Riociguat for treatment of PAH in children from 6 to less than 18 years old

• Register: EUCTR
• Last refreshed on: 4 April 2022
• Main ID: EUCTR2014-003952-29-HU
• Date of registration: 06/07/2015
• Prospective Registration: Yes
• Primary sponsor: Bayer AG
• Public title: Riociguat for treatment of PAH in children from 6 to less than 18 years old
• Scientific title: Open-label, individual dose titration study to evaluate safety, tolerability and pharmacokinetics of riociguat in children from 6 to less than 18 years of age with pulmonary arterial hypertension (PAH) - PATENT-CHILD
• Date of first enrolment: 25/08/2015
• Target sample size: 20
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-003952-29
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Colombia, France, Germany, Hungary, Italy, Japan, Mexico, Netherlands, Poland, Romania, Spain, Taiwan, Turkey, United Kingdom, United States

Contacts

• Name: Bayer Clin. Trials Contact CTP Team
• Affiliation: Bayer AG

• Name: Bayer Clin. Trials Contact CTP Team
• Affiliation: Bayer AG

Key inclusion & exclusion criteria

Inclusion criteria:
1. Children aged =6 to <18 years
2. Diagnosed with PAH :
- Idiopathic (IPAH)
- Hereditable (HPAH)
- PAH associated with (APAH)
o Connective tissue disease
o Congenital heart disease with shunt closure more than 6 months ago (no open shunts, confirmed by RHC no less than 4 months after surgery)
Regardless of the type of PAH, the following findings are not exclusionary:
o Patent foramen ovale (PFO)
o And asymptomatic, isolated, ostium secundum atrial septal defect (OSASD) = 1 cm (both confirmed by echocardiogram) and not associated with hemodynamic alterations indicative of significant shunt, e.g. Qp/Qs ratio less <1.5:1 are not exclusionary
3. Diagnosis of PAH confirmed by right heart catheterization (RHC) at any time prior to enrolment (for patients with closed shunts – RHC no less than 4 months after surgery)
4. Pulmonary arterial hypertension confirmed by a RHC at any time prior to start of study, with mean pulmonary artery pressure (PAPmean) =25 mmHg at rest, pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) =15 mmHg, and pulmonary vascular resistance (PVR) >240 dyn•sec•cm-5 (i.e., =3.0 wood units•m2)
5. Patients must be on standard of care PAH medications, allowing
Endothelin Receptor Antagonists (ERA) and/or Prostacyclin Analogues
(PCA), for at least 12 weeks prior to baseline visit.
Two groups of patients will be included:
o Prevalent: Patients currently on PAH medication (allowing ERA and/or PCA)who need additional treatment (discretion of the investigator)
o Incident: Treatment naïve patients initiated on PAH medication (allowing ERA and/or PCA) and then riociguat added once patients are stable on standard of care
6. WHO functional class I-III
7. Adolescent females of childbearing potential can only be included in the study if a pregnancy test is negative. Adolescent females of childbearing potential must agree to receive sexual counseling and use effective contraception and receive sexual counseling as applicable. ‘Effective contraception’ is defined as progestogen-only hormonal contraception associated with inhibition of ovulation (implant), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), or any combination of adequate methods of birth control (e.g. condoms with hormonal contraception). Agreement to use contraception is required from the signing of the informed consent form up until 4 weeks after the last study drug administration.
8. Young men must agree to use adequate contraception when sexually active.
9. Written inform consent provided and if applicable child assent provided
Are the trial subjects under 18? yes
Number of subjects for this age range: 20
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Concomitant use of the following medication: phosphodiesterase (PDE) 5 inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase PDE inhibitors (theophylline, dipyridamole) nitrates or NO donors (such as amyl nitrite) in any form
(Footnote: Pretreatment with the phosphodiesterase (PDE) 5 inhibitor
Sildenafil is allowed up to 24 h prior to start of riociguat treatment (Visit
1). Pretreatment with the phosphodiesterase (PDE) 5 inhibitor tadalafil
is allowed up to 3 days prior to start of riociguat treatment (Visit 1).
Patients are not expected to be withdrawn from treatment with PDE5i
for the purpose of entering into this trial. During the period without
PDE5i, patients who received treatment with PDE5i are expected to be
on stable clinical condition and receiving standard of care treatment with
ERA and/or PCAs.)
2. Pretreatment with NO donors (e.g. nitrates) within the last 2-weeks before visit 1. The use of any drug including NO acutely for testing during catheterization is not an exclusion criterion.
3. Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization or any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening
4. Systolic blood pressure (SBP) more than 5 mmHg lower than the age-, sex- and height-adapted level of the 50th SBP percentile (NHBPEP, 2004)
5. History of left-sided heart disease, including valvular disease or heart failure
6. Pulmonary hypertension related to conditions other than specified in the inclusion criteria
7. WHO functional class IV
8. Pulmonary veno-occlusive disease
9. Screening aspartate transaminase (AST) and/ or alanine transaminase (ALT) more than 3 times the upper limit of normal (ULN)
10. Non-stable disease status, e.g. , signs and symptoms of decompensated right heart failure
11. Severe bronchial asthma
12. Severe restrictive lung disease
13. Severe congenital abnormalities of the lung, thorax, and diaphragm
14. Clinically relevant hepatic dysfunction (especially Child Pugh C)
15. Renal insufficiency (estimated glomerular filtration rate <30 mL/min e.g. calculated based on Schwartz formula)
16. Subject with hypersensitivity to the investigational drug or any of the excipients
17. Active smoking of tobacco of any type or quantity. Smoking
marijuana is also not permitted.
18. Subjects with any other condition that is not recommended with riociguat
19. Previous assignment to treatment during this study
20. Previous (within 30 days) or concomitant participation in another clinical study with investigational medicinal product(s)
21. Any condition that, according to treating physician, might jeopardize subject's participation and compliance with procedures indicated in this protocol.
22. PH associated with idiopathic interstitial pneumonia (PH-IIP)


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Hypertension, Pulmonary

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Trade Name: Adempas
Product Name: Adempas 0.5 mg
Product Code: BAY63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: Adempas
Product Name: Adempas 1.0 mg
Product Code: BAY63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.0-

Trade Name: Adempas
Product Name: Adempas 1.5 mg
Product Code: BAY63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY 63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.5-

Trade Name: Adempas
Product Name: Adempas 2.0 mg
Product Code: BAY63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.0-

Trade Name: Adempas
Product Name: Adempas 2.5 mg
Product Code: BAY63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-

Product Name: Riociguat granules 0.3% for oral application
Product Code: BAY63-2521
Pharmaceutical Form: Granules for oral solution
INN or Proposed INN: Riociguat
CAS

Primary Outcome(s)

Secondary Objective: Secondary objectives: exploratory efficacy. To characterize the pharmacodynamic profile of riociguat comprising the following exploratory parameters: time to clinical worsening (TTCW), exercise capacity (6MWD test), functional capacity (measured by WHO FC), laboratory biomarkers (NT-proBNP or BNP), Quality of Life (QoL) measurements (SF-10, PedsQL), echocardiographic variables and taste assessment (questionnaire).

Timepoint(s) of evaluation of this end point: Assessment of Adverse Events at baseline, at all visits in the titration phase and maintenance phase, and every 3-4 months in the extension phase.
Left hand x-ray at baseline, end of study treatment period (week 24) and every 12 months in the extension phase until growth plates are closed.

Main Objective: The primary objective is to evaluate safety, tolerability and
pharmacokinetics

Primary end point(s): - Incidence of adverse events and serious adverse events
- recording of vital signs
- left-hand x-ray
Pharmacokinetics/Pharmacodynamics analyses

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Changes from baseline to end of treatment (week 24)

Secondary end point(s): - 6-Minute Walking Distance (6MWD).
- WHO functional class.
- N-terminal prohormone brain-type natriuretic peptide.
- Quality of Life scores (parent questionnaire and in children able to understand questions):
Child Health-related Questionnaire (SF-10) and PedsQL Generic Core scales self-report
- Echocardiographic parameters including:
o pulmonary arterial systolic pressure (PASP),
o tricuspid annular plane systolic excursion (TAPSE),
o pericardial effusion,
o left ventricular eccentricity index,
o estimated right atrial pressure
o right ventricular pressure by tricuspide regurgitant jet velocity
o acceleration time of pulmonary flow, and
o right heart dimensions
o computing of cardiac output
- Time to clinical worsening defined as:
o hospitalization for right heart failure,
o death,
o lung transplantation,
o Pott’s anastomosis and atrioseptostomy
o worsening of PAH symptoms, which must include either an increase in WHO functional class, OR both appearance/worsening symptoms of right heart failure AND need for additional PAH therapy.
-Taste and texture of the pediatric formulation(s) must be assessed by use of a questionnaire.

Secondary ID(s)

BAY63-2521/15681

NCT02562235

Source(s) of Monetary Support

Bayer AG

Ethics review

Status: Approved
Approval date: 07/08/2015
Contact:

Results

• Results available: Yes
• Date Posted: 19/09/2020
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-003952-29/results