Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease
Conditions
Keywords
pulmonary vascular disease, macitentan, heart failure with preserved ejection fraction
Brief summary
The aim of this open-label (OL) extension trial is to study the long-term safety and efficacy of macitentan in subjects with heart failure with preserved ejection fraction (HFpEF) and pulmonary vascular disease (PVD) beyond the treatment in the double-blind parent SERENADE study (AC-055G202, NCT03153111). Furthermore, this OL extension study will give eligible subjects of the main study (SERENADE/AC-055G202, NCT03153111) an opportunity to continue or start receiving macitentan.
Interventions
DRUGmacitentan 10 mg
macitentan 10 mg, film-coated tablet, oral use
Sponsors
Almac Clinical Technologies
Frontier Science & Technology Research Foundation, Inc.
Covance
Chiltern International Ltd.
WorldCare Clinical, LLC
AcitGraph
Medidata Solutions
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Subjects who remained in main study (SERENADE/AC-055G202, NCT03153111) after randomization and who meet the eligibility criteria described will be eligible to enter this single-arm OL extension study. All enrolled subjects will receive macitentan 10 mg. For this OL extension study no primary efficacy endpoint has been defined and all efficacy endpoints are of exploratory nature. The ones listed below are considered safety endpoints.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated Informed Consent Form (ICF). * Participant remained in the main study (SERENADE/AC-055G202, NCT03153111) for: a) 52 weeks after randomization if entered this Open-label (OL) extension study prior to protocol Version 4, b) At least 24 weeks after randomization if entering this OL extension study under protocol Version 4 * A woman of childbearing potential is eligible only if: (1) Negative pre-treatment serum pregnancy test; (2) Agreement to undertake monthly pregnancy tests from the enrollment visit up to at least 30 days after study treatment discontinuation; and (2) Agreement to use reliable contraception from at least 30 days prior to the enrollment visit up to at least 30 days after study treatment discontinuation.
Exclusion criteria
* Premature discontinuation of study treatment in the main study (SERENADE/AC-055G202, NCT03153111) due to an adverse event related to: (1) Edema or fluid retention; (2) Worsening of heart failure; (3) Liver aminotransferase elevation; and (4) Study treatment, based on investigators' discretion * Liver aminotransferase elevations, at the enrollment visit, fulfilling the following criteria: (1) Alanine amino transferase (ALT) / aspartate aminotransferase (AST) greater than or equal to (\>=) 8 \* the upper limit of normal (ULN); (2) ALT/AST \>= 3 \* ULN and associated clinical symptoms of liver injury, for example: nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, myalgia, fever); and (3) ALT/AST \>= 3 \* ULN and associated increase in total bilirubin to \>= 2 \* ULN * Treatment with the following forbidden medications within 1 month prior to the enrollment visit: (1) Treatments that may interfere with the assessment of efficacy (that is, endothelin receptor antagonists, prostanoids, phosphodiesterase-5 inhibitors, guanylate cyclase stimulators); (2) Strong cytochrome P-450 3A4 (CYP3A4) inducers such as rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, or St. John's wort; (3) Strong CYP3A4 inhibitors such as ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir or a moderate dual CYP3A4/CYP2C9 inhibitor (for example, fluconazole or amiodarone) or co-administration of a combination of moderate CYP3A4 (for example, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitors (for example, miconazole, piperine), in the 1-month period prior to baseline. This will not necessarily apply to participants who are already well-managed on such an ongoing combination; and (4) any other investigational treatment * Pregnant, planning to be become pregnant or lactating. * Any known factor or disease that might interfere with treatment compliance, study conduct, or interpretation of the results, such as drug or alcohol dependence or psychiatric disease. * Known hypersensitivity to macitentan or drugs of the same class, or any of the study drug excipients (for example, soy lecithin, lactose)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52 | Baseline and Week 52 | Change from baseline in eGFR rate at Week 52 was reported. |
| Number of Participants With All-cause Deaths up to 30 Days After Study Treatment Discontinuation | Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks) | 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. |
| Number of Participants With All-cause Hospital Admissions up to 30 Days After Study Treatment Discontinuation | Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks) | Number of participants with all-cause hospital admissions up to 30 days after study treatment discontinuation were reported. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) up to 30 Days After Study Treatment Discontinuation | Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks) | 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. |
| Number of Participants With TEAEs Leading to Premature Discontinuation of Study Treatment | Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks) | 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. |
| Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 24 | Baseline and Week 24 | Change from baseline in systolic and diastolic arterial BP at Week 24 was reported. |
| Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 52 | Baseline and Week 52 | Change from baseline in systolic and diastolic arterial BP at Week 52 was reported. |
| Change From Baseline in Pulse Rate at Week 24 | Baseline and Week 24 | Change from baseline in pulse rate at Week 24 was reported. |
| Change From Baseline in Pulse Rate at Week 52 | Baseline and Week 52 | Change from baseline in pulse rate at Week 52 was reported. |
| Change From Baseline in Body Weight at Week 24 | Baseline and Week 24 | Change from baseline in body weight at Week 24 was reported. |
| Change From Baseline in Body Weight at Week 52 | Baseline and Week 52 | Change from baseline in body weight at Week 52 was reported. |
| Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks) | 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. |
| Change From Baseline in Hemoglobin at Week 24 | Baseline and Week 24 | Change from baseline in hemoglobin at Week 24 was reported. |
| Change From Baseline in Hemoglobin at Week 52 | Baseline and Week 52 | Change from baseline in hemoglobin at Week 52 was reported. |
| Change From Baseline in Leukocytes and Platelets at Week 24 | Baseline and Week 24 | Change from baseline in leukocytes and platelets at Week 24 was reported. |
| Change From Baseline in Leukocytes and Platelets at Week 52 | Baseline and Week 52 | Change from baseline in leukocytes and platelets at Week 52 was reported. |
| Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 24 | Baseline and Week 24 | Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 24 was reported. |
| Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 52 | Baseline and Week 52 | Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 52 was reported. |
| Change From Baseline in Bilirubin at Week 24 | Baseline and Week 24 | Change from baseline in bilirubin at Week 24 was reported. |
| Change From Baseline in Bilirubin at Week 52 | Baseline and Week 52 | Change from baseline in bilirubin at Week 52 was reported. |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24 | Baseline and Week 24 | Change from baseline in eGFR rate at Week 24 was reported. |
Countries
Argentina, Austria, Brazil, Bulgaria, Denmark, France, Germany, Hungary, Israel, Poland, Romania, Russia, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Macitentan 10 mg Eligible participants who remained in the main study (NCT03153111) for at least 24 weeks after randomization, entered this open-label extension study to receive macitentan 10 milligrams (mg) tablet orally once daily until the end of the treatment (treatment exposure ranged from 0.4 to 126 weeks). | 91 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 11 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Macitentan 10 mg |
|---|---|
| Age, Continuous | 72.7 years STANDARD_DEVIATION 9.21 |
| Age, Customized 85 years and over | 8 Participants |
| Age, Customized From 18 to 64 years | 14 Participants |
| Age, Customized From 65 to 84 years | 69 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized White | 87 Participants |
| Region of Enrollment ARGENTINA | 1 Participants |
| Region of Enrollment AUSTRIA | 2 Participants |
| Region of Enrollment BRAZIL | 2 Participants |
| Region of Enrollment BULGARIA | 8 Participants |
| Region of Enrollment DENMARK | 2 Participants |
| Region of Enrollment FRANCE | 5 Participants |
| Region of Enrollment GERMANY | 4 Participants |
| Region of Enrollment ISRAEL | 23 Participants |
| Region of Enrollment POLAND | 7 Participants |
| Region of Enrollment ROMANIA | 4 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 14 Participants |
| Region of Enrollment SWEDEN | 2 Participants |
| Region of Enrollment UNITED KINGDOM | 3 Participants |
| Region of Enrollment UNITED STATES | 14 Participants |
| Sex: Female, Male Female | 59 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 11 / 91 |
| other Total, other adverse events | 45 / 91 |
| serious Total, serious adverse events | 49 / 91 |
Outcome results
Primary
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.
Time frame: Baseline and Week 24
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure; n specifies those participants who were analyzed for specific category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 24 | Alanine Aminotransferase | -0.49 units per liter (U/L) | Standard Deviation 7.59 |
| Macitentan 10 mg | Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 24 | Aspartate Aminotransferase | -0.2 units per liter (U/L) | Standard Deviation 7.76 |
Primary
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.
Time frame: Baseline and Week 52
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 52 | Alanine Aminotransferase | 0.10 U/L | Standard Deviation 7.529 |
| Macitentan 10 mg | Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 52 | Aspartate Aminotransferase | 1.2 U/L | Standard Deviation 6.52 |
Primary
Change From Baseline in Bilirubin at Week 24
Change from baseline in bilirubin at Week 24 was reported.
Time frame: Baseline and Week 24
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Bilirubin at Week 24 | -0.0970 micromoles per liter (mcmol/L) | Standard Deviation 4.20548 |
Primary
Change From Baseline in Bilirubin at Week 52
Change from baseline in bilirubin at Week 52 was reported.
Time frame: Baseline and Week 52
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Bilirubin at Week 52 | 0.2041 mcmol/L | Standard Deviation 4.65018 |
Primary
Change From Baseline in Body Weight at Week 24
Change from baseline in body weight at Week 24 was reported.
Time frame: Baseline and Week 24
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Body Weight at Week 24 | 0.25 kilograms (kg) | Standard Deviation 6.353 |
Primary
Change From Baseline in Body Weight at Week 52
Change from baseline in body weight at Week 52 was reported.
Time frame: Baseline and Week 52
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Body Weight at Week 52 | -0.16 kg | Standard Deviation 8.2 |
Primary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24
Change from baseline in eGFR rate at Week 24 was reported.
Time frame: Baseline and Week 24
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24 | -4.05 milliliters/minute/1.73 meter square | Standard Deviation 11.766 |
Primary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52
Change from baseline in eGFR rate at Week 52 was reported.
Time frame: Baseline and Week 52
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52 | -1.80 milliliters/minute/1.73 meter square | Standard Deviation 13.51 |
Primary
Change From Baseline in Hemoglobin at Week 24
Change from baseline in hemoglobin at Week 24 was reported.
Time frame: Baseline and Week 24
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Hemoglobin at Week 24 | -4.13 grams per liter (g/L) | Standard Deviation 11.324 |
Primary
Change From Baseline in Hemoglobin at Week 52
Change from baseline in hemoglobin at Week 52 was reported.
Time frame: Baseline and Week 52
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Hemoglobin at Week 52 | -1.10 grams per litre (g/L) | Standard Deviation 13.241 |
Primary
Change From Baseline in Leukocytes and Platelets at Week 24
Change from baseline in leukocytes and platelets at Week 24 was reported.
Time frame: Baseline and Week 24
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Leukocytes and Platelets at Week 24 | Leukocytes | -0.078 10^9 cells/L | Standard Deviation 1.6871 |
| Macitentan 10 mg | Change From Baseline in Leukocytes and Platelets at Week 24 | Platelets | 1.39 10^9 cells/L | Standard Deviation 36.102 |
Primary
Change From Baseline in Leukocytes and Platelets at Week 52
Change from baseline in leukocytes and platelets at Week 52 was reported.
Time frame: Baseline and Week 52
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Leukocytes and Platelets at Week 52 | Leukocytes | -0.503 10^9 cells/L | Standard Deviation 1.509 |
| Macitentan 10 mg | Change From Baseline in Leukocytes and Platelets at Week 52 | Platelets | -9.02 10^9 cells/L | Standard Deviation 37.285 |
Primary
Change From Baseline in Pulse Rate at Week 24
Change from baseline in pulse rate at Week 24 was reported.
Time frame: Baseline and Week 24
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Pulse Rate at Week 24 | 0.59 beats per minute (bpm) | Standard Deviation 9.706 |
Primary
Change From Baseline in Pulse Rate at Week 52
Change from baseline in pulse rate at Week 52 was reported.
Time frame: Baseline and Week 52
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Pulse Rate at Week 52 | 2.62 bpm | Standard Deviation 18.441 |
Primary
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.
Time frame: Baseline and Week 24
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 24 | Systolic BP | -5.01 millimeters of mercury (mmHg) | Standard Deviation 13.152 |
| Macitentan 10 mg | Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 24 | Diastolic BP | -3.34 millimeters of mercury (mmHg) | Standard Deviation 9.903 |
Primary
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.
Time frame: Baseline and Week 52
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 52 | Systolic BP | -2.10 mmHg | Standard Deviation 20.855 |
| Macitentan 10 mg | Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 52 | Diastolic BP | -0.79 mmHg | Standard Deviation 11.685 |
Primary
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.
Time frame: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Macitentan 10 mg | Number of Participants With All-cause Deaths up to 30 Days After Study Treatment Discontinuation | 11 Participants |
Primary
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.
Time frame: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Macitentan 10 mg | Number of Participants With All-cause Hospital Admissions up to 30 Days After Study Treatment Discontinuation | 42 Participants |
Primary
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.
Time frame: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Macitentan 10 mg | Number of Participants With TEAEs Leading to Premature Discontinuation of Study Treatment | 25 Participants |
Primary
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.
Time frame: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) up to 30 Days After Study Treatment Discontinuation | TEAEs | 81 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) up to 30 Days After Study Treatment Discontinuation | TESAEs | 49 Participants |
Primary
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.
Time frame: Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
Population: The safety analysis set included all participants who received at least 1 dose of macitentan 10 mg. Here, N (number of participants analyzed) specifies number of participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Hemoglobin:LL<100 | 10 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Hematocrit: LL(<0.28-females;<0.32-males) | 5 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Leukocytes: HH (>20.0) | 1 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Lymphocytes: LLL (<0.5) | 1 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Lymphocytes: LL (<0.8) | 10 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Alanine Aminotransferase: HH (>3 ULN) | 1 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Aspartate Aminotransferase: HH (>3 ULN) | 1 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Bilirubin: HH (>2 ULN) | 1 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Bilirubin: HHH (>5 ULN) | 1 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Creatinine: HH (>1.5 ULN) | 2 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Urea Nitrogen: HH (>2.5 ULN) | 3 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Urate: HH (>590) | 15 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Urate: HHH (>720) | 3 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Potassium: LLL (<3.0) | 1 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Potassium: HH (>5.5) | 5 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Magnesium: HHH (>1.23) | 1 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Calcium: LLL (<1.75) | 1 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Calcium: LL (<2.0) | 2 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Alkaline Phosphatase: HH (>2.5 ULN) | 1 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Sodium: LLL (<130) | 3 Participants |
| Macitentan 10 mg | Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation | Potassium: LL (<3.2) | 5 Participants |