Parent and/or Legal Guardian ICF and Adult patient ICF: A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Parallel-Group Study with Open-Label Extension Period to Assess the Efficacy and Safety of Selexipag as Add-On Treatment to Standard of Care in Children Aged ≥2 to <18 years with Pulmonary Arterial Hypertension

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Actelion Pharmaceuticals Ltd.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

27 Feb 2020 → ongoing

Decision date (initial)

2023-03-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson and Johnson

External identifiers

EU CT number

2022-501012-34-00

EudraCT number

2019-002817-21

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Others, Safety

To evaluate whether the addition of selexipag to Standard of Care treatment delays disease progression in children with PAH in comparison to placebo.

Conditions and MedDRA coding

Pulmonary Arterial Hypertension

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-000997-PIP01-10

Plan to share IPD

Yes

IPD plan description

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 1. Parent(s) (preferably both, if available, or as per local requirements, or their legally authorized representatives [LARs]) must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to allow the child to participate in the study. Assent is also required of children capable of understanding the nature of the study (typically 7 years of age and older) as described in Informed Consent Process in Section 10.4, Regulatory, Ethical, and Study Oversight Considerations.
2. 2. Male and female participants between ≥2 and <18 years of age weighing ≥9 kg at Randomization.
3. 3. PAH diagnosis confirmed by documented historical RHC performed at any time before participant's screening, and characterized by: • mPAP ≥25 mmHg, AND • Pulmonary arterial wedge pressure (PAWP) ≤15 mmHg (in the absence of pulmonary vein obstruction and/or significant lung disease, PAWP can be replaced by left atrial pressure or, in absence of mitral stenosis, by left ventricular end diastolic pressure) AND • Indexed PVR index (PVRi) >3 Wood units × m2.
4. 4. PAH (WHO Group 1), including patients with Down syndrome, of the following etiologies: • Idiopathic PAH (IPAH). • Heritable PAH (HPAH). • PAH associated with congenital heart disease (PAH-aCHD): – PAH with coincidental CHD (ie, a small atrial septal defect, ventricular septal defect, or patent ductus arteriosus that does not itself account for the development of elevated PVR) and if approved by the BCAC, refer to Section 10.4). – Post-operative PAH (persisting / recurring/ developing ≥6 months after repair of CHD). • Drug or toxin-induced. • PAH associated with HIV.
5. 5. WHO FC II and III.
6. 6. Participants treated with at least 1 PAH-specific treatment, eg, an ERA and/or a PDE-5 inhibitor/soluble guanylate cyclase stimulator, provided that the treatment dose(s) has been stable for at least 3 months prior to first dose of study intervention.
7. 7. A female participant of childbearing potential (for a definition refer to section 10.6) is eligible only if the following apply: Has a negative highly sensitive serum pregnancy test (β-human chorionic gonadotropin) at screening and a negative urine pregnancy test at randomization. Agrees to undertake urine pregnancy tests every 4 weeks (+/-3 days) during the study and up to at least 30 days after study treatment discontinuation. If sexually active, practicing an effective method of birth control consistent with local regulations regarding the use of birth control methods for participants participating in clinical studies until 30 days after last dose of study intervention. Examples of acceptable methods of contraception are located in Section 10.6. It is the responsibility of the investigator to ensure appropriate counselling, including consultation with a specialist (if needed), to the subject and/or parent(s) / LAR(s) on the acceptable method of contraception. To ensure compliance, the study personnel must remind female participants of childbearing potential who are sexually active and their parent(s) / LAR(s) at each visit to use the methods of contraception defined for this study. These reminders must be documented in the source documents.

Exclusion criteria 28

1. 1. PAH due to portal hypertension, schistosomiasis, pulmonary venoocclusive disease, and/or pulmonary capillary hemangiomatosis.
2. 18. Severe renal insufficiency (estimated creatinine clearance <30 mL/min or serum creatinine >221 μmol/L)
3. 19 Severe coronary heart disease or unstable angina as assessed by the investigator
4. 2. PAH associated with Eisenmenger syndrome.
5. 20. Myocardial infarction within the last 6 months prior to enrollment
6. 21. Decompensated cardiac failure if not under close supervision
7. 22. Severe arrhythmias as assessed by the investigator
8. 23. Cerebrovascular events (eg, transient ischemic attack, stroke) within the last 3 months prior to first dose of study intervention.
9. 24. Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to PH
10. 25. Pregnant, planning to become pregnant, or lactating
11. 26. Known allergies, hypersensitivity, or intolerance to selexipag or its excipients (Selexipag IB)
12. 10. Treatment with inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and fluconazole) from 2 weeks prior to randomization until the last dose of study intervention + 3 days
13. 27. 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
14. 3. Moderate to large left-to-right shunts.
15. 4. Cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, univentricular heart, or pulmonary atresia with ventricular septal defect, as well as subjects with Fontan-palliation.
16. 5. Participants with PH due to lung disease and/or hypoxia or history of bronchopulmonary dysplasia. For participants with Down syndrome, exclusion of lung disease and hypoxia causing PH must be documented (eg, normal oxygen saturation in absence of history of lung disease, computed tomography scan, polysomnography, lung function tests).
17. 6. Previous exposure to Uptravi® (selexipag).
18. 7. Treatment with prostacyclin (epoprostenol) or prostacyclin analogs (ie, treprostinil, iloprost, beraprost) within 2 months prior to randomization or scheduled to receive any of these treatments during the study.
19. 8. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the planned first dose of study intervention or is currently enrolled in an investigational study
20. 9. Treatment with strong and moderate inhibitors of CYP2C8 (eg, gemfibrozil, clopidogrel, deferasirox, teriflunomide) from 2 weeks prior to randomization until the last dose of study intervention +3 days
21. 11. Any PAH-related surgical intervention planned, or subjects listed for organ transplantation related to PAH.
22. 12. Known concomitant life-threatening disease with a life expectancy <12 months
23. 13. History or current suspicion of intussusception or ileus or gastrointestinal obstruction, per the investigator's judgment
24. 14. Uncontrolled thyroid disease, per the investigator's judgment
25. 15. Hemoglobin or hematocrit <75% of the lower limit of normal range
26. 16. Known severe or moderate hepatic impairment, ie, Child-Pugh Class B or C
27. 17. Clinical signs of hypotension that, in the investigator's judgment, would preclude initiation of a PAH-specific therapy
28. 28. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the child (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to disease progression from randomization up to 7 days after study treatment discontinuation.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Placebo 4

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Actelion Pharmaceuticals Ltd.

Sponsor organisation

Actelion Pharmaceuticals Ltd.

Address

Gewerbestrasse 16

City

Allschwil

Postcode

4123

Country

Switzerland

Scientific contact point

Organisation

Actelion Pharmaceuticals Ltd.

Contact name

CTIS Point of Contact

Public contact point

Organisation

Actelion Pharmaceuticals Ltd.

Contact name

CTIS Point of Contact

Third parties 4

Locations

13 EU/EEA countries · 36 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 71 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications