Riociguat in Children With Pulmonary Arterial Hypertension (PAH)

This study was designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of riociguat at age-, sex- and body-weight-adjusted doses of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID in children from ≥6 to less than 18 years with pulmonary arterial hypertension (PAH) group 1. The study design consisted of a main study part followed by an optional long-term extension part. The main treatment period consisted of two phases: titration phase up to 8 weeks and a maintenance phase up to 16 weeks.


Eligibility Criteria:
Inclusion Criteria:

* Children from 6 years to less than 18 years of age with pulmonary arterial hypertension (PAH)
* 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) 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

* PAH diagnosed by right heart catheterization (RHC) at any time prior to enrolment (for patients with closed shunts - RHC no less than 4 months after surgery)
* PAH 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•m\^2)
* 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 PAH medication (allowing ERA and/or PCA) 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 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.
  * 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. The use of any drug including NO acutely for testing during catheterization is not an exclusion criterion.
* 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
* WHO functional class IV
* 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/1.73m\^2 e.g. calculated based on Schwartz formula)
* PH associated with idiopathic interstitial pneumonia (PH-IIP)