0 |
,| DB-placebo | 85.4 | 85.6 | 0.2 | 87.4 | 2.0 | 87.1 | 1.6 |
Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12
NOTE: The MAESTRO-OL study was exploratory in nature and no primary efficacy and safety endpoint were defined in the clinical protocol. This and the other exploratory efficacy outcome measures posted were selected to be reported as a primary endpoints. All efficacy analyses were considered exploratory. The analyses of the exploratory efficacy endpoints focused on the absolute values and on the change from DB baseline to Week 16 in the DB study and to Month 6 and Month 12 in the OL study. For missing 6MWD values in the OL study, the following imputation rules were applied: If the reason for missing data was death, a distance of zero (0) meters was imputed for all 6MWD visits from the date of death. For any other reasons, the last available value was carried forward. (NCT01739400)
Timeframe: From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.
| Intervention | meter (m) (Mean) |
|---|
| 6MWD at DB study baseline | 6MWD at Week 16 in DB study | Change in 6MWD from DB study baseline to Week 16 | 6MWD at Month 6 in OL study | Change in 6MWD from DB study baseline to Month 6 | 6MWD at Month 12 in OL study | Change in 6MWD from DB study baseline to Month 12 |
|---|
| DB-macitentan | 370.6 | 395.1 | 24.4 | 396.8 | 26.2 | 397.1 | 26.5 |
,| DB-placebo | 381.6 | 399.9 | 18.2 | 425.0 | 43.4 | 421.5 | 39.9 |
Change in Borg Dyspnea Score at Month 6 and 12
The Borg dyspnea score rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). For missing Borg dyspnea index values in the OL study, the following imputation rules were applied: If the reason for missing data was death, a value of 10 was imputed for all Borg visits from the date of death. For any other reasons, the last available value was carried forward. (NCT01739400)
Timeframe: From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.
| Intervention | score on a scale (Mean) |
|---|
| Borg dyspnea score at DB study baseline | Borg dyspnea score at Week 16 in DB study | Change from DB study baseline to Week 16 | Borg dyspnea score at Month 6 in OL study | Change from DB study baseline to Month 6 | Borg dyspnea score at Month 12 in OL study | Change from DB study baseline to Month 12 |
|---|
| DB-macitentan | 3.0 | 2.7 | -0.3 | 2.8 | -0.1 | 2.9 | -0.1 |
,| DB-placebo | 2.9 | 1.9 | -0.2 | 2.5 | -0.4 | 2.6 | -0.3 |
Change From Baseline to Week 16 in WHO Functional Class
A shift in WHO functional classes is considered an 'improvement' when shifting to a lower class (e.g. from class III to class II) or a 'worsening' when shifting to a higher class (e.g. from class III to class IV). Definition of functional classes as follows - Class I: no symptoms with exercise or at rest. Class II: No symptoms at rest but uncomfortable and short of breath with normal activity such as climbing a flight of stairs, grocery shopping, or making the bed. Class III: May not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting (e.g. doing normal chores around the house, have to take breaks while doing activities of daily living). Class IV: Symptoms at rest and severe symptoms with any activity. Most patients also have edema in the feet and ankles as result of right heart failure. (NCT01743001)
Timeframe: From baseline to Week 16
| Intervention | Participants (Count of Participants) |
|---|
| WHO functional class 1 at Week 16 | WHO functional class 2 at Week 16 | WHO functional class 3 at Week 16 | WHO functional class 4 at Week 16 | Unchanged from baseline to Week 16 | Improvement from baseline to Week 16 | Worsening from baseline to Week 16 |
|---|
| Macitentan | 3 | 72 | 38 | 1 | 103 | 10 | 1 |
,| Placebo | 1 | 79 | 32 | 0 | 95 | 16 | 1 |
Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index
This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 16 compared to baseline. The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement. (NCT01743001)
Timeframe: From baseline to Week 16
| Intervention | Score on a scale (Mean) |
|---|
| Borg dyspnea index score at baseline | Borg dyspnea index score at Week 16 | Change from baseline to Week 16 |
|---|
| Macitentan | 3.00 | 2.78 | -0.22 |
,| Placebo | 2.94 | 2.66 | -0.29 |
Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD)
The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. (NCT01743001)
Timeframe: From baseline to Week 16
| Intervention | meter (Mean) |
|---|
| 6MWD at baseline | 6MWD at Week 16 | Change in 6MWD from baseline to Week 16 |
|---|
| Macitentan | 368.7 | 387.1 | 18.3 |
,| Placebo | 380.3 | 399.9 | 19.7 |
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. (NCT01841762)
Timeframe: From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.
| Intervention | Intra-class correlation coefficient (Number) |
|---|
| ICCs of Cardiopulmonary Symptoms domain | ICCs of Cardiovascular Symptoms domain | ICCs of Physical Impacts domain | ICCs of Cognitive/Emotional Impacts domain |
|---|
| Macitentan | 0.94 | 0.93 | 0.91 | 0.84 |
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. (NCT01841762)
Timeframe: From ePRO period 1 (Days -14 to -8) to ePRO period 2 (Days -7 to -1) in screening period.
| Intervention | Ratio of variance (Number) |
|---|
| Cronbach's Alpha for Cardiopulmonary Symptoms | Cronbach's Alpha for Cardiovascular Symptoms | Cronbach's Alpha for Physical Impacts Domain | Cronbach's Alpha for Cognitive/Emotional Impacts |
|---|
| Macitentan | 0.81 | 0.88 | 0.92 | 0.87 |
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. (NCT01841762)
Timeframe: From Day 1 (Baseline Visit) to End of Study visit (EoS).
| Intervention | Participants (Count of Participants) |
|---|
| Participants with AEs | Participants with severe intensity AEs | Participants with SAEs | Participants prematurely discontinued study drug |
|---|
| Macitentan | 228 | 36 | 49 | 17 |
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. (NCT01841762)
Timeframe: From Screening Visit (Day -14) to End of Treatment (EOT) Visit (Visit 4, Week 16)
| Intervention | Items (Number) |
|---|
| Item number in symptoms part of baseline | Item number in symptoms part at Week 16 | Item number in impacts part at baseline | Item number in impacts part at Week 16 |
|---|
| Macitentan | 16 | 11 | 25 | 11 |
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. (NCT01841762)
Timeframe: From Screening period (Days -7 to -1) to Week 16 (7-day period prior to Week 16 visit).
| Intervention | Score on a scale (Median) |
|---|
| Cardiopulmonary Symptoms domain score at baseline | Cardiopulmonary Symptoms domain score at Week 8 | Cardiopulmonary Symptoms domain score at Week 16 | Cardiovascular Symptoms domain score at baseline | Cardiovascular Symptoms domain score at Week 8 | Cardiovascular Symptoms domain score at Week 16 | Physical Impacts domain score at baseline | Physical Impacts domain score at Week 8 | Physical Impacts domain score at Week 16 | Cogn./Emotional Impacts domain score at baseline | Cogn./Emotional Impacts domain score at Week 8 | Cogn./Emotional Impacts domain score at Week 16 |
|---|
| Macitentan | 1.0 | 0.8 | 0.7 | 0.4 | 0.2 | 0.2 | 1.3 | 1.0 | 0.9 | 0.8 | 0.8 | 0.5 |
Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Corrected Hemodynamic Values
The main analysis of the primary efficacy endpoint of PVR was repeated which excluded data for 13 subjects with corrected hemodynamic values. The hemodynamic values were reported after the SDV assessment clinical database closure. (NCT02021292)
Timeframe: From baseline to Week 16
| Intervention | Percent of baseline PVR (Geometric Mean) |
|---|
| Macitentan | 68.4 |
| Placebo | 86.1 |
Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest.
The primary efficacy endpoint is defined as the PVR at rest at Week 16 expressed as percent of baseline PVR at rest. (NCT02021292)
Timeframe: From baseline to Week 16
| Intervention | percent of baseline PVR (Geometric Mean) |
|---|
| Macitentan | 73.0 |
| Placebo | 87.2 |
Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24
WHO functional classes are defined as follows: 1) class I: no symptoms with exercise or at rest. No limitation of activity. 2) class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). 3) class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. 4) class IV: symptoms at rest (such as dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms (e.g. may faint especially while bending over with their heads lowered). Patients in class IV manifest signs of right heart failure. Shifting to a higher class (e.g. from class III to class IV) represents a 'worsening' while shifting to a lower class (e.g. from class III to class II) means an 'improvement'. (NCT02021292)
Timeframe: From baseline to Week 24
| Intervention | Participants (Count of Participants) |
|---|
| WHO functional class I at baseline | WHO functional class II at baseline | WHO functional class III at baseline | WHO functional class IV at baseline | WHO functional class I at Week 24 | WHO functional class II at Week 24 | WHO functional class III at Week 24 | WHO functional class IV at Week 24 | Worsened | Not worsened - total | Not Worsened - unchanged | Not worsened - improved |
|---|
| Macitentan | 0 | 12 | 28 | 0 | 3 | 15 | 22 | 0 | 0 | 40 | 31 | 9 |
,| Placebo | 0 | 6 | 33 | 1 | 1 | 10 | 26 | 3 | 3 | 37 | 29 | 8 |
Post-hoc Analysis of Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD) Excluding Subjects With Implausible Hemodynamic Findings
The same analysis for the secondary endpoint, 6MWD, is repeated on the full analysis set excluding 14 subjects with implausible hemodynamic findings. (NCT02021292)
Timeframe: From baseline to Week 24
| Intervention | meter (Least Squares Mean) |
|---|
| Macitentan | 37.41 |
| Placebo | 0.23 |
Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Implausible Hemodynamic Findings
The main analysis of the primary efficacy endpoint of PVR was repeated which excluded 14 subjects with implausible hemodynamic findings. (NCT02021292)
Timeframe: From baseline to Week 16
| Intervention | Percent of baseline PVR (Geometric Mean) |
|---|
| Macitentan | 73.9 |
| Placebo | 86.6 |
Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD).
The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. (NCT02021292)
Timeframe: From baseline to Week 24
| Intervention | meter (Mean) |
|---|
| 6MWD (m) at baseline | 6MWD (m) at Week 24 | Change in 6MWD (m) from baseline to Week 24 |
|---|
| Macitentan | 353.0 | 388.0 | 35.0 |
,| Placebo | 351.2 | 352.2 | 1.0 |
Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT).
This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 24 compared to baseline. The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement. (NCT02021292)
Timeframe: From baseline to Week 24
| Intervention | Score on a scale (Mean) |
|---|
| Borg dyspnea index score at baseline | Borg dyspnea index score at Week 24 | Change from baseline to Week 24 |
|---|
| Macitentan | 4.2 | 4.1 | -0.1 |
,| Placebo | 4.2 | 4.4 | 0.3 |
Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Including Subjects With Corrected Hemodynamic Values
The main analysis of the primary efficacy endpoint of PVR was repeated after the voluntary right heart catheterization source data verification (SDV) and independent medical review of hemodynamic data corrected for 13 subjects reported after the clinical database closure. (NCT02021292)
Timeframe: From baseline to Week 16
| Intervention | Percent of baseline PVR (Geometric Mean) |
|---|
| Macitentan | 71.5 |
| Placebo | 87.6 |
Number of Participants With Hemoglobin Abnormalities
Number of participants with hemoglobin abnormalities were reported. It included hemoglobin less than (<) 80 grams per liter (g/L), hemoglobin <100 g/L, hemoglobin greater than or equal to (>=) 80 g/L and <100 g/L, hemoglobin <100g/L and a decrease of >20 g/L from baseline, decrease of >20 g/L in hemoglobin from baseline, decrease of >20 g/L and <=50 g/L in hemoglobin from baseline, and decrease of >50 g/L in hemoglobin from baseline. (NCT02060721)
Timeframe: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 1 to 82 months)
| Intervention | Participants (Count of Participants) |
|---|
| Hemoglobin < 80 g/L | Hemoglobin <100 g/L | Hemoglobin >= 80 g/L and <100 g/L | Hemoglobin <100g/L and a decrease of >20 g/L from baseline | Decrease of >20 g/L in hemoglobin from baseline | Decrease of >20 g/L and <=50 g/L in hemoglobin from baseline | Decrease of >50 g/L in hemoglobin from baseline |
|---|
| Macitentan 10 Milligrams (mg) | 0 | 7 | 7 | 6 | 32 | 31 | 5 |
Number of Participants With Liver Tests Abnormalities
Number of participants with liver tests abnormalities were reported. It included alanine aminotransferase (ALT) or aspartate aminotransferase (AST): >=3 x Upper limit of the normal range (ULN), >=3 and <5 x ULN, >=5 ULN, and >=5 and <8 x ULN, >= 8 x ULN, and total bilirubin >=2 x ULN. (NCT02060721)
Timeframe: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 1 to 82 months)
| Intervention | Participants (Count of Participants) |
|---|
| ALT or AST >=3 x ULN | ALT or AST >=3 and <5 x ULN | ALT or AST >=5 x ULN | ALT or AST >=5 and <8 x ULN | ALT or AST >=8 x ULN | Total Bilirubin >=2 x ULN |
|---|
| Macitentan 10 Milligrams (mg) | 2 | 1 | 1 | 0 | 1 | 8 |
Change From Baseline in Body Weight at Month 6
Change from baseline in body weight at Month 6 was reported. (NCT02060721)
Timeframe: Baseline and Month 6
| Intervention | kilograms (kg) (Mean) |
|---|
| Macitentan 10 Milligrams (mg) | -0.35 |
Change From Baseline in Pulse Rate at Month 6
Change from baseline in pulse rate at Month 6 was reported. (NCT02060721)
Timeframe: Baseline and Month 6
| Intervention | Beats per minute (Mean) |
|---|
| Macitentan 10 Milligrams (mg) | -1.1 |
Number of Participants With AEs Leading to Study Drug Discontinuation
Number of participants with AEs leading to study drug discontinuation was reported. (NCT02060721)
Timeframe: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 1 to 82 months)
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 Milligrams (mg) | 9 |
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. TEAEs are those events that started after administration of the first dose and up to safety follow-up visit/end of study, that is, 30 days after the last dose of study medication. (NCT02060721)
Timeframe: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 1 to 82 months)
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 Milligrams (mg) | 72 |
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)
A serious adverse event (SAE) is any untoward medical occurrence that at any dose resulting in any of following outcomes: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product. Treatment-emergent SAEs were those events that started after administration of the first dose and up to safety follow-up visit/end of study, that is, 30 days after the last dose of study medication. (NCT02060721)
Timeframe: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 1 to 82 months)
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 Milligrams (mg) | 44 |
Change From Baseline in Blood Pressure at Month 6
Change from baseline in blood pressure at Month 6 (both systolic blood pressure [SBP] and diastolic blood pressure [DBP]) was reported. (NCT02060721)
Timeframe: Baseline and Month 6
| Intervention | Millimeters of mercury (mmHg) (Mean) |
|---|
| SBP | DBP |
|---|
| Macitentan 10 Milligrams (mg) | -0.4 | -2.8 |
PVR at Rest at Week 12 Expressed as Percent of Baseline PVR at Rest
Pulmonary vascular resistance (PVR) was assessed at rest by right heart catheterization (RHC). (NCT02070991)
Timeframe: From randomization up to end of treatment period (Week 12)
| Intervention | percentage of baseline PVR (Geometric Mean) |
|---|
| Macitentan | 66.31 |
| Placebo | 71.23 |
NT-proBNP at Week 12 Expressed as Percent of Baseline NT-proBNP at Rest
(NCT02070991)
Timeframe: From randomization up to end of treatment period (Week 12)
| Intervention | percentage of baseline NT-proBNP (Geometric Mean) |
|---|
| Macitentan | 91.56 |
| Placebo | 118.90 |
Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP)
(NCT02070991)
Timeframe: From randomization up to end of treatment period (Week 12)
| Intervention | mmHg (Mean) |
|---|
| PAWP at baseline | PAWP at Week 12 | Change in PAWP from baseline to Week 12 |
|---|
| Macitentan | 19.1 | 19.9 | 0.8 |
,| Placebo | 19.7 | 20.8 | 1.1 |
Change From Baseline to Week 12 in Cardiac Index (CI)
(NCT02070991)
Timeframe: From randomization up to end of treatment period (Week 12)
| Intervention | L/min/m^2 (Mean) |
|---|
| CI at baseline | CI at Week 12 | Change in CI from baseline to Week 12 |
|---|
| Macitentan | 2.32 | 2.69 | 0.37 |
,| Placebo | 2.33 | 2.30 | -0.03 |
Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG)
(NCT02070991)
Timeframe: From randomization up to end of treatment period (Week 12)
| Intervention | mmHg (Mean) |
|---|
| DPG at baseline | DPG at Week 12 | Change in DPG from baseline to Week 12 |
|---|
| Macitentan | 11.8 | 7.0 | -4.8 |
,| Placebo | 11.4 | 7.0 | -4.3 |
Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP)
(NCT02070991)
Timeframe: From randomization up to end of treatment period (Week 12)
| Intervention | mmHg (Mean) |
|---|
| mPAP at baseline | mPAP at Week 12 | Change in mPAP from baseline to Week 12 |
|---|
| Macitentan | 44.6 | 41.1 | -3.5 |
,| Placebo | 45.9 | 42.1 | -3.8 |
Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)
(NCT02070991)
Timeframe: From randomization up to end of treatment period (Week 12)
| Intervention | mmHg (Mean) |
|---|
| mRAP at baseline | mRAP at Week 12 | Change in mRAP from baseline to Week 12 |
|---|
| Macitentan | 12.1 | 11.2 | -0.9 |
,| Placebo | 13.0 | 11.3 | -1.6 |
Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment
The main endpoint is the number of participants who had at least one of the following: A) significant fluid retention, defined as increase in body weight at any time by ≥ 5% or ≥ 5 kg from baseline due to fluid overload and/or parenteral administration of diuretics. B) Worsening of NYHA functional class from baseline. (NCT02070991)
Timeframe: From randomization up to End-of-Study (Week 12 + 30 days follow-up) plus 1 calendar day
| Intervention | Participants (Count of Participants) |
|---|
| Total participants with at least one condition | Participants with fluid retention | Participants with worsening in NYHA FC | Participants with both conditions |
|---|
| Macitentan | 7 | 7 | 1 | 1 |
,| Placebo | 4 | 3 | 2 | 1 |
Evaluation of the Reliability and the Construct Validity of the Cognitive/Emotional Impacts Domain of the PAH-SYMPACT
"The Cognitive/Emotional Impacts domain consists of 4 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to not at all/with no difficulty at all and value 4 corresponds to very much/extremely/ not able at all. The impacts part of the PAH-SYMACT was administered on Day 7 of the symptoms part administration. Items in the impact part have a 7 day recall period. An average Cognitive/Emotional Impacts domain score is determined based on the 4 items in the domain. It was administered two times prior to administration of Macitentan (Visit 2, Baseline) and during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16)." (NCT02081690)
Timeframe: From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)
| Intervention | Score on a scale (Mean) |
|---|
| Cogn/Emotional Impacts domain score at baseline | Cogn/Emotional Impacts domain score at week 8 | Cogn/Emotional Impacts domain score at week 16 |
|---|
| Macitentan | 0.87 | 0.88 | 0.91 |
Evaluation of the Reliability and the Construct Validity of the Cardiovascular Symptoms Domain of the PAH-SYMPACT
"The Cardiovascular Symptoms domain consists of 5 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to no symptoms and value 4 corresponds to very severe symptoms. The symptoms part of the PAH-SYMPACT was administered daily over a 7 day period. The recall period of symptom items is the last 24 hours. An average Cardiovascular Symptoms domain score is determined based on the daily scores of the 5 items. It was administered two times (daily during 7 days each time) prior to administration of Macitentan (Visit 2, Baseline) and daily during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16)." (NCT02081690)
Timeframe: From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)
| Intervention | Score on a scale (Median) |
|---|
| Cardiovascular Symptoms domain score at baseline | Cardiovascular Symptoms domain score at week 8 | Cardiovascular Symptoms domain score at week 16 |
|---|
| Macitentan | 0.58 | 0.54 | 0.54 |
Evaluation of the Reliability and the Construct Validity of the Cardiopulmonary Symptoms Domain of the PAH-SYMPACT
"The Cardiopulmonary Symptoms domain consists of 6 items reported on a 5-point Likert scale (from 0 to 4). The value 0 means no symptom and value 4 corresponds to very severe symptoms.The symptoms part of the PAH-SYMPACT was administered daily over a 7 day period. The recall period of symptom items is the last 24 hours. An average Cardiopulmonary Symptoms domain score is determined based on the daily scores of the 6 items. It was administered two times (daily during 7 days each time) prior to administration of Macitentan (Visit 2, Baseline) and daily during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16)." (NCT02081690)
Timeframe: From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)
| Intervention | Score on a scale (Mean) |
|---|
| Cardiopulmonary Symptoms domain score at baseline | Cardiopulmonary Symptoms domain score at week 8 | Cardiopulmonary Symptoms domain score at week 16 |
|---|
| Macitentan | 0.90 | 0.89 | 0.89 |
Evaluation of the Reliability and the Construct Validity of the Physical Impacts Domain of the PAH-SYMPACT
"The Physical Impacts domain consists of 7 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to not at all/with no difficulty at all and value 4 corresponds to very much/extremely/ not able at all. The impacts part of the PAH-SYMACT was administered on Day 7 of the symptoms part administration. Items in the impact part have a 7 day recall period. An average Physical Impacts domain score is determined based on the 7 items in the domain. It was administered two times prior to administration of Macitentan (Visit 2, Baseline) and during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16)." (NCT02081690)
Timeframe: From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)
| Intervention | Score on a scale (Mean) |
|---|
| Physical Impacts domain score at baseline | Physical Impacts domain score at week 8 | Physical Impacts domain score at week 16 |
|---|
| Macitentan | 1.13 | 1.15 | 1.25 |
Change From Baseline in Right Ventricular End Diastolic Volume (RVEDV) to Week 26
Change from baseline to Week 26 in RVEDV assessed by cardiac MRI was reported. (NCT02310672)
Timeframe: Baseline to Week 26
| Intervention | mL (Least Squares Mean) |
|---|
| Macitanten 10 mg | -6.22 |
Change From Baseline in Right Ventricular Ejection Fraction (RVEF) to Week 26 (% Blood Volume)
Change from baseline to Week 26 in RVEF based on pulmonary artery flow assessed by cardiac MRI was reported. (NCT02310672)
Timeframe: Baseline to Week 26
| Intervention | Percentage of blood volume (Least Squares Mean) |
|---|
| Macitanten 10 mg | 10.14 |
Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR)
Ratio of Week 26 to baseline PVR as assessed by RHC was reported. PVR represents the resistance against which the right ventricle needs to pump. PVR is determined by right heart catheterization (RHC). PVR was calculated as 80*(Mean pulmonary arterial pressure [mPAP] -[Pulmonary capillary wedge pressure {PCWP} or Left ventricular end diastolic pressure {LVEDP} if PCWP not available/cardiac output [CO]). Primary analysis were based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is. (NCT02310672)
Timeframe: Baseline and Week 26
| Intervention | Ratio (Geometric Mean) |
|---|
| Macitanten 10 mg | 0.63 |
Change From Baseline in Six-minutes Walk Distance (6MWD) to Week 26
6MWD is a non-encouraged test performed in a 30 meter (m) long flat corridor, where the participant is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. This test is used to assess exercise capacity. The test was performed about 30 minutes after study drug administration. Any increase in the walk distance was considered improvement from baseline. (NCT02310672)
Timeframe: Baseline to Week 26
| Intervention | Meters (Least Squares Mean) |
|---|
| Macitanten 10 mg | 38.85 |
Change From Baseline in Right Ventricular Stroke Volume (RVSV) to Week 26
Change from baseline in RVSV assessed by cardiac magnetic resonance imaging (MRI) from pulmonary artery flow was reported at Week 26. Primary analysis were based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is. (NCT02310672)
Timeframe: Baseline and Week 26
| Intervention | milliliters (mL) (Least Squares Mean) |
|---|
| Macitanten 10 mg | 15.17 |
Change From Baseline in Right Ventricular End Systolic Volume (RVESV) to Week 26
Change from baseline to Week 26 in RVESV assessed by cardiac MRI was reported. (NCT02310672)
Timeframe: Baseline to Week 26
| Intervention | mL (Least Squares Mean) |
|---|
| Macitanten 10 mg | -16.39 |
Change From Baseline in Right Ventricle (RV) Mass to Week 26
Change from baseline to Week 26 in RV mass assessed by cardiac MRI was reported. (NCT02310672)
Timeframe: Baseline to Week 26
| Intervention | Grams (Least Squares Mean) |
|---|
| Macitanten 10 mg | -10.10 |
Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)
mRAP is the mean blood pressure in the right atrium of the heart. (NCT02382016)
Timeframe: From enrollment/baseline to Week 12 in the DB treatment period
| Intervention | mmHg (Mean) |
|---|
| mRAP at baseline | mRAP at Week 12 | Change in mRAP from baseline to Week 12 |
|---|
| Macitentan 10 mg | 7.3 | 9.0 | 1.6 |
,| Placebo | 6.7 | 7.0 | 0.3 |
Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2)
SVO2 help assess tissue oxygen delivery. It describes the percentage of oxygen bound to hemoglobin in the blood which returns to the heart. This reflects the amount of residual oxygen in the blood after oxygen extraction by the tissues throughout the body. (NCT02382016)
Timeframe: From enrollment/baseline to Week 12 in the DB treatment period
| Intervention | percent of oxygen bound to hemoglobin (Mean) |
|---|
| SVO2 at baseline | SVO2 at Week 12 | Change in SVO2 from baseline to Week 12 |
|---|
| Macitentan 10 mg | 69.2 | 70.3 | 1.1 |
,| Placebo | 69.9 | 70.7 | 0.8 |
Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR)
TPR is the resistance the pulmonary circulation that must be overcome in order for the blood flow to occur. It takes into account the blood pressure in the pulmonary arteries and the cardiac output. It is an important measurement to monitor the function of the pulmonary circulation and detect disease progression or improvement. (NCT02382016)
Timeframe: From enrollment/baseline to Week 12 in the DB treatment period
| Intervention | dyn*sec/cm^5 (Mean) |
|---|
| TPR at baseline | TPR at Week 12 | Change in TPR from baseline to Week 12 |
|---|
| Macitentan 10 mg | 689.3 | 489.4 | -199.8 |
,| Placebo | 671.5 | 653.1 | -18.3 |
Change From Baseline to Week 12 in WHO Functional Class (FC)
Changes from baseline to Week 12 in WHO FC were dichotomized as worsening (i.e., change > 0) versus no change or improvement (i.e., change ≤ 0). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure. (NCT02382016)
Timeframe: From enrollment/baseline to Week 12 in the DB treatment period
| Intervention | Participants (Count of Participants) |
|---|
| WHO FC I at baseline | WHO FC II at baseline | WHO FC III at baseline | WHO FC IV at baseline | WHO FC I at Week 12 | WHO FC II at Week 12 | WHO FC III at Week 12 | WHO FC IV at Week 12 | Improved from baseline to Week 12 | Worsened from baseline to Week 12 | Unchanged from baseline to Week 12 |
|---|
| Macitentan 10 mg | 1 | 27 | 15 | 0 | 3 | 27 | 13 | 0 | 9 | 6 | 28 |
,| Placebo | 1 | 23 | 18 | 0 | 4 | 23 | 15 | 0 | 7 | 1 | 34 |
Relative Change From Baseline to Week 12 in Pulmonary Vascular Resistance (PVR).
The relative change from baseline to Week 12 in PVR is expressed as a ratio of Week 12 to baseline PVR. (NCT02382016)
Timeframe: From enrollment/baseline to Week 12 in the Double Blind (DB) treatment period
| Intervention | ratio (Geometric Mean) |
|---|
| Macitentan 10 mg | 0.63 |
| Placebo | 0.98 |
Change From Baseline to Week 12 in the Biomarker N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
NT-proBNP functions as a strong indicator of prognosis in patients with pulmonary hypertension (PH). The relative change from baseline to Week 12 in NT-proBNP is expressed as a ratio of Week 12 to baseline NT-proBNP. (NCT02382016)
Timeframe: From enrollment/baseline to Week 12 in the DB treatment period
| Intervention | ratio (Geometric Mean) |
|---|
| Macitentan 10 mg | 0.86 |
| Placebo | 1.04 |
Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD)
The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. (NCT02382016)
Timeframe: From enrollment/baseline to Week 12 in the DB treatment period
| Intervention | meter (Mean) |
|---|
| 6MWD at baseline | 6MWD at Week 12 | Change of 6MWD from baseline to Week 12 |
|---|
| Macitentan 10 mg | 385.8 | 392.2 | 6.4 |
,| Placebo | 383.2 | 380.8 | -2.4 |
Change From Baseline to Week 12 in Cardiac Index
The cardiac index is an assessment of the function of the heart and relates the cardiac output to the patient's body size (the patient's body surface area). (NCT02382016)
Timeframe: From enrollment/baseline to Week 12 in the DB treatment period
| Intervention | L/min/m^2 (Mean) |
|---|
| Cardiac index at baseline | Cardiac index at Week 12 | Change in cardiac index at Week 12 |
|---|
| Macitentan 10 mg | 3.1 | 3.7 | 0.6 |
,| Placebo | 2.9 | 3.0 | 0.1 |
Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP)
mPAP is the mean blood pressure inside the pulmonary artery which moves the blood from the heart to the lungs. Monitoring of mPAP can detect small changes in the function of the heart. (NCT02382016)
Timeframe: From enrollment/baseline to Week 12 in the DB treatment period
| Intervention | mmHg (Mean) |
|---|
| mPAP at baseline | mPAP at Week 12 | Change in mPAP at Week 12 |
|---|
| Macitentan 10 mg | 46.4 | 40.0 | -6.4 |
,| Placebo | 43.8 | 44.2 | 0.4 |
Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC)
WHO FC is a classification which reflects disease severity based on symptoms. WHO Functional Classification of pulmonary hypertension comprises of Class I (participants with pulmonary hypertension but without resulting limitation of physical activity), II (participants with pulmonary hypertension resulting in slight limitation of physical activity), III (participants with pulmonary hypertension resulting in marked limitation of physical activity) and IV (participants with pulmonary hypertension with inability to carry out any physical activity without symptoms). Change from baseline in WHO FC was reported. WHO FC was categorized as worsening (change greater than [>] 0); improvement (change less than [<] 0); or no change (change equals to [=] 0). (NCT02554903)
Timeframe: Baseline to Week 12
| Intervention | Participants (Count of Participants) |
|---|
| Worsening | No change | Improvement |
|---|
| Macitentan 10 Milligrams (mg) | 2 | 13 | 10 |
,| Placebo | 2 | 15 | 8 |
Change From Baseline to Week 12 in Pulmonary Arterial Wedge Pressure (PAWP)
PAWP was collected in the eCRF. PAWP is pressure within the pulmonary arterial system when the catheter tip is 'wedged' in the tapering branch of one of the pulmonary arteries. Change from baseline to Week 12 in PAWP was measured at rest and no correction for multiple testing was applied. (NCT02554903)
Timeframe: Baseline to Week 12
| Intervention | mmHg (Mean) |
|---|
| Macitentan 10 Milligrams (mg) | 4.0 |
| Placebo | 1.0 |
Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)
mRAP was collected in the eCRF (electronic case record form). Right atrial pressure (RAP) is the blood pressure in the right atrium of the heart. Change from baseline to Week 12 in mRAP was measured at rest and no correction for multiple testing was applied. (NCT02554903)
Timeframe: Baseline to Week 12
| Intervention | millimeters of mercury (mmHg) (Mean) |
|---|
| Macitentan 10 Milligrams (mg) | 0.8 |
| Placebo | -1.4 |
Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR)
TPR was calculated as mPAP/CO where mPAP is mean pulmonary arterial pressure and CO is cardiac output. Change from baseline to Week 12 in TPR was calculated at rest and no correction for multiple testing was applied. (NCT02554903)
Timeframe: Baseline to Week 12
| Intervention | Wood Unit (Mean) |
|---|
| Macitentan 10 Milligrams (mg) | -1.399 |
| Placebo | -0.993 |
Change From Baseline to Week 12 in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels
NT-proBNP levels in the blood are used for diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure. (NCT02554903)
Timeframe: Baseline to Week 12
| Intervention | nanograms/Liter (ng/L) (Mean) |
|---|
| Macitentan 10 Milligrams (mg) | 1325.68 |
| Placebo | 1573.44 |
Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SvO2)
Mixed venous oxygen saturation measures the end result of oxygen consumption and delivery. Change from baseline to Week 12 in SvO2 was reported and measured at rest and no correction for multiple testing was applied. (NCT02554903)
Timeframe: Baseline to Week 12
| Intervention | Percentage of SvO2 (Mean) |
|---|
| Macitentan 10 Milligrams (mg) | 4.260 |
| Placebo | 4.100 |
Pulmonary Vascular Resistance (PVR) Ratio of Week 12 to Baseline
PVR ratio equals to Week 12 PVR / Baseline PVR. PVR represents the resistance against which the right ventricle needs to pump. PVR was calculated using the following formula: mean pulmonary arterial pressure (mPAP) - pulmonary artery wedge pressure (PAWP)/cardiac output (CO); where mPAP and PAWP were measured at end-expiration and CO was measured in triplicate using the thermodilution method. (NCT02554903)
Timeframe: Baseline to Week 12
| Intervention | Ratio (Mean) |
|---|
| Macitentan 10 Milligrams (mg) | 0.585 |
| Placebo | 0.757 |
Change From Baseline to Week 12 in Cardiac Index (CI)
CI was calculated as Cardiac Output (CO)/body surface area (BSA), where CO is Thermodilution Cardiac Output (Liters per minute [L/min]) and BSA (m^2) equals to 0.007184*weight^0.425 (kilograms)*height^0.725 (centimeter). CI was represented in liters per minute per square meter (L/min/m^2). Change from baseline to Week 12 in CI was measured at rest and no correction for multiple testing was applied. (NCT02554903)
Timeframe: Baseline to Week 12
| Intervention | L/min/m^2 (Mean) |
|---|
| Macitentan 10 Milligrams (mg) | 0.093 |
| Placebo | 0.041 |
Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP)
mPAP was collected in the eCRF. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Change from baseline to Week 12 in mPAP was measured at rest and no correction for multiple testing was applied. (NCT02554903)
Timeframe: Baseline to Week 12
| Intervention | mmHg (Mean) |
|---|
| Macitentan 10 Milligrams (mg) | -3.84 |
| Placebo | -3.86 |
Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP)
Change from baseline to Week 26 in mean Right Atrial Pressure (mRAP) was measured. Missing values were imputed using a LOCF approach. (NCT02558231)
Timeframe: Baseline, Week 26
| Intervention | mmHg (Least Squares Mean) |
|---|
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | -1.78 |
| Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | -1.69 |
Change From Baseline to Week 26 in Total Pulmonary Resistance
Change from baseline to Week 26 in total pulmonary resistance was measured. Total pulmonary resistance was calculated as mPAP/CO*80, where CO is cardiac output. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach. (NCT02558231)
Timeframe: Baseline, Week 26
| Intervention | dynes*second per centimeter^5 (Least Squares Mean) |
|---|
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | -511.88 |
| Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | -514.28 |
Number of Participants With Disease Progression Event
Number of participants with disease progression event were reported. Disease progression event as adjudicated by the CEC, defined as any of the following: a. Death (all causes; adjudicated for PAH relationship); b. Hospitalization for worsening PAH; c. Initiation of prostacyclin, a prostacyclin analog, or a prostacyclin receptor agonist for worsening PAH; d. Clinical worsening defined as a post-baseline decrease in 6MWD by more than (>) 15 percent (%) from the highest 6MWD obtained at or after baseline, accompanied by WHO FC III or IV (both conditions confirmed at two consecutive post-baseline visits separated by 1-21 days). (NCT02558231)
Timeframe: Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months)
| Intervention | Participants (Count of Participants) |
|---|
| Week 26 | Month 12 | Month 18 | Month 24 | Month 30 | End of Analysis Period (up to 40 months) |
|---|
| Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | 13 | 20 | 23 | 25 | 27 | 27 |
,| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | 8 | 13 | 15 | 15 | 16 | 16 |
Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC)
WHO FC is a classification graded from Class I to IV which reflects disease severity based on symptoms. Worsening was defined as death or hospitalization due to PAH. Class I: No limitation of activity; Class II: slight limitation with ordinary activities; Class III: may not have symptoms at rest but greatly limited activities; Class IV: symptoms at rest and inability to carry out any physical activity without symptoms. Missing values were imputed using a LOCF approach. (NCT02558231)
Timeframe: Week 26
| Intervention | percentage of participants (Number) |
|---|
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | 99.2 |
| Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | 97.5 |
Change From Baseline to Week 26 in Venous Oxygen Saturation (%)
Change from baseline to Week 26 in venous oxygen saturation was measured. Missing values were imputed using a LOCF approach. (NCT02558231)
Timeframe: Baseline, Week 26
| Intervention | percentage of oxygen saturation (Least Squares Mean) |
|---|
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | 5.59 |
| Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | 6.79 |
Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels
The change from baseline to Week 26 in NT-proBNP was expressed as the ratio of Week 26 to baseline NT-proBNP (Week 26 divided by baseline). A geometric least square mean ratio of Week 26 to baseline NT-proBNP <1 corresponds to a reduction in NT-proBNP from baseline. Missing values were imputed using a LOCF approach. (NCT02558231)
Timeframe: Baseline, Week 26
| Intervention | ratio (Geometric Least Squares Mean) |
|---|
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | 0.26 |
| Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | 0.25 |
Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP)
Change from baseline to Week 26 in mean Pulmonary Arterial Pressure (mPAP) was measured. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Missing values were imputed using a LOCF approach. (NCT02558231)
Timeframe: Baseline, Week 26
| Intervention | millimeters of mercury (mmHg) (Least Squares Mean) |
|---|
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | -12.92 |
| Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | -12.20 |
Change From Baseline to Week 26 in Cardiac Index
Change from baseline to Week 26 in cardiac index was measured. Cardiac index is the amount of blood pumped by the heart, per minute, per meter square of body surface area. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach. (NCT02558231)
Timeframe: Baseline, Week 26
| Intervention | liters per minute per meter square (Least Squares Mean) |
|---|
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | 0.97 |
| Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | 0.84 |
Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD)
The change from baseline to Week 26 in 6MWD was calculated as Week 26 minus baseline. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. Missing values were imputed using a LOCF approach. (NCT02558231)
Timeframe: Baseline, Week 26
| Intervention | meter (Least Squares Mean) |
|---|
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | 54.96 |
| Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | 56.39 |
Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR)
Change from baseline to Week 26 in PVR was expressed as the ratio of Week 26 to baseline PVR value (Week 26 divided by baseline) using re-calculated PVR. PVR was determined by right heart catheterization (RHC). A geometric least square mean ratio of Week 26 to baseline PVR less than (<) 1 corresponds to a reduction in PVR from baseline. Missing values were imputed using a last observation carried forward (LOCF) approach. (NCT02558231)
Timeframe: Baseline, Week 26
| Intervention | ratio (Geometric Least Squares Mean) |
|---|
| Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) | 0.46 |
| Double Oral Therapy (Macitentan, Tadalafil, and Placebo) | 0.48 |
Change in NT-proB-type Natriuretic Peptide (NT-pro-BNP)
The normal range for NT-pro-BNP is less than 300 picograms of BNP per milliliter (pg/ml) of blood; higher levels are less favorable. (NCT02651272)
Timeframe: Baseline, 16 weeks
| Intervention | pg/mL (Number) |
|---|
| Macitentan | 10528 |
Change in Right Arterial Pressure (RAP)
RAP will be assessed by right heart catheterization. Normal range is 2-6 mmHg. (NCT02651272)
Timeframe: Baseline, 16 weeks
| Intervention | mmHg (Number) |
|---|
| Macitentan | -5 |
Change in Systemic Vascular Resistance Index (SVR)
Systemic vascular resistance (SVR) will be assessed with this formula Systemic Vascular Resistance (SVR) = 80x(Mean Arterial Pressure - Mean Venous Pressure or CVP) / Cardiac Output. Normal range is 800 - 1200 dynes-sec/cm-5. (NCT02651272)
Timeframe: Baseline, Week 16
| Intervention | dynes-sec/cm-5. (Number) |
|---|
| Macitentan | -528 |
Change in Systolic Pulmonary Artery Pressure (SPAP)
SPAP will be assessed by right heart catheterization. Normal range is 15-25 mm Hg. (NCT02651272)
Timeframe: Baseline, 16 weeks
| Intervention | mmHg (Number) |
|---|
| Macitentan | 7 |
Change in Systolic Right Ventricular Pressure (RVSP)
RVSP will be assessed by right heart catheterization. Normal range is 15-25 mmHg. (NCT02651272)
Timeframe: Baseline, 16 weeks
| Intervention | mmHg (Number) |
|---|
| Macitentan | 3 |
Number of Participants With Treatment-emergent Adverse Events
The occurrence of treatment emergent AEs includes having any of the following: vaso-occlusive crises requiring hospitalization; acute congestive heart failure; hypotension (defined as a mean arterial pressure less than 60mmHg); decrease in hemoglobin concentration by greater than 1 g/dL. (NCT02651272)
Timeframe: 20 weeks
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan | 0 |
World Health Organization (WHO) Functional Classification
"The WHO functional classification will be assessed and documented with the WHO Class.~Class I Patients with pulmonary hypertension (PH) but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope.~Class II Patients with PH resulting in a slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.~Class III Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope.~Class IV Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.~The Class is inversely related to function." (NCT02651272)
Timeframe: 16 weeks
| Intervention | participants (Number) |
|---|
| Class 1 | Class 2 | Class 3 | Class 4 |
|---|
| Macitentan | 0 | 0 | 1 | 0 |
Assess Change of Borg Dyspnea Index
The Borg Dyspnea Index (BDI) is a 0 to 10 rated self reported numerical score used to measure dyspnea during submaximal exercise and will be administered immediately following the 6MWT. The higher the score, the more dyspnea. (NCT02651272)
Timeframe: Baseline, 16 weeks
| Intervention | score on a scale (Number) |
|---|
| Macitentan | 6 |
Change in 6 Minute Walk Distance (6MWD)
The 6 minute walk test (6MWT) assesses distance walked over 6 minutes (6MWD) as a sub-maximal test of aerobic capacity/endurance. Participants will walk at their normal pace for 6 minutes. (NCT02651272)
Timeframe: Baseline, 16 weeks
| Intervention | meters (Number) |
|---|
| Macitentan | -89 |
Change in Cardiac Index (CI)
Cardiac index (CI) will be measured in L/min/m^2. The normal range for CI is 2.5 to 4 L/min/m^2. (NCT02651272)
Timeframe: Baseline to Week 16
| Intervention | L/min/m^2 (Number) |
|---|
| Macitentan | .23 |
Change in Cardiac Output (CO)
Cardiac output (CO) will be measured in L/min/m^2. The normal range for CO is 4 to 8 L/min/m^2. (NCT02651272)
Timeframe: Baseline, Week 16
| Intervention | L/min/m^2 (Number) |
|---|
| Macitentan | .29 |
Change in Diastolic Pulmonary Artery Pressure (PADP)
PADP will be assessed by right heart catheterization. Normal range is 8-15 mmHg. (NCT02651272)
Timeframe: Baseline, 16 weeks
| Intervention | mmHg (Number) |
|---|
| Macitentan | -5 |
Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks
Number of participants with WHF events were reported. A WHF event includes HF death, hospitalization for WHF or an urgent visit for WHF. (NCT03153111)
Timeframe: Weeks 16, 24, 36, 52
| Intervention | Participants (Count of Participants) |
|---|
| Week 16 | Week 24 | Week 36 | Week 52 |
|---|
| Macitentan | 12 | 14 | 17 | 18 |
,| Placebo | 5 | 6 | 9 | 13 |
Percent of Baseline N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Assessed at Week 24
Percent of baseline NT-proBNP assessed at Week 24 was reported. Percent of baseline is calculated as the ratio of the Week 24 NT-proBNP value over baseline value, expressed in percentage. NT-proBNP is one of the best established cardiovascular response markers among all available surrogates in heart failure (HF). (NCT03153111)
Timeframe: Week 24
| Intervention | percentage of baseline NT-proBNP (Geometric Mean) |
|---|
| Macitentan | 108.39 |
| Placebo | 106.27 |
Change From Baseline to Week 24 in the Clinical Summary Score Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) Score
The KCCQ is a validated health related quality of life measure for heart failure. The KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Clinical summary score is one of the quality of life variable of interest derived from KCCQ. Clinical summary score is the mean of domains: physical limitations score (6 items) and total symptom score (2 items [symptoms frequency and symptom burden]). The score is calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicating better health status. (NCT03153111)
Timeframe: Baseline to Week 24
| Intervention | score on a scale (Mean) |
|---|
| Macitentan | -2.37 |
| Placebo | 0.89 |
Change From Baseline to Week 24 in Accelerometer-assessed Proportion of Time Spent in Light to Vigourous Physical Activity
Physical activity is assessed by accelerometer as the proportion of time spent in light to vigorous physical activity based on a threshold of greater than (>)100 activity counts per minute and expressed as change from baseline to Week 24. (NCT03153111)
Timeframe: Baseline to Week 24
| Intervention | proportion of time spent (Mean) |
|---|
| Macitentan | -0.024 |
| Placebo | -0.005 |
Change From Baseline in Peak VO2 Up to Week 52
Change from baseline in peak VO2 up to Week 52 was reported. (NCT03153137)
Timeframe: Baseline up to Week 52
| Intervention | mL/kg/min (Least Squares Mean) |
|---|
| Placebo | -0.92 |
| Macitentan | -0.31 |
Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment
Number of participants with AEs leading to premature discontinuation of study treatment was reported. AEs leading to premature discontinuation of study treatment were those with action taken with study drug reported as 'permanently discontinued' by the investigator. (NCT03153137)
Timeframe: Up to 56 weeks
| Intervention | Participants (Count of Participants) |
|---|
| Placebo | 1 |
| Macitentan | 3 |
Number of Participants With Treatment-emergent Adverse Events (AEs)
An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. (NCT03153137)
Timeframe: Up to 56 weeks
| Intervention | Participants (Count of Participants) |
|---|
| Placebo | 44 |
| Macitentan | 48 |
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)
SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. (NCT03153137)
Timeframe: Up to 56 weeks
| Intervention | Participants (Count of Participants) |
|---|
| Placebo | 9 |
| Macitentan | 13 |
Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP)
Change from baseline in ALT, AST and AP were reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | Units per liter (U/L) (Mean) |
|---|
| ALT: Baseline | ALT: Week 8 | ALT: Week 16 | ALT: Week 32 | ALT: Week 52 | AST: Baseline | AST: Week 8 | AST: Week 16 | AST: Week 32 | AST: Week 52 | AP: Baseline | AP: Week 8 | AP: Week 16 | AP: Week 32 | AP: Week 52 |
|---|
| Macitentan | 28.5 | -1.8 | -1.6 | -2.1 | -0.3 | 28.3 | -4.4 | -3.9 | -4.7 | -3.2 | 100.2 | -8.5 | -7.1 | -1.1 | -7.0 |
,| Placebo | 26.7 | -0.8 | -0.2 | -0.4 | -0.2 | 25.8 | -0.7 | -0.5 | 0.9 | -0.6 | 106.4 | -7.6 | -4.7 | -10.1 | -12.9 |
Change From Baseline in Albumin and Protein
Change from baseline in albumin and protein was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | grams per liter (g/L) (Mean) |
|---|
| Albumin: Baseline | Albumin: Week 8 | Albumin: Week 16 | Albumin: Week 32 | Albumin: Week 52 | Protein: Baseline | Protein: Week 8 | Protein: Week 16 | Protein: Week 32 | Protein: Week 52 |
|---|
| Macitentan | 49.56 | -1.73 | -0.82 | 0.38 | -0.53 | 75.4 | -3.8 | -1.9 | -0.3 | -2.5 |
,| Placebo | 48.64 | -0.74 | 0.61 | 0.79 | -0.08 | 75.0 | -1.5 | -0.3 | -0.2 | -1.8 |
Change From Baseline in Alpha Fetoprotein
Change from baseline in alpha fetoprotein was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | micrograms per milliliter (ug/L) (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 3.326 | -0.061 | 0.160 | 0.191 | 0.240 |
,| Placebo | 3.145 | 0.006 | 0.055 | 0.033 | 0.068 |
Change From Baseline in Bilirubin and Direct Bilirubin
Change from baseline in bilirubin and direct bilirubin was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | micromole per liter (umol/L) (Mean) |
|---|
| Bilirubin: Baseline | Bilirubin: Week 8 | Bilirubin: Week 16 | Bilirubin: Week 32 | Bilirubin: Week 52 | Direct Bilirubin: Baseline | Direct Bilirubin: Week 8 | Direct Bilirubin: Week 16 | Direct Bilirubin: Week 32 | Direct Bilirubin: Week 52 |
|---|
| Macitentan | 17.28 | -1.08 | -1.76 | 0.29 | -1.02 | 4.38 | -0.22 | -0.28 | -0.04 | -0.24 |
,| Placebo | 14.65 | 0.62 | 1.98 | 1.47 | 0.69 | 4.04 | -0.06 | 0.24 | 0.00 | 0.28 |
Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) Up to Week 16
Change from baseline in peak VO2 up to Week 16 was reported. (NCT03153137)
Timeframe: Baseline up to Week 16
| Intervention | Milliliter/kilogram/minute (mL/kg/min) (Mean) |
|---|
| Placebo | -0.67 |
| Macitentan | -0.16 |
Change From Baseline in Creatinine
Change from baseline in creatinine was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | micromole/liter (umol/L) (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 78.9 | -6.2 | -0.3 | -1.8 | 0.4 |
,| Placebo | 78.1 | -2.0 | -1.1 | 2.2 | -1.5 |
Change From Baseline in Cystatin C
Change from baseline in cystatin C was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | milligrams per liter (mg/L) (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 0.718 | -0.019 | -0.019 | -0.021 | 0.010 |
,| Placebo | 0.742 | -0.026 | -0.017 | -0.038 | -0.001 |
Change From Baseline in Erythrocytes and Reticulocytes
Change from baseline in erythrocytes and reticulocytes at Week 8, Week 16, Week 32 and Week 52 was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | 10^12 cells per liter (Mean) |
|---|
| Erythrocytes: Baseline | Erythrocytes: Week 8 | Erythrocytes: Week 16 | Erythrocytes: Week 32 | Erythrocytes: Week 52 | Reticulocytes: Baseline: | Reticulocytes: Week 8 | Reticulocytes: Week 16 | Reticulocytes: Week 32 |
|---|
| Macitentan | 5.205 | -0.297 | -0.264 | -0.090 | -0.184 | 0.070 | -0.006 | -0.001 | -0.008 |
,| Placebo | 5.251 | 0.048 | 0.012 | -0.031 | -0.096 | 0.075 | -0.006 | -0.003 | -0.003 |
Change From Baseline in Gamma Glutamyl Transferase
Change from baseline in gamma glutamyl transferase was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | Units per liter (U/L) (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 79.4 | -5.5 | 0.7 | -5.3 | -6.7 |
,| Placebo | 67.6 | -4.8 | -4.4 | -1.3 | -3.2 |
Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium
Change from baseline in glucose, cholesterol, triglycerides, sodium, potassium, chloride and calcium was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | mmol/L (Mean) |
|---|
| Glucose: Baseline | Glucose: Week 8 | Glucose: Week 16 | Glucose: Week 32 | Glucose: Week 52 | Cholesterol: Baseline | Cholesterol: Week 8 | Cholesterol: Week 16 | Cholesterol: Week 32 | Cholesterol: Week 52 | Triglycerides: Baseline | Triglycerides: Week 8 | Triglycerides: Week 16 | Triglycerides: Week 32 | Triglycerides: Week 52 | Sodium: Baseline | Sodium: Week 8 | Sodium: Week 16 | Sodium: Week 32 | Sodium: Week 52 | Potassium: Baseline | Potassium: Week 8 | Potassium: Week 16 | Potassium: Week 32 | Potassium: Week 52 | Chloride: Baseline | Chloride: Week 8 | Chloride: Week 16 | Chloride: Week 32 | Chloride: Week 52 | Calcium: Baseline | Calcium: Week 8 | Calcium: Week 16 | Calcium: Week 32 | Calcium: Week 52 |
|---|
| Macitentan | 5.15 | -0.46 | -0.04 | -0.12 | -0.28 | 3.705 | -0.238 | -0.190 | -0.059 | -0.093 | 1.057 | -0.071 | -0.004 | 0.024 | -0.020 | 140.8 | -0.2 | -0.6 | -0.3 | -1.0 | 4.391 | -0.030 | 0.030 | -0.033 | -0.003 | 103.3 | 1.3 | 0.3 | 0.3 | 0.4 | 2.479 | -0.062 | -0.050 | -0.004 | -0.035 |
,| Placebo | 4.97 | 0.00 | 0.17 | 0.24 | -0.03 | 3.653 | -0.182 | -0.065 | 0.060 | -0.065 | 1.126 | -0.061 | -0.099 | 0.123 | -0.067 | 141.2 | -0.5 | -1.1 | -0.7 | -1.1 | 4.364 | -0.074 | -0.013 | -0.011 | -0.031 | 103.9 | 0.2 | -0.4 | -0.1 | 0.4 | 2.458 | -0.006 | -0.002 | 0.035 | -0.021 |
Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets
Change from baseline in leucocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets at Week 8, Week 16, Week 32 and Week 52 was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | 10^9 cells per liter (Mean) |
|---|
| Leukocytes: Baseline | Leukocytes: Week 8 | Leukocytes: Week 16 | Leukocytes: Week 32 | Leukocytes: Week 52 | Neutrophils: Baseline | Neutrophils: Week 8 | Neutrophils: Week 16 | Neutrophils: Week 32 | Neutrophils: Week 52 | Lymphocytes: Baseline | Lymphocytes: Week 8 | Lymphocytes: Week 16 | Lymphocytes: Week 32 | Lymphocytes: Week 52 | Baseline: Monocytes | Monocytes: Week 8 | Monocytes: Week 16 | Monocytes: Week 32 | Monocytes: Week 52 | Eosinophils: Baseline | Eosinophils: Week 8 | Eosinophils: Week 16 | Eosinophils: Week 32 | Eosinophils: Week 52 | Basophils: Baseline | Basophils: Week 8 | Basophils: Week 16 | Basophils: Week 32 | Basophils: Week 52 | Platelets: Baseline | Platelets: Week 8 | Platelets: Week 16 | Platelets: Week 32 | Platelets: Week 52 |
|---|
| Macitentan | 5.693 | -1.001 | -0.378 | -0.237 | -0.715 | 3.831 | -0.743 | -0.373 | -0.254 | -0.627 | 1.263 | -0.165 | 0.042 | 0.126 | -0.033 | 0.409 | -0.081 | -0.050 | -0.071 | -0.077 | 0.151 | 0.014 | 0.002 | 0.029 | 0.015 | 0.040 | -0.002 | 0.000 | 0.016 | 0.006 | 178.1 | -9.1 | -3.0 | 8.2 | -5.7 |
,| Placebo | 6.270 | -0.242 | -0.199 | 0.417 | -0.554 | 4.100 | -0.133 | -0.291 | 0.494 | -0.384 | 1.489 | -0.113 | 0.073 | 0.047 | -0.082 | 0.416 | -0.017 | 0.002 | -0.018 | -0.039 | 0.207 | -0.003 | 0.016 | -0.100 | -0.046 | 0.055 | -0.002 | 0.004 | -0.003 | -0.003 | 184.3 | -5.9 | -5.4 | -7.8 | -11.2 |
Change From Baseline in Oxygen Saturation (SpO2)
Change from baseline in SpO2 was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | percent of oxygen saturation (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 92.8 | 1.2 | 0.8 | 1.4 | 0.9 |
,| Placebo | 92.6 | 0.0 | 0.5 | 0.8 | 1.4 |
Change From Baseline in Prothrombin International Normalized Ratio
Change from baseline in prothrombin international normalized ratio was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | Ratio (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 1.516 | -0.054 | 0.049 | 0.033 | -0.120 |
,| Placebo | 1.434 | -0.009 | 0.015 | 0.171 | -0.044 |
Change From Baseline in Body Weight
Change from baseline in body weight was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | kilograms (kg) (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 67.38 | 0.43 | 0.58 | 0.77 | 1.30 |
,| Placebo | 68.89 | -0.38 | 0.21 | 0.73 | 1.44 |
Change From Baseline in Urea Nitrogen
Change from baseline in urea nitrogen was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | millimoles per liter (mmol/L) (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 5.08 | -0.09 | 0.06 | -0.25 | 0.04 |
,| Placebo | 5.26 | -0.30 | -0.04 | 0.02 | -0.06 |
Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) Up to Week 16
Change from baseline in mean count per minute of daily PA-Ac up to Week 16 was reported. The daily physical activity (counts per min) of the participant was assessed via accelerometer during daytime. The accelerometer was given to the participant at Visit 1, and data was collected for 9 consecutive daily daytime periods after Visit 1 (baseline) to Visit 4 (Week 16). (NCT03153137)
Timeframe: Baseline up to Week 16
| Intervention | counts per minute (Mean) |
|---|
| Placebo | -14.34 |
| Macitentan | -3.02 |
Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values
"Number of participants with treatment-emergent markedly laboratory abnormal laboratory values were reported. Abnormal values for platelets (LL < 75); Lymphocytes (HH > 4.0); Neutrophils (LL < 1.5); Prothrombin International Normalized Ratio: HH (greater than and equal to [>=] 1.5 upper limit of normal [ULN]), Ratio: HH >= 2.5 ULN); Bilirubin (HH >= 2 ULN); Alkaline Phosphatase (HH > 2.5 ULN); Glomerular Filtration Rate (LL < 60); Glucose (HH > 8.9); Triglycerides (HH > 3.42). Here HH refers to values above the normal range, where H stands for high and LL refers to values below the normal range where L stands for low." (NCT03153137)
Timeframe: Up to 56 weeks
| Intervention | Participants (Count of Participants) |
|---|
| Platelets: LL (< 75) | Lymphocytes: HH (> 4.0) | Neutrophils: LL (< 1.5) | Prothrombin International Normalized Ratio: HH (>= 1.5 ULN) | Prothrombin International Normalized Ratio: HH (>= 2.5 ULN) | Bilirubin: HH (>= 2 ULN) | Alkaline Phosphatase: HH (> 2.5 ULN) | Glomerular Filtration Rate: LL (< 60) | Glucose: LL (< 3.0) | Glucose: HH (> 8.9) | Triglycerides: HH (> 3.42) |
|---|
| Macitentan | 1 | 1 | 2 | 5 | 1 | 2 | 0 | 1 | 2 | 2 | 1 |
,| Placebo | 2 | 0 | 0 | 3 | 1 | 1 | 1 | 1 | 0 | 0 | 3 |
Change From Baseline in Prothrombin Time
Change from baseline in prothrombin time was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | Seconds (sec) (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 15.37 | -0.53 | 0.36 | 0.03 | -1.20 |
,| Placebo | 14.72 | -0.23 | 0.04 | 1.45 | -0.64 |
Change From Baseline in Hematocrit
Change from baseline in hematocrit was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | Liter/Liter (L/L) (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 0.471 | -0.030 | -0.023 | -0.009 | -0.021 |
,| Placebo | 0.472 | 0.002 | 0.003 | 0.003 | -0.010 |
Change From Baseline in Pulse Rate
Change from baseline in pulse rate at Week 8, Week 16, Week 32 and Week 52 was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | beats per minute (bpm) (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 78.2 | -5.9 | -0.1 | 1.1 | -2.9 |
,| Placebo | 81.3 | -3.9 | 0.1 | 0.2 | -0.7 |
Change From Baseline in Hemoglobin
Change from baseline in hemoglobin was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | grams per liter (g/L) (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 159.5 | -8.7 | -8.7 | -7.3 | -7.1 |
,| Placebo | 160.4 | 0.0 | 0.0 | 1.3 | -2.9 |
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP)
Change from baseline in systolic and diastolic arterial BP at Week 8, Week 16, Week 32 and Week 52 was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | millimeters of mercury (mmHg) (Mean) |
|---|
| Baseline | Systolic BP: Week 8 | Systolic BP: Week 16 | Systolic BP: Week 32 | Systolic BP: Week 52 | Diastolic BP: Week 8 | Diastolic BP: Week 16 | Diastolic BP: Week 32 | Diastolic BP: Week 52 |
|---|
| Macitentan | 117.0 | -0.4 | -4.6 | -3.1 | -4.8 | -0.1 | -3.1 | -1.4 | -2.8 |
,| Placebo | 116.0 | 2.5 | 0.5 | -6.3 | 0.0 | -0.2 | -0.6 | 1.3 | 1.3 |
Change From Baseline in Urate
Change from baseline in urate was reported. (NCT03153137)
Timeframe: Baseline, Week 8, Week 16, Week 32 and Week 52
| Intervention | umol/L (Mean) |
|---|
| Baseline | Week 8 | Week 16 | Week 32 | Week 52 |
|---|
| Macitentan | 372.7 | -53.6 | -37.8 | -56.7 | -25.8 |
,| Placebo | 360.0 | -0.8 | 2.8 | 16.0 | 1.1 |
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) up to 30 Days After Study Treatment Discontinuation
An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is a suspected transmission of any infectious agent via a medicinal product, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. Any AE and SAE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) within the analysis set was considered to be treatment-emergent. (NCT03714815)
Timeframe: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
| Intervention | Participants (Count of Participants) |
|---|
| TEAEs | TESAEs |
|---|
| Macitentan 10 mg | 81 | 49 |
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24
Change from baseline in eGFR rate at Week 24 was reported. (NCT03714815)
Timeframe: Baseline and Week 24
| Intervention | milliliters/minute/1.73 meter square (Mean) |
|---|
| Macitentan 10 mg | -4.05 |
Change From Baseline in Body Weight at Week 52
Change from baseline in body weight at Week 52 was reported. (NCT03714815)
Timeframe: Baseline and Week 52
| Intervention | kg (Mean) |
|---|
| Macitentan 10 mg | -0.16 |
Change From Baseline in Bilirubin at Week 52
Change from baseline in bilirubin at Week 52 was reported. (NCT03714815)
Timeframe: Baseline and Week 52
| Intervention | mcmol/L (Mean) |
|---|
| Macitentan 10 mg | 0.2041 |
Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation
Number of participants with treatment-emergent MLAs (Hemoglobin [grams/Liter{L}], Hematocrit [L/L], Leukocytes [10^9cells/L], Lymphocytes [10^9cells/L], Alanine Aminotransferase [Units/L {U/L}], Aspartate Aminotransferase [U/L], Bilirubin [micromoles/L {mcmol/L}], Alkaline Phosphatase [U/L], Creatinine [mcmol/L], Urea Nitrogen [mmol/L], Urate [mcmol/L], Potassium [mmol/L], Sodium [mmol/L], Magnesium [mmol/L], Calcium [mmol/L] were reported. Abnormalities that occurred after study treatment start and up to 30 days after study treatment discontinuation, that were not present at baseline, were treatment-emergent. Here, > signifies greater than; < signifies less than; ULN signifies upper limit of normal; and L=Low, H=High, LL=low/low, HH=high/high, LLL=lower/worse than LL, HHH=higher/worse than HH. (NCT03714815)
Timeframe: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
| Intervention | Participants (Count of Participants) |
|---|
| Hemoglobin:LL<100 | Hematocrit: LL(<0.28-females;<0.32-males) | Leukocytes: HH (>20.0) | Lymphocytes: LLL (<0.5) | Lymphocytes: LL (<0.8) | Alanine Aminotransferase: HH (>3 ULN) | Aspartate Aminotransferase: HH (>3 ULN) | Alkaline Phosphatase: HH (>2.5 ULN) | Bilirubin: HH (>2 ULN) | Bilirubin: HHH (>5 ULN) | Creatinine: HH (>1.5 ULN) | Urea Nitrogen: HH (>2.5 ULN) | Urate: HH (>590) | Urate: HHH (>720) | Sodium: LLL (<130) | Potassium: LLL (<3.0) | Potassium: LL (<3.2) | Potassium: HH (>5.5) | Magnesium: HHH (>1.23) | Calcium: LLL (<1.75) | Calcium: LL (<2.0) |
|---|
| Macitentan 10 mg | 10 | 5 | 1 | 1 | 10 | 1 | 1 | 1 | 1 | 1 | 2 | 3 | 15 | 3 | 3 | 1 | 5 | 5 | 1 | 1 | 2 |
Change From Baseline in Body Weight at Week 24
Change from baseline in body weight at Week 24 was reported. (NCT03714815)
Timeframe: Baseline and Week 24
| Intervention | kilograms (kg) (Mean) |
|---|
| Macitentan 10 mg | 0.25 |
Change From Baseline in Bilirubin at Week 24
Change from baseline in bilirubin at Week 24 was reported. (NCT03714815)
Timeframe: Baseline and Week 24
| Intervention | micromoles per liter (mcmol/L) (Mean) |
|---|
| Macitentan 10 mg | -0.0970 |
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 52
Change from baseline in systolic and diastolic arterial BP at Week 52 was reported. (NCT03714815)
Timeframe: Baseline and Week 52
| Intervention | mmHg (Mean) |
|---|
| Systolic BP | Diastolic BP |
|---|
| Macitentan 10 mg | -2.10 | -0.79 |
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 24
Change from baseline in systolic and diastolic arterial BP at Week 24 was reported. (NCT03714815)
Timeframe: Baseline and Week 24
| Intervention | millimeters of mercury (mmHg) (Mean) |
|---|
| Systolic BP | Diastolic BP |
|---|
| Macitentan 10 mg | -5.01 | -3.34 |
Change From Baseline in Leukocytes and Platelets at Week 52
Change from baseline in leukocytes and platelets at Week 52 was reported. (NCT03714815)
Timeframe: Baseline and Week 52
| Intervention | 10^9 cells/L (Mean) |
|---|
| Leukocytes | Platelets |
|---|
| Macitentan 10 mg | -0.503 | -9.02 |
Change From Baseline in Leukocytes and Platelets at Week 24
Change from baseline in leukocytes and platelets at Week 24 was reported. (NCT03714815)
Timeframe: Baseline and Week 24
| Intervention | 10^9 cells/L (Mean) |
|---|
| Leukocytes | Platelets |
|---|
| Macitentan 10 mg | -0.078 | 1.39 |
Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 52
Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 52 was reported. (NCT03714815)
Timeframe: Baseline and Week 52
| Intervention | U/L (Mean) |
|---|
| Alanine Aminotransferase | Aspartate Aminotransferase |
|---|
| Macitentan 10 mg | 0.10 | 1.2 |
Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 24
Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 24 was reported. (NCT03714815)
Timeframe: Baseline and Week 24
| Intervention | units per liter (U/L) (Mean) |
|---|
| Alanine Aminotransferase | Aspartate Aminotransferase |
|---|
| Macitentan 10 mg | -0.49 | -0.2 |
Number of Participants With TEAEs Leading to Premature Discontinuation of Study Treatment
An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Any AE occurring at or after the study treatment start up to 30 days after EOT within the analysis set was considered to be treatment-emergent. (NCT03714815)
Timeframe: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 25 |
Number of Participants With All-cause Hospital Admissions up to 30 Days After Study Treatment Discontinuation
Number of participants with all-cause hospital admissions up to 30 days after study treatment discontinuation were reported. (NCT03714815)
Timeframe: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 42 |
Number of Participants With All-cause Deaths up to 30 Days After Study Treatment Discontinuation
Number of participants with all-cause deaths up to 30 days after study treatment discontinuation were reported. All-cause deaths are defined as all anticipated and unanticipated deaths due to any cause. (NCT03714815)
Timeframe: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 11 |
Change From Baseline in Pulse Rate at Week 24
Change from baseline in pulse rate at Week 24 was reported. (NCT03714815)
Timeframe: Baseline and Week 24
| Intervention | beats per minute (bpm) (Mean) |
|---|
| Macitentan 10 mg | 0.59 |
Change From Baseline in Hemoglobin at Week 52
Change from baseline in hemoglobin at Week 52 was reported. (NCT03714815)
Timeframe: Baseline and Week 52
| Intervention | grams per litre (g/L) (Mean) |
|---|
| Macitentan 10 mg | -1.10 |
Change From Baseline in Hemoglobin at Week 24
Change from baseline in hemoglobin at Week 24 was reported. (NCT03714815)
Timeframe: Baseline and Week 24
| Intervention | grams per liter (g/L) (Mean) |
|---|
| Macitentan 10 mg | -4.13 |
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52
Change from baseline in eGFR rate at Week 52 was reported. (NCT03714815)
Timeframe: Baseline and Week 52
| Intervention | milliliters/minute/1.73 meter square (Mean) |
|---|
| Macitentan 10 mg | -1.80 |
Change From Baseline in Pulse Rate at Week 52
Change from baseline in pulse rate at Week 52 was reported. (NCT03714815)
Timeframe: Baseline and Week 52
| Intervention | bpm (Mean) |
|---|
| Macitentan 10 mg | 2.62 |
Change From Baseline in Prothrombin Time Over Time
Change from baseline in prothrombin time over time was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | seconds (Mean) |
|---|
| Week 26 | Week 52 | Week 78 | Week 104 | Week 130 |
|---|
| Macitentan 10 mg | -0.31 | -0.05 | -0.38 | -1.12 | -0.57 |
Number of Participants With TEAEs Leading to Death
An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Any AE occurring at or after the study treatment start up to 30 days after EOT (limits included) within the analysis set was considered to be treatment-emergent. (NCT03775421)
Timeframe: Up to 133 weeks
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 1 |
Number of Participants With TEAEs Leading to Premature Discontinuation of Study Treatment
An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Any AE occurring at or after the study treatment start up to 30 days after EOT (limits included) within the analysis set was considered to be treatment-emergent. (NCT03775421)
Timeframe: Up to 133 weeks
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 2 |
Number of Participants With Treatment-emergent Marked Laboratory Abnormalities up to 30 Days After Study Treatment Discontinuation
Number of participants with treatment-emergent marked laboratory abnormalities (Hemoglobin [gram/Liter {g/L}], Platelets [giga/L {10^9 cells/L}], Leukocytes [10^9 cells/L], Lymphocytes [10^9 cells/L], Neutrophils [10^9 cells/L], Prothrombin International Normalized Ratio [PINR;Ratio], Aspartate Aminotransferase [Units/L {U/L}], Bilirubin [micromoles/L {mcmol/L}], Alkaline Phosphatase [U/L], Glomerular Filtration Rate [milliliter/minute/1.73 meter square], Glucose [millimoles/L {mmol/L}], Potassium [mmol/L], Sodium [mmol/L], Triglycerides [mmol/L] were reported. Abnormalities that occurred after study treatment start and up to 30 days after study treatment discontinuation, that were not present at baseline, were treatment-emergent. Marked laboratory abnormalities reported for at least 1 participant were reported in this outcome measure. >=:greater than or equal to; >:greater than; <:less than; ULN: upper limit of normal; L:Low, H:High, LLL:lower/worse than LL, HHH:higher/worse than HH. (NCT03775421)
Timeframe: Up to 133 weeks
| Intervention | Participants (Count of Participants) |
|---|
| Hemoglobin: LL<100 | Platelets: LL (< 75) | Leukocytes: LLL (< 1.9) | Leukocytes: LL (< 3.0) | Lymphocytes: HH (> 4.0) | Neutrophils: LL (< 1.5) | PINR: HH (>=1.5 ULN) | PINR: HHH (>= 2.5 ULN) | Aspartate Aminotransferase: HH (>=3 ULN) | Bilirubin: HH (>=2 ULN) | Alkaline Phosphatase: HH (> 2.5 ULN) | GFR: LL (< 60) | Glucose: LL (< 3.0) | Glucose: HH (> 8.9) | Potassium: HH (>5.5) | Sodium: LLL (<130) | Triglycerides: HH (>3.42) |
|---|
| Macitentan 10 mg | 1 | 3 | 2 | 10 | 1 | 3 | 4 | 1 | 1 | 1 | 1 | 1 | 2 | 3 | 1 | 1 | 3 |
Change From Baseline in Body Weight Over Time
Change from baseline in body weight over time was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | kilograms (kg) (Mean) |
|---|
| Week 26 | Week 52 | Week 78 | Week 104 | Week 130 |
|---|
| Macitentan 10 mg | 0.8 | 0.9 | 1.7 | 2.0 | 2.6 |
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Any AE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent. (NCT03775421)
Timeframe: Up to 133 weeks
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 68 |
Number of Participants With Treatment-emergent Serious AEs (TESAEs)
An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. Any SAE occurring at or after the study treatment start up to 30 days after EOT (limits included) within the analysis set was considered to be TESAEs. (NCT03775421)
Timeframe: Up to 133 weeks
| Intervention | Participants (Count of Participants) |
|---|
| Macitentan 10 mg | 18 |
Change From Baseline in Glomerular Filtration Rate (GFR) Over Time
Change from baseline in GFR over time was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | milliliters/minute/1.73 meter square (Mean) |
|---|
| Week 26 | Week 52 | Week 78 | Week 104 | Week 130 |
|---|
| Macitentan 10 mg | -0.9 | -2.0 | -0.5 | 0.4 | -1.7 |
Change From Baseline in Hematocrit Over Time
Change from baseline in hematocrit over time was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | Liters/Liter (L/L) (Mean) |
|---|
| Week 26 | Week 52 | Week 78 | Week 104 | Week 130 |
|---|
| Macitentan 10 mg | -0.016 | -0.007 | -0.011 | -0.008 | 0.010 |
Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP), and Gamma Glutamyl Transferase (GGT) Over Time
Change from baseline in ALT, AST, AP, and GGT over time were reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | U/L (Mean) |
|---|
| ALT: Week 26 | ALT: Week 52 | ALT: Week 78 | ALT: Week 104 | ALT: Week 130 | AST: Week 26 | AST: Week 52 | AST: Week 78 | AST: Week 104 | AST: Week 130 | AP: Week 26 | AP: Week 52 | AP: Week 78 | AP: Week 104 | AP: Week 130 | GGT: Week 26 | GGT: Week 52 | GGT: Week 78 | GGT: Week 104 | GGT: Week 130 |
|---|
| Macitentan 10 mg | -2.0 | -2.1 | -2.7 | -6.8 | -13.7 | -1.3 | -1.7 | -3.0 | -6.1 | -21.3 | -7.7 | -1.9 | -6.6 | -21.8 | 6.7 | -1.2 | 1.2 | -2.2 | -3.2 | 1.0 |
Change From Baseline in Bilirubin, Direct Bilirubin, and Creatinine Over Time
Change from baseline in bilirubin, direct bilirubin, and creatinine over time were reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | micromoles per liter (mcmol/L) (Mean) |
|---|
| Bilirubin: Week 26 | Bilirubin: Week 52 | Bilirubin: Week 78 | Bilirubin: Week 104 | Bilirubin: Week 130 | Direct Bilirubin: Week 26 | Direct Bilirubin: Week 52 | Direct Bilirubin: Week 78 | Direct Bilirubin: Week 104 | Direct Bilirubin: Week 130 | Creatinine: Week 26 | Creatinine: Week 52 | Creatinine: Week 78 | Creatinine: Week 104 | Creatinine: Week 130 |
|---|
| Macitentan 10 mg | -0.9 | -1.1 | -0.5 | -0.8 | -1.3 | -0.1 | 0.0 | 0.0 | -0.2 | -1.0 | 0.2 | 0.9 | 0.8 | 0.1 | -0.7 |
Change From Baseline in Leukocytes, Neutrophils, Lymphocytes, and Platelets Over Time
Change from baseline in leukocytes, neutrophils, lymphocytes, and platelets over time were reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | 10^9 cells/L (Mean) |
|---|
| Leukocytes: Week 26 | Leukocytes: Week 52 | Leukocytes: Week 78 | Leukocytes: Week 104 | Leukocytes: Week 130 | Neutrophils: Week 26 | Neutrophils: Week 52 | Neutrophils: Week 78 | Neutrophils: Week 104 | Neutrophils: Week 130 | Lymphocytes: Week 26 | Lymphocytes: Week 52 | Lymphocytes: Week 78 | Lymphocytes: Week 104 | Lymphocytes: Week 130 | Platelets: Week 26 | Platelets: Week 52 | Platelets: Week 78 | Platelets: Week 104 | Platelets: Week 130 |
|---|
| Macitentan 10 mg | -0.358 | -0.222 | -0.300 | -0.255 | -0.560 | -0.185 | -0.074 | -0.233 | -0.105 | -0.400 | -0.153 | -0.098 | -0.016 | -0.089 | -0.113 | -9.2 | -4.3 | -8.1 | -11.1 | 6.7 |
Change From Baseline in Peak Oxygen Uptake/Consumption (VO2)
Change from baseline in peak VO2 was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline, Week 52, and Week 104
| Intervention | Milliliters per kilogram per minute (Mean) |
|---|
| Week 52 | Week 104 |
|---|
| Macitentan 10 mg | -0.82 | -0.93 |
Change From Baseline in Peripheral Oxygen Saturation (SpO2) Over Time
Change from baseline in SpO2 over time was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | percentage of SpO2 (%) (Mean) |
|---|
| Week 26 | Week 52 | Week 78 | Week 104 | Week 130 |
|---|
| Macitentan 10 mg | 0.2 | 0.2 | -0.5 | 0.3 | 3.3 |
Change From Baseline in Prothrombin International Normalized Ratio Over Time
Change from baseline in prothrombin international normalized ratio over time was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | ratio (Mean) |
|---|
| Week 26 | Week 52 | Week 78 | Week 104 | Week 130 |
|---|
| Macitentan 10 mg | -0.06 | -0.06 | -0.12 | -0.16 | -0.07 |
Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac)
Change from baseline in mean count per minute of daily PA-Ac was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline, Week 26, Week 52, Week 78, and Week 104
| Intervention | mean count per minute (Mean) |
|---|
| Week 26 | Week 52 | Week 78 | Week 104 |
|---|
| Macitentan 10 mg | 19.74 | 44.58 | 99.14 | -62.87 |
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) Over Time
Change from baseline in systolic and diastolic arterial BP over time was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | millimeters of mercury (mmHg) (Mean) |
|---|
| Systolic BP: Week 26 | Systolic BP: Week 52 | Systolic BP: Week 78 | Systolic BP: Week 104 | Systolic BP: Week 130 | Diastolic BP: Week 26 | Diastolic BP: Week 52 | Diastolic BP: Week 78 | Diastolic BP: Week 104 | Diastolic BP: Week 130 |
|---|
| Macitentan 10 mg | -0.7 | -1.7 | -0.7 | 0.7 | -12 | -2.9 | -0.9 | -1.6 | 2.6 | -0.7 |
Change From Baseline in Pulse Rate Over Time
Change from baseline in pulse rate over time was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | beats per minute (bpm) (Mean) |
|---|
| Week 26 | Week 52 | Week 78 | Week 104 | Week 130 |
|---|
| Macitentan 10 mg | -2.1 | 0.9 | -1.3 | -1.7 | -0.3 |
Change From Baseline in Hemoglobin Over Time
Change from baseline in hemoglobin over time was reported in this outcome measure. (NCT03775421)
Timeframe: Baseline up to Week 130
| Intervention | g/L (Mean) |
|---|
| Week 26 | Week 52 | Week 78 | Week 104 | Week 130 |
|---|
| Macitentan 10 mg | -6.0 | -4.0 | -5.0 | -2.4 | 5.7 |
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. (NCT03904693)
Timeframe: Baseline, EDBT (up to 16 weeks)
| Intervention | Ratio (Geometric Mean) |
|---|
| Treatment-naive And Prior ERA Strata: Macitentan 10 Milligrams (mg) | 0.77 |
| Treatment-naive And Prior ERA Strata: M/T FDC | 0.55 |
| Treatment-naive And Prior PDE-5i Strata: Tadalafil 20 mg | 0.78 |
| Treatment-naive And Prior PDE-5i Strata: M/T FDC | 0.56 |