Riociguat in Children With Pulmonary Arterial Hypertension (PAH)

Inclusion Criteria:

- Children aged ≥6 to <18 years

- Diagnosed with PAH :

- Idiopathic (IPAH)

- Hereditable (HPAH)

- PAH associated with (APAH)

- Connective tissue disease

- 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:

- Patent foramen ovale (PFO) ≤ 1 cm (confirmed by echocardiogram) is not exclusionary

- Asymptomatic, isolated, ostium secundum atrial septal defect (OS-ASD) ≤ 1 cm
(confirmed by echocardiogram) and not associated with hemodynamic alterations
indicative of significant shunt, e.g. Qp/Qs ratio less <1.5:1 is not exclusionary

- 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)

- 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)

- 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:

- Prevalent: Patients currently on monotherapy who need additional treatment (discretion
of the investigator)

- 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

- WHO functional class I-III

- 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 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.

- Young men must agree to use adequate contraception when sexually active.

- Written inform consent provided and if applicable child assent provided

Exclusion Criteria:

- 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

- Pretreatment with NO donors (e.g. nitrates) within the last 2-weeks before visit 1

- 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

- Systolic blood pressure (SBP) more than 5 mmHg lower than the age-, sex- and
height-adapted level of the 50th SBP percentile (NHBPEP, 2004)

- History of left-sided heart disease, including valvular disease or heart failure

- Pulmonary hypertension related to conditions other than specified in the inclusion
criteria

- Pulmonary veno-occlusive disease

- Screening aspartate transaminase (AST) and/ or alanine transaminase (ALT) more than 3
times the upper limit of normal (ULN)

- Severe restrictive lung disease

- Severe congenital abnormalities of the lung, thorax, and diaphragm

- Clinically relevant hepatic dysfunction (especially Child Pugh C)

- Renal insufficiency (estimated glomerular filtration rate <30 mL/min/1.73m2 e.g.
calculated based on Schwartz formula, for detailed calculation instructions

- PH associated with idiopathic interstitial pneumonia (PH-IIP)