Chronic Thromboembolic Pulmonary Hypertension
Conditions
Keywords
CTEPH, selexipag
Brief summary
Selexipag is available in many countries for the treatment of pulmonary arterial hypertension (PAH). Due to the similarities between PAH and chronic thromboembolic pulmonary hypertension (CTEPH) and the observed efficacy of other PAH medicines in CTEPH, it is believed that selexipag could benefit to patients with CTEPH. This study aims to assess the efficacy and safety of selexipag in participants with inoperable or persistent/recurrent CTEPH.
Detailed description
Participants will be recruited in two sequential cohorts: approximately the first 90 randomized participants will undergo a right heart catheterization (RHC) (and left heart catheterization LHC, if needed) with measurement of pulmonary vascular resistance (PVR) at Week 20 and will constitute the hemodynamic cohort; the remaining participants will constitute the non-hemodynamic cohort; who do not require a post-baseline hemodynamic assessment. They will undergo the same overall study assessments as the hemodynamic cohort excepted for RHC at Week 20.
Interventions
DRUGSelexipag
oral tablets containing 200 µg of selexipag. Depending on the iMTD, participants will receive 1 to 8 tablets at each administration
DRUGPlacebo
Oral tablets without active compound
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Signed and dated informed consent form * Male and female participants from greater than or equal to (\>) 18 (or the legal age of consent in the jurisdiction in which the study is taking place) and less then or equal to (\<=85) years old at Screening (Visit 1) * With established diagnosis of inoperable CTEPH (i.e., technically non-operable) or persistent/recurrent CTEPH after pulmonary endarterectomy (PEA) and/or balloon pulmonary angioplasty (BPA), as confirmed by the corresponding adjudication committee * With pulmonary hypertension (PH) in WHO FC I-IV. * Participant able to perform the 6-minute walk test (6MWT) with a minimum distance of 100 m and a maximum distance of 450 m at screening visit. * Women of childbearing potential must have a negative pregnancy test at screening and randomization and must agree to undertake monthly urine pregnancy tests, and to use a reliable method of birth control from screening visit up to at least 30 days after study treatment discontinuation. If a hormonal contraceptive is chosen it must be taken for at least 1 month prior to randomization. Main
Exclusion criteria
* Planned or current treatment with another investigational treatment up to 3 months prior to randomization. * Any known factor or disease that might interfere with treatment compliance, study conduct, or interpretation of the results, such as drug or alcohol dependence or psychiatric disease. * Known concomitant life-threatening disease with a life expectancy \< 12 months. * Planned balloon pulmonary angioplasty within 26 weeks after randomization. * Change in dose or initiation of new PH-specific therapy within 90 days prior to the baseline RHC (and LHC, if needed) qualifying for enrollment for the hemodynamic cohort and within 90 days prior to randomization (Visit 2) for the non-hemodynamic cohort * Treatment with prostacyclin (epoprostenol), prostacyclin analogs (i.e., treprostinil, iloprost, beraprost) or prostacyclin receptor agonists (i.e., selexipag) within 90 days prior to randomization (visit 2) except those given at vasodilator testing during RHC * Change in dose or initiation of new diuretics and/or calcium channel blockers within 1 week prior to baseline RHC (and LHC, if needed) * Any co-morbid condition that may influence the ability to perform a reliable and reproducible 6MWT, including use of walking aids (cane, walker, etc). * Any other criteria as per selexipag Summary of Product Characteristics (SmPC). *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 20 | Baseline (Day 1, pre-dose), within 2 to 5 hours post-dose on Week 20 | Change from baseline in PVR at Week 20 was reported. PVR was measured by accessing the vessel either from right heart catheterization or left heart catheterization, if required. Change from baseline in PVR was measured as percent ratio of post treatment value (Week 20) to pre-treatment value (baseline). |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Czechia, Denmark, Germany, Hungary, Israel, Italy, Malaysia, Mexico, Netherlands, Poland, Portugal, Russia, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 321 participants were screened, of which 128 were randomly assigned and received study intervention.
Participants by arm
| Arm | Count |
|---|---|
| Double-blind Period: Placebo Participants received a single oral tablet of placebo matching to selexipag 200 micrograms (mcg) in the evening of Day 1 and continued the same dose (200 mcg) twice daily (BID) on Day 2. Upon first dose toleration, placebo dose was up-titrated with weekly increments of 200 mcg until reaching the individual maximum tolerated dose (iMTD) in the range of 200 to 1600 mcg BID. The up-titration up to Week 12 was followed by a stable maintenance treatment period with the iMTD (reached at Week 12) until Week 26. After Week 26 up to end of DB treatment (EDBT) period, further up-titration was done but not above 1600 mcg, BID (maximum duration: 24.6 months). For participants with moderate hepatic impairment (Child-Pugh B) or who were concomitantly taking a moderate Cytochrome P-450 2C8 (CYP2C8) inhibitor, the dosing frequency was to be once daily (QD). | 64 |
| Double-blind Period: Selexipag Participants received a single oral tablet of selexipag 200 mcg in the evening of Day 1 and continued the same dose (200 mcg) BID on Day 2. Upon first dose toleration, selexipag dose was up-titrated with weekly increments of 200 mcg until reaching the iMTD in the range of 200 to 1600 mcg BID. The up-titration up to Week 12 was followed by a stable maintenance treatment period with the iMTD (reached at Week 12) until Week 26. After Week 26 up to EDBT period, further up-titration was done but not above 1600 mcg, BID (maximum duration: 27.7 months). For participants with moderate hepatic impairment (Child-Pugh B) or who were concomitantly taking a moderate CYP2C8 inhibitor, the dosing frequency was to be QD. | 64 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double Blind Period (Up to 27.7 Months) | Death | 1 | 0 | 0 | 0 |
| Double Blind Period (Up to 27.7 Months) | Other | 1 | 1 | 0 | 0 |
| Double Blind Period (Up to 27.7 Months) | Physician Decision | 2 | 2 | 0 | 0 |
| Double Blind Period (Up to 27.7 Months) | Sponsor decision | 44 | 47 | 0 | 0 |
| Double Blind Period (Up to 27.7 Months) | Withdrawal by Subject | 7 | 8 | 0 | 0 |
| Open Label Period (Up to 20.8 Months) | Physician Decision | 0 | 0 | 1 | 0 |
| Open Label Period (Up to 20.8 Months) | Sponsor Decision | 0 | 0 | 7 | 6 |
| Open Label Period (Up to 20.8 Months) | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Double-blind Period: Placebo | Double-blind Period: Selexipag | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 40 Participants | 28 Participants | 68 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 36 Participants | 60 Participants |
| Age, Continuous | 64 years STANDARD_DEVIATION 13.22 | 62 years STANDARD_DEVIATION 14.38 | 63 years STANDARD_DEVIATION 13.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 8 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 55 Participants | 109 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 12 Participants | 7 Participants | 19 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 46 Participants | 52 Participants | 98 Participants |
| Region of Enrollment ARGENTINA | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment AUSTRALIA | 1 Participants | 3 Participants | 4 Participants |
| Region of Enrollment BELGIUM | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment BRAZIL | 5 Participants | 6 Participants | 11 Participants |
| Region of Enrollment BULGARIA | 1 Participants | 3 Participants | 4 Participants |
| Region of Enrollment CANADA | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment CHINA | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment CZECH REPUBLIC | 1 Participants | 2 Participants | 3 Participants |
| Region of Enrollment DENMARK | 4 Participants | 3 Participants | 7 Participants |
| Region of Enrollment GERMANY | 6 Participants | 9 Participants | 15 Participants |
| Region of Enrollment HUNGARY | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment ISRAEL | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment ITALY | 2 Participants | 3 Participants | 5 Participants |
| Region of Enrollment MEXICO | 4 Participants | 1 Participants | 5 Participants |
| Region of Enrollment POLAND | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment PORTUGAL | 5 Participants | 1 Participants | 6 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 4 Participants | 3 Participants | 7 Participants |
| Region of Enrollment SLOVAKIA | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment SOUTH KOREA | 7 Participants | 2 Participants | 9 Participants |
| Region of Enrollment SPAIN | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment SWEDEN | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment TAIWAN | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment THAILAND | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment TURKEY | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment UKRAINE | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment UNITED KINGDOM | 5 Participants | 6 Participants | 11 Participants |
| Region of Enrollment UNITED STATES | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Female | 47 Participants | 46 Participants | 93 Participants |
| Sex: Female, Male Male | 17 Participants | 18 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 64 | 3 / 64 | 0 / 9 | 0 / 6 |
| other Total, other adverse events | 45 / 64 | 60 / 64 | 9 / 9 | 5 / 6 |
| serious Total, serious adverse events | 16 / 64 | 9 / 64 | 0 / 9 | 1 / 6 |
Outcome results
Primary
Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 20
Change from baseline in PVR at Week 20 was reported. PVR was measured by accessing the vessel either from right heart catheterization or left heart catheterization, if required. Change from baseline in PVR was measured as percent ratio of post treatment value (Week 20) to pre-treatment value (baseline).
Time frame: Baseline (Day 1, pre-dose), within 2 to 5 hours post-dose on Week 20
Population: Hemodynamic set (HES) included all assigned participants in the hemodynamic cohort.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Double-blind Period: Placebo | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 20 | 89.52 Percent ratio |
| Double-blind Period: Selexipag | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 20 | 85.15 Percent ratio |
Comparison: Ratio of Geometric mean of Selexipag to Placebo was reported.p-value: 0.41295% CI: [0.84, 1.07]ANCOVA