Chronic Thromboembolic Pulmonary Hypertension
Conditions
Interventions
Investigational treatment:
Double-blind and open-label selexipag 200 µg, oral tablets in childproof
bottles, up-titrated to allow each subject to reach their individual maximum
tolerated dose (iMTD)
Sponsors
Actelion Pharmaceuticals
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Signed and dated ICF. 2. Male and female subjects >=18 (or the legal age of consent in the jurisdiction in which the study is taking place) and = 400 dyn.sec/cm5 or >= 5 Wood units for the hemodynamic cohort and PVR at rest >= 300 dyn.sec/cm5 or >=3.75 Wood units for the non-hemodynamic cohort - mean pulmonary arterial pressure (mPAP) >= 25 mmHg; - Pulmonary arterial wedge pressure (PAWP) = 400 dyn.sec/cm5 or >= 5 Wood units for the hemodynamic cohort and PVR at rest >=300 dyn.sec/cm5 or >=3,75 Wood units for the non-hemodynamic cohort; mPAP >= 25 mmHg; PAWP = 400 dyn.sec/cm5 or 5 Wood units for the hemodynamic cohort and PVR at rest >=300 dyn.sec/cm5 or >=3,75 Wood units for the non-hemodynamic cohort; mPAP >= 25 mmHg; PAWP <= 15 mmHg, or, if not available or unreliable, an LVEDP <= 15 mmHg. 4. PH in WHO FC I-IV. 5. Subject able to perform the 6MWT with a minimum distance of 100 m and a maximum distance of 450 m at screening visit (Visit 1). 6. A woman of childbearing potential [see definition in Section 4.5.1] is eligible only if all the following applies: a. Negative serum pregnancy test at Screening and a negative urine pregnancy test at randomization. b. Agreement to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation. c. Agreement to use one of the methods of birth control described in Section 4.5 from Screening v
Exclusion criteria
Exclusion criteria: 1. Planned BPA within 26 weeks after randomization. 2. 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 3. Treatment with prostacyclin (epoprostenol), prostacyclin analogs (i.e., treprostinil, iloprost, beraprost) or prostacyclin receptor agonists (i.e., selexipag/Uptravi) within 90 days prior to randomization (Visit 2), except those given at vasodilator testing during RHC 4. Change in dose or initiation of new diuretics and/or calcium channel blockers within 1 week prior to baseline RHC (and LHC if needed). Exclusion criteria related to comorbidities 5. Severe coronary heart disease or unstable angina as assessed by the investigator. 6. Myocardial infarction within the last 6 months prior to screening. 7. Decompensated cardiac failure if not under close supervision. 8. Severe arrhythmias as assessed by the investigator. 9. Cerebrovascular events (e.g., transient ischemic attack, stroke) within the last 3 months prior to screening. 10. Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension. 11. Known or suspicion of pulmonary veno-occlusive disease. Exclusion criteria related to selexipag use 12. Known and documented severe hepatic impairment. 13. Severe renal failure (estimated glomerular filtration rate 2.5 mg/dL) at screening. 14. Known or suspected uncontrolled thyroid disease as per investigator judgment. 15. Pregnant, planning to be become pregnant or lactating. 16. Treatment with strong inhibitors of cytochrome P-450 2C8 (CYP2C8; e.g., gemfibrozil) within 14 days prior to randomization. 17. Systolic blood pressure
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary efficacy endpoint(s): PVR (pulmonary vascular resistance) at Week 20, assessed at rest, within 2-5 hours post dose, expressed as a percent of baseline PVR. Timepoint(s) of evaluation of this end point Assessed at rest in screening period (Day -60 to Day -14; baseline) and assessed at rest within 2-5 hours post-dose at Week 20 during treatment period. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary efficacy endpoints 1 Change from baseline in 6MWD to Week 26 (key secondary endpoint). 2 TTCW: Time to clinical worsening (according to the CHMP definition, (key secondary endpoint) up to Week 52, defined as at least one of the following components confirmed by the CEC when applicable: All-cause death; Non-planned PH-related hospitalization; PH-related deterioration identified by at least one of the following: Increase from baseline in WHO FC4 Deterioration by at least 15% in exercise capacity as measured by the 6MWD; New Signs or symptoms of right heart failure defined as a reported AE with one of the following preferred terms: *CTEPH*, *pulmonary hypertension*, *right ventricular failure*, *right ventricular dysfunction* and *acute right ventricular failure*. The investigation of a composite endpoint that reflects the TTCW has been encouraged by the European Medicines Agency. 3 All cause death or hospitalisations related to PH worsening 4 Proportion of subjects with improvement in WHO FC from baseline to Week 26. 5 Change from baseline to Week 26 in PAH-SYMPACT* cardiopulmonary symptom domain and cardiovascular symptom domain. 6 Change from baseline to Week 26 in the Borg dyspnea index (BDI)/Borg CR10. 7 Change from baseline to Week 26 in NT-proBNP. Safety endpoints - Treatment-emergent adverse events (AEs)2 up to 3 days after study treatment discontinuation at each analysis time point. - Serious adverse events (SAEs) up to 30 days after study treatment discontinuation at each analysis time point. - AEs leading to premature discontinuation of study treatment at each analysis time point. - Change in vital signs (systolic and diastolic arterial blood pressure and pulse rate) and body weight from baseline to all assessed time points during the study at each analysis time point. - Treatment-emergent marked laboratory abnormalities up to 3 days after study treatment discontinuation as detailed in Appendix 2 at each analysis ti | — |
Countries
Netherlands
Outcome results
None listed