Pulmonary Arterial Hypertension
Conditions
Keywords
pulmonary arterial hypertension SERAPHIN
Brief summary
The AC-055-302/SERAPHIN study will be an event-driven Phase III study, comparing two different doses of macitentan (ACT-064992) (3 and 10 mg) vs placebo in patients with symptomatic PAH. The main study objective is to demonstrate that macitentan (ACT-064992) prolongs time to the first morbidity or mortality event, and to evaluate the benefit/risk profile of macitentan (ACT-064992) in the treatment of patients with symptomatic PAH.
Interventions
DRUGmacitentan (ACT-064992)
Tablet, 3 mg dosage, once daily
DRUGplacebo
Matching placebo, once daily
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent prior to initiation of any study mandated procedure. 2. Patients with symptomatic pulmonary arterial hypertension (PAH) in modified World Health Organization (WHO) functional class II to IV. 3. Patients with the following types of pulmonary arterial hypertension (PAH) belonging to groups 1.1 to 1.3 of the Venice classification: * Idiopathic (IPAH); * Familial (FPAH); or * Related to: * Collagen vascular disease; * Simple, congenital systemic-to-pulmonary shunts at least 1 year post surgical repair; * Human immunodeficiency virus (HIV) infection; or * Drugs and toxins. 4. PAH diagnosis confirmed by hemodynamic evaluation performed prior to randomization and showing all of the following: * Mean pulmonary artery pressure (mPAP) \> 25 mmHg at rest; * Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) \< 15 mmHg; and * Pulmonary vascular resistance (PVR) at rest \>= 320 dyn×sec/cm\^5. 5. 6-minute walk distance (6MWD) \>= 50 m. 6. Men or women \> 12 years of age (women of childbearing potential must have a negative pre-treatment serum pregnancy test and must use a reliable method of contraception).
Exclusion criteria
1. PAH associated with portal hypertension, thyroid disorders, glycogen storage disease, Gaucher''s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy. 2. PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and combined and complex systemic-to-pulmonary shunts, corrected or non corrected. 3. PAH associated with significant venous or capillary involvement (PCWP \> 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis. 4. Persistent pulmonary hypertension of the newborn. 5. Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification. 6. Moderate to severe obstructive lung disease: forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) \< 70% and FEV1 \< 65% of predicted value after bronchodilator administration. 7. Moderate to severe restrictive lung disease: total lung capacity (TLC) \< 60% of predicted value. 8. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C. 9. Estimated creatinine clearance \< 30 mL/min 10. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 1.5 times the upper limit of normal. 11. Hemoglobin \< 75% of the lower limit of the normal range. 12. Systolic blood pressure \< 100 mmHg. 13. Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements. 14. Pregnant or breast-feeding. 15. Known concomitant life-threatening disease with a life expectancy \< 12 months. 16. Body weight \< 40 kg. 17. Any condition that prevents compliance with the protocol or adherence to therapy. 18. Recently started (\< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise. 19. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to randomization. 20. Systemic treatment within 4 week prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors). 21. Treatment with cytochrome P3A (CYP3A) inducers within 4 weeks prior to randomization 22. Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients. 23. Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Up to end of treatment (data presented up to month 36) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Up to end of treatment (data presented up to month 36) | 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. |
| Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Up to end of treatment (data presented up to month 36) | Events of death due to any cause up to the end of treatment (plus 7 days) |
| Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Up to end of study (data presented up to month 36) | 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). |
| Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6 | 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. |
| Pulmonary Vascular Resistance at Baseline and Month 6 | Baseline to 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. |
| Cardiac Index at Baseline and Month 6 | Baseline to 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. |
| Change From Baseline to Month 6 in 6-minute Walk Distance | Baseline to month 6 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Summary of the First Causes of Morbidity or Mortality | Up to end of treatment (Up to 36 months) | 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 |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Bulgaria, Canada, Chile, China, Colombia, Croatia, France, Germany, Hong Kong, Hungary, India, Israel, Italy, Malaysia, Mexico, Netherlands, Norway, Peru, Poland, Romania, Russia, Serbia, Singapore, Slovakia, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 955 patients were screened from 158 centers in 39 countries, and 742 patients from 151 centers in 39 countries were randomized
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching ACT-064992 placebo tablet, once daily | 250 |
| ACT-064992 3 mg ACT-064992 tablet, 3 mg, once daily | 250 |
| ACT-064992 10 mg ACT-064992 tablet, 10 mg, once daily | 242 |
| Total | 742 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative reason | 0 | 0 | 1 |
| Overall Study | Death | 44 | 47 | 34 |
| Overall Study | Incorrect randomization | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 7 | 5 | 2 |
| Overall Study | Withdrawal of consent | 4 | 6 | 4 |
Baseline characteristics
| Characteristic | ACT-064992 3 mg | ACT-064992 10 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 7 participants | 6 participants | 7 participants | 20 participants |
| Age, Categorical >=65 years | 33 participants | 27 participants | 43 participants | 103 participants |
| Age, Categorical Between 18 and 65 years | 208 participants | 209 participants | 199 participants | 616 participants |
| Age, Continuous | 44.5 years STANDARD_DEVIATION 16.26 | 45.5 years STANDARD_DEVIATION 14.99 | 46.7 years STANDARD_DEVIATION 17.03 | 45.6 years STANDARD_DEVIATION 16.13 |
| Gender Female | 187 participants | 194 participants | 184 participants | 565 participants |
| Gender Male | 61 participants | 48 participants | 65 participants | 174 participants |
| Region of Enrollment Argentina | 16 participants | 13 participants | 14 participants | 43 participants |
| Region of Enrollment Australia | 4 participants | 4 participants | 2 participants | 10 participants |
| Region of Enrollment Austria | 1 participants | 2 participants | 1 participants | 4 participants |
| Region of Enrollment Belarus | 8 participants | 8 participants | 7 participants | 23 participants |
| Region of Enrollment Belgium | 0 participants | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Bulgaria | 3 participants | 2 participants | 1 participants | 6 participants |
| Region of Enrollment Canada | 5 participants | 4 participants | 7 participants | 16 participants |
| Region of Enrollment Chile | 10 participants | 9 participants | 9 participants | 28 participants |
| Region of Enrollment China | 29 participants | 27 participants | 31 participants | 87 participants |
| Region of Enrollment Colombia | 3 participants | 3 participants | 3 participants | 9 participants |
| Region of Enrollment Croatia | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Denmark | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment France | 3 participants | 3 participants | 5 participants | 11 participants |
| Region of Enrollment Germany | 14 participants | 13 participants | 17 participants | 44 participants |
| Region of Enrollment Hong Kong | 2 participants | 1 participants | 1 participants | 4 participants |
| Region of Enrollment Hungary | 3 participants | 2 participants | 1 participants | 6 participants |
| Region of Enrollment India | 17 participants | 15 participants | 15 participants | 47 participants |
| Region of Enrollment Israel | 6 participants | 8 participants | 6 participants | 20 participants |
| Region of Enrollment Italy | 2 participants | 1 participants | 2 participants | 5 participants |
| Region of Enrollment Malaysia | 2 participants | 3 participants | 2 participants | 7 participants |
| Region of Enrollment Mexico | 13 participants | 14 participants | 13 participants | 40 participants |
| Region of Enrollment Netherlands | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Norway | 0 participants | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Peru | 2 participants | 2 participants | 3 participants | 7 participants |
| Region of Enrollment Poland | 7 participants | 7 participants | 7 participants | 21 participants |
| Region of Enrollment Romania | 5 participants | 6 participants | 5 participants | 16 participants |
| Region of Enrollment Russian Federation | 24 participants | 23 participants | 25 participants | 72 participants |
| Region of Enrollment Serbia | 5 participants | 4 participants | 7 participants | 16 participants |
| Region of Enrollment Singapore | 5 participants | 4 participants | 4 participants | 13 participants |
| Region of Enrollment Slovakia | 2 participants | 3 participants | 1 participants | 6 participants |
| Region of Enrollment South Africa | 7 participants | 8 participants | 9 participants | 24 participants |
| Region of Enrollment Spain | 5 participants | 6 participants | 4 participants | 15 participants |
| Region of Enrollment Sweden | 2 participants | 2 participants | 3 participants | 7 participants |
| Region of Enrollment Taiwan | 5 participants | 5 participants | 4 participants | 14 participants |
| Region of Enrollment Thailand | 7 participants | 9 participants | 9 participants | 25 participants |
| Region of Enrollment Turkey | 1 participants | 1 participants | 1 participants | 3 participants |
| Region of Enrollment Ukraine | 5 participants | 5 participants | 4 participants | 14 participants |
| Region of Enrollment United Kingdom | 1 participants | 3 participants | 1 participants | 5 participants |
| Region of Enrollment United States | 25 participants | 19 participants | 23 participants | 67 participants |
| World Health Organisation Functional Class Class I | 0 participants | 1 participants | 0 participants | 1 participants |
| World Health Organisation Functional Class Class II | 138 participants | 120 participants | 129 participants | 387 participants |
| World Health Organisation Functional Class Class III | 105 participants | 116 participants | 116 participants | 337 participants |
| World Health Organisation Functional Class Class IV | 5 participants | 5 participants | 4 participants | 14 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 219 / 249 | 227 / 250 | 222 / 242 |
| serious Total, serious adverse events | 137 / 249 | 130 / 250 | 109 / 242 |
Outcome results
Primary
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
Time frame: Up to end of treatment (data presented up to month 36)
Population: All randomized patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 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) | Kaplan-Meier estimate at Month 6 | 80.1 percentage of participants-Kaplan Meier |
| Placebo | 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) | Kaplan-Meier estimate at Month 12 | 71.4 percentage of participants-Kaplan Meier |
| Placebo | 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) | Kaplan-Meier estimate at Month 18 | 61.5 percentage of participants-Kaplan Meier |
| Placebo | 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) | Kaplan-Meier estimate at Month 24 | 57.3 percentage of participants-Kaplan Meier |
| Placebo | 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) | Kaplan-Meier estimate at Month 30 | 50.2 percentage of participants-Kaplan Meier |
| Placebo | 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) | Kaplan-Meier estimate at Month 36 | 47.0 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | 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) | Kaplan-Meier estimate at Month 36 | 55.0 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | 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) | Kaplan-Meier estimate at Month 6 | 89.3 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | 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) | Kaplan-Meier estimate at Month 24 | 65.5 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | 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) | Kaplan-Meier estimate at Month 30 | 61.9 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | 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) | Kaplan-Meier estimate at Month 12 | 81.6 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | 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) | Kaplan-Meier estimate at Month 18 | 72.5 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | 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) | Kaplan-Meier estimate at Month 12 | 85.5 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | 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) | Kaplan-Meier estimate at Month 18 | 79.9 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | 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) | Kaplan-Meier estimate at Month 36 | 63.2 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | 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) | Kaplan-Meier estimate at Month 24 | 74.3 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | 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) | Kaplan-Meier estimate at Month 6 | 92.7 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | 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) | Kaplan-Meier estimate at Month 30 | 70.0 percentage of participants-Kaplan Meier |
p-value: 0.010897.5% CI: [0.516, 0.96]Log Rank
p-value: <0.000197.5% CI: [0.392, 0.762]Log Rank
Secondary
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.
Time frame: Baseline to month 6
Population: All randomized patients participating in the pharmacokinetic/pharmacodynamic sub-study
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Cardiac Index at Baseline and Month 6 | Month 6 | 2.21 L/min/m^2 |
| Placebo | Cardiac Index at Baseline and Month 6 | Baseline | 2.54 L/min/m^2 |
| Placebo | Cardiac Index at Baseline and Month 6 | Change from Baseline to Month 6 | -0.33 L/min/m^2 |
| ACT-064992 3 mg | Cardiac Index at Baseline and Month 6 | Month 6 | 2.69 L/min/m^2 |
| ACT-064992 3 mg | Cardiac Index at Baseline and Month 6 | Baseline | 2.34 L/min/m^2 |
| ACT-064992 3 mg | Cardiac Index at Baseline and Month 6 | Change from Baseline to Month 6 | 0.36 L/min/m^2 |
| ACT-064992 10 mg | Cardiac Index at Baseline and Month 6 | Baseline | 2.63 L/min/m^2 |
| ACT-064992 10 mg | Cardiac Index at Baseline and Month 6 | Change from Baseline to Month 6 | 0.30 L/min/m^2 |
| ACT-064992 10 mg | Cardiac Index at Baseline and Month 6 | Month 6 | 2.93 L/min/m^2 |
Secondary
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.
Time frame: Baseline to month 6
Population: All randomized patients excluding 1 patient in the placebo group who did not start study treatment and 2 patients in the ACT-064992 3 mg group who did not follow appropriate consent procedures and were not included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Month 6 in 6-minute Walk Distance | Baseline | 352 metres | Standard Deviation 110.6 |
| Placebo | Change From Baseline to Month 6 in 6-minute Walk Distance | Change from baseline at Month 6 | -9.4 metres | Standard Deviation 100.59 |
| ACT-064992 3 mg | Change From Baseline to Month 6 in 6-minute Walk Distance | Baseline | 364 metres | Standard Deviation 95.5 |
| ACT-064992 3 mg | Change From Baseline to Month 6 in 6-minute Walk Distance | Change from baseline at Month 6 | 7.4 metres | Standard Deviation 93.15 |
| ACT-064992 10 mg | Change From Baseline to Month 6 in 6-minute Walk Distance | Baseline | 363 metres | Standard Deviation 93.2 |
| ACT-064992 10 mg | Change From Baseline to Month 6 in 6-minute Walk Distance | Change from baseline at Month 6 | 12.5 metres | Standard Deviation 83.54 |
Secondary
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.
Time frame: Baseline to month 6
Population: All randomized patients excluding 1 patient in the placebo group who did not start study treatment and 2 patients in the ACT-064992 3 mg group who did not follow appropriate consent procedures and were not included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6 | 32 participants |
| ACT-064992 3 mg | Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6 | 49 participants |
| ACT-064992 10 mg | Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6 | 54 participants |
Secondary
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.
Time frame: Baseline to month 6
Population: All randomized patients participating in the pharmacokinetic/pharmacodynamic sub-study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Pulmonary Vascular Resistance at Baseline and Month 6 | Baseline | 886 (dyn*sec/cm^5) | Full Range 587 |
| Placebo | Pulmonary Vascular Resistance at Baseline and Month 6 | Month 6 | 1042 (dyn*sec/cm^5) | Full Range 656 |
| ACT-064992 3 mg | Pulmonary Vascular Resistance at Baseline and Month 6 | Baseline | 945 (dyn*sec/cm^5) | Full Range 541 |
| ACT-064992 3 mg | Pulmonary Vascular Resistance at Baseline and Month 6 | Month 6 | 736 (dyn*sec/cm^5) | Full Range 434 |
| ACT-064992 10 mg | Pulmonary Vascular Resistance at Baseline and Month 6 | Baseline | 907 (dyn*sec/cm^5) | Full Range 550 |
| ACT-064992 10 mg | Pulmonary Vascular Resistance at Baseline and Month 6 | Month 6 | 680 (dyn*sec/cm^5) | Full Range 497 |
Secondary
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).
Time frame: Up to end of study (data presented up to month 36)
Population: All randomized patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 6 | 94.7 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 12 | 91.4 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 18 | 89.3 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 24 | 87.2 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 30 | 82.6 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 36 | 80.7 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 36 | 80.0 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 6 | 96.4 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 24 | 87.3 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 30 | 83.4 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 12 | 93.9 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 18 | 91.4 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 12 | 95.0 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 18 | 93.3 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 36 | 82.9 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 24 | 89.1 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 6 | 96.3 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 30 | 86.9 percentage of participants-Kaplan Meier |
p-value: 0.831297.5% CI: [0.653, 1.673]Log Rank
p-value: 0.250997.5% CI: [0.464, 1.282]Log Rank
Secondary
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)
Time frame: Up to end of treatment (data presented up to month 36)
Population: All randomized patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 30 | 89.8 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 12 | 93.6 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 36 | 89.8 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 18 | 92.4 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 24 | 91.7 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 6 | 95.2 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 6 | 97.1 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 30 | 89.9 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 24 | 91.7 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 18 | 94.6 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 36 | 87.3 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 12 | 95.6 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 36 | 93.3 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 6 | 97.4 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 12 | 96.4 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 24 | 94.8 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 30 | 93.3 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 18 | 94.8 percentage of participants-Kaplan Meier |
p-value: 0.924997.5% CI: [0.477, 1.976]Log Rank
p-value: 0.203797.5% CI: [0.287, 1.418]Log Rank
Secondary
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.
Time frame: Up to end of treatment (data presented up to month 36)
Population: All randomized patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 6 | 84.8 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 12 | 76.7 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 18 | 69.0 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 24 | 67.9 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 30 | 62.0 percentage of participants-Kaplan Meier |
| Placebo | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 36 | 55.4 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 36 | 67.1 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 6 | 90.8 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 24 | 75.1 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 30 | 70.3 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 12 | 84.9 percentage of participants-Kaplan Meier |
| ACT-064992 3 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 18 | 78.1 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 12 | 89.8 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 18 | 84.8 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 36 | 70.6 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 24 | 81.7 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 6 | 94.6 percentage of participants-Kaplan Meier |
| ACT-064992 10 mg | Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) | Kaplan-Meier Estimate at Month 30 | 77.9 percentage of participants-Kaplan Meier |
p-value: 0.014697.5% CI: [0.462, 0.97]Log Rank
p-value: <0.000197.5% CI: [0.335, 0.747]Log Rank
Other Pre-specified
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
Time frame: Up to end of treatment (Up to 36 months)
Population: All randomized patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Summary of the First Causes of Morbidity or Mortality | Other worsening of PAH | 93 participants |
| Placebo | Summary of the First Causes of Morbidity or Mortality | Death | 17 participants |
| Placebo | Summary of the First Causes of Morbidity or Mortality | Prostanoid initiation (i.v. or s.c.) | 6 participants |
| Placebo | Summary of the First Causes of Morbidity or Mortality | Lung transplantation | 0 participants |
| ACT-064992 3 mg | Summary of the First Causes of Morbidity or Mortality | Lung transplantation | 1 participants |
| ACT-064992 3 mg | Summary of the First Causes of Morbidity or Mortality | Other worsening of PAH | 72 participants |
| ACT-064992 3 mg | Summary of the First Causes of Morbidity or Mortality | Prostanoid initiation (i.v. or s.c.) | 1 participants |
| ACT-064992 3 mg | Summary of the First Causes of Morbidity or Mortality | Death | 21 participants |
| ACT-064992 10 mg | Summary of the First Causes of Morbidity or Mortality | Lung transplantation | 0 participants |
| ACT-064992 10 mg | Summary of the First Causes of Morbidity or Mortality | Death | 16 participants |
| ACT-064992 10 mg | Summary of the First Causes of Morbidity or Mortality | Prostanoid initiation (i.v. or s.c.) | 1 participants |
| ACT-064992 10 mg | Summary of the First Causes of Morbidity or Mortality | Other worsening of PAH | 59 participants |