Riociguat in Children With Pulmonary Arterial Hypertension (PAH)
Condition: Hypertension, Pulmonary
MeSH terms: Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hypertension
Intervention: Riociguat (Adempas, BAY63-2521)
Intervention description: For children with body-weight <50 kg at screening: body-weight adjusted dose equivalent to the exposure of (0.5 mg) 1.0 - 2.5 mg three times a day, IDT in adults treated for PAH; oral suspension. For children ≥50 kg at screening: 1.0 to 2.5 mg three times a day; oral tablet.
Intervention MeSH terms: Riociguat
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 6 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Pulmonary arterial hypertension

Summary:

      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)