Chronic Thromboembolic Pulmonary Hypertension
Conditions
Keywords
Chronic thromboembolic pulmonary hypertension (CTEPH)
Brief summary
Study to evaluate if macitentan is efficient, safe and tolerable enough to be used for treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH).
Interventions
DRUGMacitentan
Macitentan 10 mg, oral tablet, to be taken once daily.
DRUGPlacebo
Matching placebo oral tablet, to be taken 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
18 Years to 84 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Subject with CTEPH (WHO Group 4) judged as inoperable due to the localization of the obstruction being surgically inaccessible (i.e., distal disease). * Female of childbearing potential must have a negative pre-treatment serum pregnancy test, be advised on appropriate methods of contraception, and agree to use 2 reliable methods of contraception.
Exclusion criteria
* Previous pulmonary endarterectomy. * Recurrent thromboembolism despite sufficient oral anticoagulants. * Symptomatic acute pulmonary embolism in the 6-month period prior to randomization. * Known moderate-to-severe restrictive lung disease (i.e., TLC \< 60% of predicted value) or obstructive lung disease (i.e., FEV1 \< 70% of predicted, with FEV1/FVC \< 65%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema). * Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements in the 3-month period prior to Screening visit or during the Screening period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest. | From baseline to Week 16 | The primary efficacy endpoint is defined as the PVR at rest at Week 16 expressed as percent of baseline PVR at rest. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD). | From baseline to Week 24 | The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. |
| Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT). | From baseline to Week 24 | This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 24 compared to baseline. The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement. |
| Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | From baseline to Week 24 | WHO functional classes are defined as follows: 1) class I: no symptoms with exercise or at rest. No limitation of activity. 2) class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). 3) class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. 4) class IV: symptoms at rest (such as dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms (e.g. may faint especially while bending over with their heads lowered). Patients in class IV manifest signs of right heart failure. Shifting to a higher class (e.g. from class III to class IV) represents a 'worsening' while shifting to a lower class (e.g. from class III to class II) means an 'improvement'. |
Countries
Belgium, China, Czechia, France, Germany, Hungary, Lithuania, Mexico, Poland, Russia, South Korea, Switzerland, Thailand, Turkey (Türkiye), Ukraine, United Kingdom
Participant flow
Recruitment details
A total of 48 sites in 20 countries screened subjects for recruitment. The study was conducted (i.e., randomized subjects) in a total of 36 sites across 16 countries: Belgium, China, Czech Republic, France, Germany, Hungary, Lithuania, Mexico, Poland, Russia, Thailand, Turkey, South Korea, Switzerland, Ukraine, and the United Kingdom).
Pre-assignment details
Target screening period from Visit 1 up to Randomization was maximum of 30 days, but longer period (up to 60 days) was permitted with pre-approval from Actelion. Total of 186 subjects were screened. Of these, 80 subjects were randomized in 1:1 ratio to macitentan 10 milligram (mg) (n = 40) and placebo (n = 40). All randomized subjects were treated.
Participants by arm
| Arm | Count |
|---|---|
| Macitentan Macitentan 10 mg, oral tablet, to be taken once daily. | 40 |
| Placebo Matching placebo oral tablet, to be taken once daily. | 40 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Macitentan | Placebo | Total |
|---|---|---|---|
| 6-minute walk distance (6MWD) | 353.0 meter STANDARD_DEVIATION 87.9 | 351.2 meter STANDARD_DEVIATION 73.79 | 352.1 meter STANDARD_DEVIATION 80.64 |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 14 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 26 Participants | 52 Participants |
| Age, Continuous | 60.0 years | 58.0 years | 59.0 years |
| Body Mass Index (BMI) | 25.7 kg/m^2 | 26.0 kg/m^2 | 25.7 kg/m^2 |
| Pulmonary vascular resistance (PVR) | 929.2 dynes*sec/cm^5 STANDARD_DEVIATION 379.65 | 984.3 dynes*sec/cm^5 STANDARD_DEVIATION 487.06 | 956.8 dynes*sec/cm^5 STANDARD_DEVIATION 434.78 |
| Region of Enrollment Asia | 15 Participants | 14 Participants | 29 Participants |
| Region of Enrollment Eastern Europe | 17 Participants | 19 Participants | 36 Participants |
| Region of Enrollment Latin America | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Western Europe | 7 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Female | 26 Participants | 25 Participants | 51 Participants |
| Sex: Female, Male Male | 14 Participants | 15 Participants | 29 Participants |
| Time since diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) | 1.7 years STANDARD_DEVIATION 2.36 | 1.2 years STANDARD_DEVIATION 1.95 | 1.5 years STANDARD_DEVIATION 2.16 |
| Use of pulmonary arterial hypertension (PAH) medication NO | 16 Participants | 15 Participants | 31 Participants |
| Use of pulmonary arterial hypertension (PAH) medication YES | 24 Participants | 25 Participants | 49 Participants |
| WHO functional class class I | 0 Participants | 0 Participants | 0 Participants |
| WHO functional class class II | 12 Participants | 6 Participants | 18 Participants |
| WHO functional class class III | 28 Participants | 33 Participants | 61 Participants |
| WHO functional class class IV | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 2 / 40 |
| other Total, other adverse events | 22 / 40 | 19 / 40 |
| serious Total, serious adverse events | 3 / 40 | 7 / 40 |
Outcome results
Primary
Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest.
The primary efficacy endpoint is defined as the PVR at rest at Week 16 expressed as percent of baseline PVR at rest.
Time frame: From baseline to Week 16
Population: Full analysis set included all subjects assigned to a study treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Macitentan | Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest. | 73.0 percent of baseline PVR |
| Placebo | Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest. | 87.2 percent of baseline PVR |
Comparison: The null hypothesis (change of PVR at rest in Week 16 in percent of baseline PVR in subjects treated with placebo or macitentan is the same) is tested on the primary endpoint by means of an analysis of covariance (ANCOVA) model on the log(e) transformed % of baseline PVR at rest at Week 16.p-value: 0.04195% CI: [0.7, 0.99]ANCOVA
Secondary
Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT).
This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 24 compared to baseline. The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement.
Time frame: From baseline to Week 24
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan | Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT). | Change from baseline to Week 24 | -0.1 Score on a scale | Standard Deviation 1.86 |
| Macitentan | Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT). | Borg dyspnea index score at baseline | 4.2 Score on a scale | Standard Deviation 2.52 |
| Macitentan | Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT). | Borg dyspnea index score at Week 24 | 4.1 Score on a scale | Standard Deviation 2.52 |
| Placebo | Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT). | Borg dyspnea index score at baseline | 4.2 Score on a scale | Standard Deviation 2.14 |
| Placebo | Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT). | Borg dyspnea index score at Week 24 | 4.4 Score on a scale | Standard Deviation 2.45 |
| Placebo | Change From Baseline to Week 24 in Borg Dyspnea Index Collected at the End of the 6-minute Walk Test (6MWT). | Change from baseline to Week 24 | 0.3 Score on a scale | Standard Deviation 2.04 |
Comparison: The null hypothesis is that the mean change from baseline is the same in the placebo and the macitentan group. Statistical model is Analysis of Covariance including Borg dyspnea index at baseline as a covariate, with Treatment as factor in the model.p-value: 0.349295% CI: [-1.21, 0.43]ANCOVA
Secondary
Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD).
The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.
Time frame: From baseline to Week 24
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan | Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD). | 6MWD (m) at baseline | 353.0 meter | Standard Deviation 87.9 |
| Macitentan | Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD). | 6MWD (m) at Week 24 | 388.0 meter | Standard Deviation 83.31 |
| Macitentan | Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD). | Change in 6MWD (m) from baseline to Week 24 | 35.0 meter | Standard Deviation 52.52 |
| Placebo | Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD). | 6MWD (m) at baseline | 351.2 meter | Standard Deviation 73.79 |
| Placebo | Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD). | 6MWD (m) at Week 24 | 352.2 meter | Standard Deviation 121.29 |
| Placebo | Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD). | Change in 6MWD (m) from baseline to Week 24 | 1.0 meter | Standard Deviation 83.24 |
Comparison: The null hypothesis is that the mean change from baseline in 6MWD at Week 24 is the same in the placebo and the macitentan group. Statistical model is ANCOVA including 6MWD at baseline as a covariate, with treatment as factor in the model.p-value: 0.032695% CI: [2.9, 65.2]ANCOVA
Secondary
Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24
WHO functional classes are defined as follows: 1) class I: no symptoms with exercise or at rest. No limitation of activity. 2) class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). 3) class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. 4) class IV: symptoms at rest (such as dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms (e.g. may faint especially while bending over with their heads lowered). Patients in class IV manifest signs of right heart failure. Shifting to a higher class (e.g. from class III to class IV) represents a 'worsening' while shifting to a lower class (e.g. from class III to class II) means an 'improvement'.
Time frame: From baseline to Week 24
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class I at baseline | 0 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class II at baseline | 12 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class III at baseline | 28 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class IV at baseline | 0 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class I at Week 24 | 3 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class II at Week 24 | 15 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class III at Week 24 | 22 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class IV at Week 24 | 0 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | Worsened | 0 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | Not worsened - total | 40 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | Not Worsened - unchanged | 31 Participants |
| Macitentan | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | Not worsened - improved | 9 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | Not Worsened - unchanged | 29 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class I at baseline | 0 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class III at Week 24 | 26 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class II at baseline | 6 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | Not worsened - total | 37 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class III at baseline | 33 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class IV at Week 24 | 3 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class IV at baseline | 1 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | Not worsened - improved | 8 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class I at Week 24 | 1 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | Worsened | 3 Participants |
| Placebo | Proportion of Subjects With Worsening in WHO Functional Class (FC) From Baseline to Week 24 | WHO functional class II at Week 24 | 10 Participants |
Comparison: The null hypothesis is the odds of worsening are the same in the placebo and the macitentan group. Logistic regression is used for Treatment Group vs. Placebo comparison to generate odds ratio, confidence levels, and p-values with treatment and WHO functional class at baseline as factors in the model.p-value: 0.096295% CI: [0.001, 1.464]ANCOVA
Post Hoc
Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Corrected Hemodynamic Values
The main analysis of the primary efficacy endpoint of PVR was repeated which excluded data for 13 subjects with corrected hemodynamic values. The hemodynamic values were reported after the SDV assessment clinical database closure.
Time frame: From baseline to Week 16
Population: Full analysis set excluding subjects with corrected hemodynamic values.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Macitentan | Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Corrected Hemodynamic Values | 68.4 Percent of baseline PVR |
| Placebo | Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Corrected Hemodynamic Values | 86.1 Percent of baseline PVR |
p-value: 0.006195% CI: [0.68, 0.93]ANCOVA
Post Hoc
Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Implausible Hemodynamic Findings
The main analysis of the primary efficacy endpoint of PVR was repeated which excluded 14 subjects with implausible hemodynamic findings.
Time frame: From baseline to Week 16
Population: Full analysis set excluding subjects with implausible hemodynamic findings.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Macitentan | Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Implausible Hemodynamic Findings | 73.9 Percent of baseline PVR |
| Placebo | Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Excluding Subjects With Implausible Hemodynamic Findings | 86.6 Percent of baseline PVR |
p-value: 0.041495% CI: [0.73, 0.99]ANCOVA
Post Hoc
Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Including Subjects With Corrected Hemodynamic Values
The main analysis of the primary efficacy endpoint of PVR was repeated after the voluntary right heart catheterization source data verification (SDV) and independent medical review of hemodynamic data corrected for 13 subjects reported after the clinical database closure.
Time frame: From baseline to Week 16
Population: Full analysis set for this post-hoc analysis included all subjects assigned to a study treatment with SDV values.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Macitentan | Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Including Subjects With Corrected Hemodynamic Values | 71.5 Percent of baseline PVR |
| Placebo | Post-hoc Analysis of Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at Rest Including Subjects With Corrected Hemodynamic Values | 87.6 Percent of baseline PVR |
Comparison: The same statistical model as for the predefined analysis (ANCOVA) was applied, including 13 subjects with corrected hemodynamic values.p-value: 0.009895% CI: [0.7, 0.95]ANCOVA
Post Hoc
Post-hoc Analysis of Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD) Excluding Subjects With Implausible Hemodynamic Findings
The same analysis for the secondary endpoint, 6MWD, is repeated on the full analysis set excluding 14 subjects with implausible hemodynamic findings.
Time frame: From baseline to Week 24
Population: Full analysis set excluding subjects with implausible hemodynamic findings.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Macitentan | Post-hoc Analysis of Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD) Excluding Subjects With Implausible Hemodynamic Findings | 37.41 meter |
| Placebo | Post-hoc Analysis of Change From Baseline to Week 24 in Exercise Capacity, as Measured by the 6-minute Walk Distance (6MWD) Excluding Subjects With Implausible Hemodynamic Findings | 0.23 meter |
p-value: 0.046895% CI: [0.54, 73.83]ANCOVA