Clinical trial NCT02562235: Riociguat in Children With Pulmonary Arterial Hypertension (PAH)
Official title: Open-label, Individual Dose Titration Study to Evaluate Safety, Tolerability and Pharmacokinetics of Riociguat in Children From 6 to Less Than 18 Years of Age With Pulmonary Arterial Hypertension (PAH)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Hypertension, Pulmonary
Keywords: Pulmonary arterial hypertension
Lead sponsor: Bayer
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-09-29
Enrollment: 24
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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)

Primary outcomes:
measure: Number of Participants With Any Treatment-emergent Adverse Events
timeFrame: From start of study drug up to 2 days after the last dose of study drug in the main study part, up to 24 weeks plus/minus 5 days.
measure: Change in Heart Rate From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Blood Pressure From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Respiratory Rate From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Number of Subjects With Transitions From Baseline in Bone Age Compared to Chronological Age
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Hematology Parameters (Platelets) From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Hematology Parameters (Lymphocytes/Leucocytes Ratio) From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Hematology Parameter (Neutrophils/Leucocytes Ratio) From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Clinical Chemistry (Alanine Aminotransferase) From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Clinical Chemistry (Aspartate Aminotransferase) From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Clinical Chemistry (Sodium) From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Clinical Chemistry (Blood Urea Nitrogen) From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Clinical Chemistry (eGFR) From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Clinical Chemistry (Urea) From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Clinical Chemistry (Gamma Glutamyl Transferase) From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Plasma Concentration of Riociguat at Week 0
timeFrame: Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)
measure: Plasma Concentration of Riociguat at Week 4
timeFrame: Week 4 (pre-dose)
measure: Plasma Concentration of Riociguat at Week 8
timeFrame: Week 8 (pre-dose)
measure: Plasma Concentration of BAY60-4552 at Week 0
timeFrame: Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)
measure: Plasma Concentration of BAY60-4552 at Week 4
timeFrame: Week 4 (pre-dose)
measure: Plasma Concentration of BAY60-4552 at Week 8
timeFrame: Week 8 (pre-dose)
Secondary outcomes:
measure: Change in 6-minute Walking Distance From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Number of Subjects With Change in WHO Functional Class From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in NT-proBNP From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in BNP From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Quality of Life Evaluated by SF-10 Questionnaire From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Quality of Life Evaluated by PedsQL Scale
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Number of Subjects With Clinical Worsening
timeFrame: Up to Week 24 (plus/minus 5 days)
measure: Change in Estimated Right Atrial Pressure From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Left Ventricular Eccentricity Index From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Pericardial Effusion From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Pulmonary Artery Acceleration Time From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Ventricular Cardiac Index From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Ventricular Cardiac Output From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Atrial Diastolic Area From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Atrial Diastolic Area Index From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Atrial Systolic Area From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Atrial Systolic Area Index From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Ventricular Fractional Area Change From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Ventricular Diastolic Area From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Ventricular Diastolic Area Index From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Ventricular Systolic Area From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Right Ventricular Systolic Area Index From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Systolic Pulmonary Artery Pressure From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Tricuspid Annular Plane Systolic Excursion From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
measure: Change in Tricuspid Regurgitation Peak Velocity From Baseline
timeFrame: Baseline and Week 24 (plus/minus 5 days)
Other outcomes:
measure: Taste and Texture (Questions 1 to 4) of the Oral Suspension of Riociguat at Week 0
timeFrame: At the beginning of the treatment (Week 0)
measure: Taste and Texture (Questions 1 to 4) the Oral Suspension of Riociguat at Week 24
timeFrame: Week 24 (plus/minus 5 days)
measure: Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 0
timeFrame: At the beginning of the treatment (Week 0)
measure: Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 24
timeFrame: Week 24 (plus/minus 5 days)
measure: Taste and Texture (Question 6) of the Oral Suspension of Riociguat at Week 0
timeFrame: At the beginning of the treatment (Week 0)
measure: Taste and Texture (Question 6) of the Oral Suspension of Riociguat in Mouth at Week 24
timeFrame: Week 24 (plus/minus 5 days)
measure: Taste and Texture (Question 7) of the Oral Suspension of Riociguat in Mouth at Week 0
timeFrame: At the beginning of the treatment (Week 0)
measure: Taste and Texture (Question 7) of the Oral Suspension of Riociguat in Mouth at Week 24
timeFrame: Week 24 (plus/minus 5 days)
measure: Expression Assessment on the Taste and Texture of Oral Suspension of Riociguat - Week 0
timeFrame: At the beginning of the treatment (Week 0)
measure: Expression Assessment on the Taste and Texture of Oral Suspension of Riociguat - Week 24
timeFrame: Week 24 (plus/minus 5 days)
Locations:
city: Cali
country: Colombia
facility: Clínica Imbanaco S.A.S
state: Valle Del Cauca
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
state: Baden-Württemberg
city: Berlin
country: Germany
facility: Deutsches Herzzentrum der Charité (DHZC)
city: Budapest
country: Hungary
facility: Gottsegen Gyorgy Orszagos Kardiovaszkularis Intezet
city: Szeged
country: Hungary
facility: SZTE ÁOK Szent Györgyi Albert Klinikai Kozpont
city: Padova
country: Italy
facility: Azienda Ospedale-Università di Padova - UOC Cardiologia Pediatrica
state: Veneto
city: Obu
country: Japan
facility: Aichi Children's Health and Medical Center
state: Aichi
city: Suita
country: Japan
facility: The University of Osaka Hospital
state: Osaka
city: Suita
country: Japan
facility: National Cerebral and Cardiovascular Center
state: Osaka
city: Shinjuku-ku
country: Japan
facility: Keio University Hospital
state: Tokyo
city: México D.F.
country: Mexico
facility: Instituto Nacional de Cardiología "Ignacio Chávez"
state: Distrito Federal
city: Huixquilucan
country: Mexico
facility: Operadora de Hospitales Angeles S. A. de C. V.
city: Wroclaw
country: Poland
facility: Wojewodzki Szpital Specjalistyczny - Wroclaw
city: Kaohsiung City
country: Taiwan
facility: Veterans General Hospital
city: Ankara
country: Turkey
facility: Hacettepe Universitesi Tip Fakultesi
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References: