Pulmonary Arterial Hypertension
Conditions
Keywords
Eisenmenger Syndrome, exercise capacity
Brief summary
Long-term study to evaluate if macitentan is safe, tolerable and efficient enough to be used for treatment of Eisenmenger syndrome.
Interventions
Macitentan 10 mg tablet, once daily.
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects with ES (including those with Down Syndrome) having completed the double-blind AC-055-305 / MAESTRO study as scheduled, i.e., who remained in the double-blind study up to Week 16 (whether or not they were still taking study drug at the end of this period).
Exclusion criteria
Subjects who prematurely discontinue double-blind study drug during the AC-055-305 / MAESTRO study due to: * an AE assessed as related to the use of study drug, * or elevated liver tests (related or unrelated to study drug).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study. | 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. |
| Change in WHO Functional Class (FC) at Month 6 and 12 | From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study. | 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. |
| Change in Borg Dyspnea Score at Month 6 and 12 | From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study. | 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. |
| Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study. | 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) |
Countries
Austria, Bulgaria, Chile, China, France, Germany, Greece, Malaysia, Mexico, Philippines, Poland, Portugal, Romania, Russia, Serbia, Spain, United Kingdom, United States, Vietnam
Participant flow
Recruitment details
The study was conducted at 51 sites in 19 countries (geographical regions: Asia-Pacific, Eastern Europe, Latin America, North America and Western Europe).
Pre-assignment details
217 of 221 subjects (111 macitentan, 110 placebo) that completed treatment in the AC-055-305/MAESTRO double-blind (DB) parent study (NCT01743001) were enrolled in the open-label (OL) study without knowledge of their study treatment allocation in the DB study (macitentan or placebo).
Participants by arm
| Arm | Count |
|---|---|
| DB-macitentan All enrolled subjects treated with macitentan in the AC-055-308 / OL study who received macitentan in the DB study (AC-055-305, NCT01743001). | 109 |
| DB-placebo All enrolled subjects treated with macitentan in the AC-055-308 / OL study who received placebo in the DB study (AC-055-305, NCT01743001). | 108 |
| Total | 217 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 7 |
Baseline characteristics
| Characteristic | Total | DB-placebo | DB-macitentan |
|---|---|---|---|
| Age categorical 12 - 17 years | 14 Participants | 2 Participants | 12 Participants |
| Age categorical 18 - 55 years | 188 Participants | 99 Participants | 89 Participants |
| Age categorical ≥ 56 years | 15 Participants | 7 Participants | 8 Participants |
| Age, Continuous | 34.6 years | 34.6 years | 34.6 years |
| Body Mass Index (BMI) | 22.08 kg/m^2 | 22.06 kg/m^2 | 22.09 kg/m^2 |
| Downs syndrome status No | 197 Participants | 98 Participants | 99 Participants |
| Downs syndrome status Yes | 20 Participants | 10 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 177 Participants | 88 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 20 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Chinese | 70 Participants | 35 Participants | 35 Participants |
| Race/Ethnicity, Customized Other | 22 Participants | 11 Participants | 11 Participants |
| Race/Ethnicity, Customized Other Asian | 22 Participants | 11 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 103 Participants | 51 Participants | 52 Participants |
| Region of Enrollment Asia-Pacific Asia-Pacific | 89 Participants | 44 Participants | 45 Participants |
| Region of Enrollment Asia-Pacific Eastern Europe | 50 Participants | 26 Participants | 24 Participants |
| Region of Enrollment Asia-Pacific Latin America | 36 Participants | 18 Participants | 18 Participants |
| Region of Enrollment Asia-Pacific North America | 5 Participants | 4 Participants | 1 Participants |
| Region of Enrollment Asia-Pacific Western Europe-Israel | 37 Participants | 16 Participants | 21 Participants |
| Sex: Female, Male Female | 143 Participants | 66 Participants | 77 Participants |
| Sex: Female, Male Male | 74 Participants | 42 Participants | 32 Participants |
| WHO Functional Class (FC) Class I | 0 Participants | 0 Participants | 0 Participants |
| WHO Functional Class (FC) Class II | 131 Participants | 65 Participants | 66 Participants |
| WHO Functional Class (FC) Class III | 86 Participants | 43 Participants | 43 Participants |
| WHO Functional Class (FC) Class IV | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 217 |
| other Total, other adverse events | 152 / 217 |
| serious Total, serious adverse events | 62 / 217 |
Outcome results
Primary
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.
Time frame: From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB-macitentan | Change in Borg Dyspnea Score at Month 6 and 12 | Change from DB study baseline to Week 16 | -0.3 score on a scale | Standard Deviation 1.4 |
| DB-macitentan | Change in Borg Dyspnea Score at Month 6 and 12 | Change from DB study baseline to Month 6 | -0.1 score on a scale | Standard Deviation 2 |
| DB-macitentan | Change in Borg Dyspnea Score at Month 6 and 12 | Borg dyspnea score at Week 16 in DB study | 2.7 score on a scale | Standard Deviation 1.9 |
| DB-macitentan | Change in Borg Dyspnea Score at Month 6 and 12 | Borg dyspnea score at Month 12 in OL study | 2.9 score on a scale | Standard Deviation 2 |
| DB-macitentan | Change in Borg Dyspnea Score at Month 6 and 12 | Borg dyspnea score at Month 6 in OL study | 2.8 score on a scale | Standard Deviation 2 |
| DB-macitentan | Change in Borg Dyspnea Score at Month 6 and 12 | Change from DB study baseline to Month 12 | -0.1 score on a scale | Standard Deviation 2.1 |
| DB-macitentan | Change in Borg Dyspnea Score at Month 6 and 12 | Borg dyspnea score at DB study baseline | 3.0 score on a scale | Standard Deviation 1.9 |
| DB-placebo | Change in Borg Dyspnea Score at Month 6 and 12 | Change from DB study baseline to Month 12 | -0.3 score on a scale | Standard Deviation 1.6 |
| DB-placebo | Change in Borg Dyspnea Score at Month 6 and 12 | Borg dyspnea score at DB study baseline | 2.9 score on a scale | Standard Deviation 1.8 |
| DB-placebo | Change in Borg Dyspnea Score at Month 6 and 12 | Borg dyspnea score at Week 16 in DB study | 1.9 score on a scale | Standard Deviation 1.6 |
| DB-placebo | Change in Borg Dyspnea Score at Month 6 and 12 | Change from DB study baseline to Week 16 | -0.2 score on a scale | Standard Deviation 1.5 |
| DB-placebo | Change in Borg Dyspnea Score at Month 6 and 12 | Borg dyspnea score at Month 6 in OL study | 2.5 score on a scale | Standard Deviation 1.8 |
| DB-placebo | Change in Borg Dyspnea Score at Month 6 and 12 | Change from DB study baseline to Month 6 | -0.4 score on a scale | Standard Deviation 1.5 |
| DB-placebo | Change in Borg Dyspnea Score at Month 6 and 12 | Borg dyspnea score at Month 12 in OL study | 2.6 score on a scale | Standard Deviation 1.9 |
Primary
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.
Time frame: From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB-macitentan | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | Change in 6MWD from DB study baseline to Week 16 | 24.4 meter (m) | Standard Deviation 71 |
| DB-macitentan | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | Change in 6MWD from DB study baseline to Month 6 | 26.2 meter (m) | Standard Deviation 77.9 |
| DB-macitentan | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | 6MWD at Week 16 in DB study | 395.1 meter (m) | Standard Deviation 88.4 |
| DB-macitentan | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | 6MWD at Month 12 in OL study | 397.1 meter (m) | Standard Deviation 103.9 |
| DB-macitentan | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | 6MWD at Month 6 in OL study | 396.8 meter (m) | Standard Deviation 96.5 |
| DB-macitentan | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | Change in 6MWD from DB study baseline to Month 12 | 26.5 meter (m) | Standard Deviation 79.8 |
| DB-macitentan | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | 6MWD at DB study baseline | 370.6 meter (m) | Standard Deviation 74.1 |
| DB-placebo | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | Change in 6MWD from DB study baseline to Month 12 | 39.9 meter (m) | Standard Deviation 55.1 |
| DB-placebo | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | 6MWD at DB study baseline | 381.6 meter (m) | Standard Deviation 76.7 |
| DB-placebo | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | 6MWD at Week 16 in DB study | 399.9 meter (m) | Standard Deviation 80.6 |
| DB-placebo | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | Change in 6MWD from DB study baseline to Week 16 | 18.2 meter (m) | Standard Deviation 53 |
| DB-placebo | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | 6MWD at Month 6 in OL study | 425.0 meter (m) | Standard Deviation 72.1 |
| DB-placebo | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | Change in 6MWD from DB study baseline to Month 6 | 43.4 meter (m) | Standard Deviation 51.5 |
| DB-placebo | Change in Exercise Capacity as Measured by 6-minute Walking Distance (6MWD) Month 6 and 12 | 6MWD at Month 12 in OL study | 421.5 meter (m) | Standard Deviation 76.5 |
Primary
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)
Time frame: From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.
Population: No imputation of missing data for oxygen saturation as assessed by SpO2 was applied. Therefore out of 109 subjects 104 subjects were analyzed at month 6 and 92 subjects at month 12 in the DB-macitentan group. In the DB-placebo group out of 108 subjects 103 subjects were analyzed at month 6 and 84 subjects at month 12.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB-macitentan | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | Change in SpO2 from DB study baseline to Week 16 | 1.1 % of oxygen saturation at rest | Standard Deviation 4 |
| DB-macitentan | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | Change in SpO2 from DB study baseline to Month 6 | 1.5 % of oxygen saturation at rest | Standard Deviation 4.9 |
| DB-macitentan | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | SpO2 at Week 16 in DB study | 85.3 % of oxygen saturation at rest | Standard Deviation 5.8 |
| DB-macitentan | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | SpO2 at Month 12 in OL study | 86.4 % of oxygen saturation at rest | Standard Deviation 6.3 |
| DB-macitentan | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | SpO2 at Month 6 in OL study | 85.9 % of oxygen saturation at rest | Standard Deviation 5.9 |
| DB-macitentan | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | Change in SpO2 from DB study baseline to Month 12 | 2.0 % of oxygen saturation at rest | Standard Deviation 4.4 |
| DB-macitentan | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | SpO2 at DB study baseline | 84.2 % of oxygen saturation at rest | Standard Deviation 5.6 |
| DB-placebo | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | Change in SpO2 from DB study baseline to Month 12 | 1.6 % of oxygen saturation at rest | Standard Deviation 4.9 |
| DB-placebo | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | SpO2 at DB study baseline | 85.4 % of oxygen saturation at rest | Standard Deviation 5 |
| DB-placebo | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | SpO2 at Week 16 in DB study | 85.6 % of oxygen saturation at rest | Standard Deviation 5.4 |
| DB-placebo | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | Change in SpO2 from DB study baseline to Week 16 | 0.2 % of oxygen saturation at rest | Standard Deviation 4.5 |
| DB-placebo | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | SpO2 at Month 6 in OL study | 87.4 % of oxygen saturation at rest | Standard Deviation 5.4 |
| DB-placebo | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | Change in SpO2 from DB study baseline to Month 6 | 2.0 % of oxygen saturation at rest | Standard Deviation 4.3 |
| DB-placebo | Change in Peripheral Oxygen Saturation (SpO2) at Rest at Month 6 and 12 | SpO2 at Month 12 in OL study | 87.1 % of oxygen saturation at rest | Standard Deviation 5 |
Primary
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.
Time frame: From baseline in DB parent study (AC-055-305, NCT01743001) up to month 12 in this OL study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class III at Month 12 in OL study | 28 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class II at DB study baseline | 66 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class I at Month 12 in OL study | 5 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class III at DB study baseline | 43 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class IV at Month 12 in OL study | 2 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class IV at DB study baseline | 0 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | Improvement from DB study baseline to Month 12 | 20 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class I at Week 16 in DB study | 3 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | Worsening from DB study baseline to Month 6 | 3 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class II at Week 16 in DB study | 70 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | Worsening from DB study baseline to Month 12 | 4 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class III at Week 16 in DB study | 36 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class II at Month 12 in OL study | 74 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | Improvement from DB study baseline to Week 16 | 10 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class II at Month 6 in OL study | 74 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | Worsening from DB study baseline to Week 16 | 0 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class IV at Week 16 in DB study | 0 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class I at Month 6 in OL study | 5 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | Improvement from DB study baseline to Month 6 | 19 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class I at DB study baseline | 0 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class III at Month 6 in OL study | 28 Participants |
| DB-macitentan | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class IV at Month 6 in OL study | 2 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class III at Month 6 in OL study | 22 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class IV at Month 6 in OL study | 0 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | Improvement from DB study baseline to Month 6 | 27 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | Worsening from DB study baseline to Month 6 | 1 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class IV at Month 12 in OL study | 0 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class II at Month 12 in OL study | 79 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class III at Month 12 in OL study | 22 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class I at Month 12 in OL study | 7 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | Improvement from DB study baseline to Month 12 | 31 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | Worsening from DB study baseline to Month 12 | 3 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class IV at Week 16 in DB study | 0 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class I at DB study baseline | 0 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class II at DB study baseline | 65 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class III at DB study baseline | 43 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class IV at DB study baseline | 0 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class I at Week 16 in DB study | 1 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class II at Week 16 in DB study | 77 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class III at Week 16 in DB study | 30 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | Improvement from DB study baseline to Week 16 | 15 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | Worsening from DB study baseline to Week 16 | 1 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class I at Month 6 in OL study | 7 Participants |
| DB-placebo | Change in WHO Functional Class (FC) at Month 6 and 12 | WHO functional class II at Month 6 in OL study | 79 Participants |