TOMORROW by Actelion

Principal Investigator: Ronald  Day
Keywords: Cardiology , Macitentan , PAH Department: Pediatric Administration
IRB Number: 00096237 Co Investigator:  
Specialty: Pediatric Cardiology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Amy Butler
amy.butler@hsc.utah.edu
801-891-9283

Brief Summary

This is a prospective, multicenter, open-label, randomized, controlled, parallel group, group-sequential, event-driven Phase3 study to evaluate efficacy, safety and PK of macitentan in children. In order to minimize potential bias related to the open-label design, site management, data management, statistical analysis as well as coordination of the independent Clinical Event Committee (CEC)will be outsourced to aCRO. The purpose of the study is to establish the efficacy and safety of macitentan in children with PAH treated with a disbursable formation using a clinical composite primary endpoint and targeting a similar exposure as seen in adults with macitentan 10 mg. The overall rationale is based on the positive Phase 3 study of macitentan in adults with PAH (AC-055-302) which showed significant clinical benefit and a good overall safety profile.

The primary objective of the study is to evaluate macitentan in comparison to Standard of Care (SoC) with regard to delaying disease progression in children with PAH. We also want to assess safety and tolerability of macitentan in children with PAH. In addition, this study will assess pharmacokinetics (PK) of macitentan in children with PAH.​

 

Inclusion Criteria

Inclusion Criteria

1. Signed informed consent by the parent(s) or legally designated representative AND assent from developmentally capable children prior to initiation of an study-mandated procedure.

2. Males or females between > 2 years and < 18 years of age.

3. Subjects with body weight >10 kg at randomization.

4. PAH diagnosis < 5 years before randomization, confirmed by historical right heart  catherization (RHC; characterized by mean pulmonary arterial  pressure  > 25 mmHg, and pulmonary arterial wedge pressure < 15 mmHg, and pulmonary vascular resistance (index PVRi  > 3 Wood Units x m2), where in the absence of pulmonary vein obstruction and/or significant lung disease PAWP can be replaced by LAP or LVEDP (in absence of mitral stenosis) assessed by heart catheterization.

5. PAH belonging to the Nice 2013 Updated Classification Group 1 (including subjects with Down syndrome) and of following etiologies:

  • Idiopathic PAH (iPAH)
  • Heritable PAH (hPAH)
  • PAH associated with congential heart disease (CHD):

− PAH with co-incidental CHD (confirmed by the Baseline Characteristics Adjudication Committee [BCAC])

− Post-operative PAH (persisting/recurring/developing > 6 months after repair of CHD)

  • Drug or toxin induced PAH
  • PAH associated with HIV
  •  PAH associated with connective tissue disease (PAH-aCTD)

6. WHO FC I to III.

7. PAH-specific treatment-naïve subjects or subjects on PAH-specific treatment (monotherapy or combination of two therapies).

8. Females of childbearing potential must have a negative pregnancy test at Screening and at Baseline, and must agree to undertake monthly pregnancy tests, and to use a reliable method of contraception (if sexually active) up to EOS.

Note: Criterion 7 - treatments other than PDE-5 inhibitors, such as prostanoids, cannot be continued in the macitentan arm, and therefore will have to be stopped if the patient is randomized into the macitentan arm.  The appropriateness of stopping such treatment will be assessed by the investigator before screening the patient for the study and will not be done for the sole objective of selecting a patient for the study.

Exclusion Criteria

Exclusion Criteria

1. Subjects with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn.

2. Subjects with PAH associated with Eisenmenger syndrome, or with moderate to large left-to-right shunts.

3. Subjects with cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriousus, univentricular heart or pulmonary atresia with ventricular septal defect, as well as subjects with Fontan-palliation.

4. Subjects with pulmonary hypertension due to bronchopulmonary dysplasia.

5. Subjects receiving a combination of > 2 PAH-specific treatments at randomization.

6. Treatment with i.v. or s.c. prostanoids within 4 weeks before randomization, unless given for vasoreactivity testing.

7. Previous treatment with macitentan at any time.

8. Treatment with another investigational drug within 4 weeks prior to randomization.

9. Any PAH-related surgical intervention planned, or subjects listed for organ transplantation related to PAH.

10. Treatment with strong inducers of CYP3A4 such as rifabutin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s wort (hypericum perforatum), within 4 weeks prior to randomization.

11. Systemic treatment with strong inhibitors of CYP3A4 such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole within 4 weeks prior to randomization.

Baseline abnormalities

12. Subjects with pulmonary vein stenosis.

13. Known concomitant life-threatening disease with a life expectancy < 12 months.

14. Hemoglobin or hematocrit < 75% of the lower limit of normal range (LLN).

15. Serum aspartate amiinotransferase and/or alanine aminotransferase > 3 × upper limit of normal range.  

16. Known severe hepatic impairment, i.e., Child-Pugh Class C.

17. Clinical signs of hypotension which in the investigator’s judgment would preclude initiation of a PAH-specific therapy.

Pregnancy and breastfeeding

18. Pregnancy (including family planning) or breastfeeding.

Other categories

19. Known hypersensitivity to ERAs or any of the excipients.

20. Drug or substance abuse, or any condition that, in the opinion of the investigator, may prevent compliance with the protocol or adherence to study treatment.