| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary arterial hypertension (PAH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary arterial hypertension (PAH) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to evaluate safety, tolerability and pharmacokinetics |
|
| E.2.2 | Secondary objectives of the trial |
| 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). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (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 |
|
| E.4 | Principal exclusion criteria |
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) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Incidence of adverse events and serious adverse events
- recording of vital signs
- left-hand x-ray
Pharmacokinetics/Pharmacodynamics analyses |
|
| E.5.1.1 | 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. |
|
| E.5.2 | 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
o right heart dimensions and
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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Changes from baseline to end of treatment (week 24) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Colombia |
| Japan |
| Mexico |
| Taiwan |
| United States |
| Turkey |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study will be reached as soon as the last visit of the last subject has been
reached in all centers in all participating countries (EU and non-EU). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 13 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 15 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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