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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bayer AG

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

23 Feb 2016 → ongoing

Decision date (initial)

2023-08-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Bayer AG, D-51368, Leverkusen, Germany

External identifiers

EU CT number

2023-503536-40-00

EudraCT number

2014-003952-29

ClinicalTrials.gov

NCT02562235

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Efficacy, Safety

The primary objective is to evaluate safety, tolerability and pharmacokinetics

Secondary objectives 1

1. 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).

Conditions and MedDRA coding

Pulmonary arterial hypertension (PAH)

Study design 1 period

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-000718-PIP01-09

Plan to share IPD

No

IPD plan description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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 (OS-ASD) ≤ 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 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

Exclusion criteria 22

1. Concomitant use of the following medications: 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/1.73m2 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Incidence of adverse events and serious adverse events
2. Recording of vital signs
3. Left-hand x-ray
4. Pharmacokinetics/Pharmacodynamics analyses

Secondary endpoints 7

1. 6-Minute Walking Distance (6MWD).
2. WHO functional class.
3. N-terminal prohormone brain-type natriuretic peptide.
4. 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
5. 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 o right heart dimensions and o computing of cardiac output
6. 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.
7. Taste and texture of the pediatric formulation(s) must be assessed by use of a questionnaire.

Investigational products

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

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bayer AG

Sponsor organisation

Bayer AG

Address

Kaiser-Wilhelm-Allee 1, Wiesdorf Wiesdorf

City

Leverkusen

Postcode

51373

Country

Germany

Scientific contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Public contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Third parties 7

Locations

2 EU/EEA countries · 3 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 18 files

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

Application history

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