Riociguat in Children With Pulmonary Arterial Hypertension (PAH)

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Hypertension, Pulmonary

Intervention / Treatment
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* Drug: Riociguat (Adempas, BAY63-2521)


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riociguat<br>Participants with age ≥6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 1.0 mg and 2.5 mg) for up to 8 weeks during the individual dose titration (IDT) phase, and followed with the last dose administered in the IDT phase for up to 16 weeks during the maintenance phase. Down-titration (up to 0.5 mg) of the dose for safety reasons was allowed at any time. | Drug: Riociguat (Adempas, BAY63-2521)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Treatment-emergent Adverse Events | An adverse event (AE), including AE in relation to a medical device (i.e. Raumedic dosing pipette), is any untoward medical occurrence in a participant administered with a pharmaceutical product and does not necessarily have to have a causal relationship with this treatment. A serious AE (SAE) is any untoward medical occurrence that at any dose is resulting in death, is lifethreatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity. AEs occurring between start of study drug and up to 2 days after the last dose were defined as treatment-emergent AEs (TEAEs). | 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. | 
| Change in Heart Rate From Baseline | Mean change in heart rate from baseline is reported. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Blood Pressure From Baseline | Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline are reported. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Respiratory Rate From Baseline | Mean change in respiratory rate from baseline is reported. | Baseline and Week 24 (plus/minus 5 days) | 
| Number of Subjects With Transitions From Baseline in Bone Age Compared to Chronological Age | X-ray of left hand was performed for each participant and bone age was determined centrally by a specialist. For each participant, the bone age was compared to the chronological age and assigned to one of the categories - delayed, in accordance or advanced, indicating the advancement or delay in the growth of the bone. Number of participants who transitioned to another category different from baseline was calculated and is reported. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Hematology Parameters (Platelets) From Baseline | Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Hematology Parameters (Lymphocytes/Leucocytes Ratio) From Baseline | Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Hematology Parameter (Neutrophils/Leucocytes Ratio) From Baseline | Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Clinical Chemistry (Alanine Aminotransferase) From Baseline | Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Clinical Chemistry (Aspartate Aminotransferase) From Baseline | Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Clinical Chemistry (Sodium) From Baseline | Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Clinical Chemistry (Blood Urea Nitrogen) From Baseline | Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Clinical Chemistry (eGFR) From Baseline | Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. eGFR = estimated glomerular filtration rate | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Clinical Chemistry (Urea) From Baseline | Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Clinical Chemistry (Gamma Glutamyl Transferase) From Baseline | Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. | Baseline and Week 24 (plus/minus 5 days) | 
| Plasma Concentration of Riociguat at Week 0 | For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. W = Week. | Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose) | 
| Plasma Concentration of Riociguat at Week 4 | For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. | Week 4 (pre-dose) | 
| Plasma Concentration of Riociguat at Week 8 | For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. | Week 8 (pre-dose) | 
| Plasma Concentration of BAY60-4552 at Week 0 | BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. W = Week | Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose) | 
| Plasma Concentration of BAY60-4552 at Week 4 | BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. | Week 4 (pre-dose) | 
| Plasma Concentration of BAY60-4552 at Week 8 | BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. | Week 8 (pre-dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6-minute Walking Distance From Baseline | 6-minute walking distance (6MWD) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. An increase in the distance walked indicates improvement in basic mobility. | Baseline and Week 24 (plus/minus 5 days) | 
| Number of Subjects With Change in WHO Functional Class From Baseline | The World Health Organization (WHO) functional class describes how severe a patient's pulmonary hypertension (PH) symptoms are. There are four different classes - I is the mildest and IV the most severe form of PH. Number of participants per change in number of classes is reported. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in NT-proBNP From Baseline | Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the participants. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in BNP From Baseline | Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the participants. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Quality of Life Evaluated by SF-10 Questionnaire From Baseline | SF-10 is a parent-completed health survey for children that contains 10 questions adapted from the Child Health Questionnaire. It is scored using nom-based scoring to produce physical and psychosocial health summary measures. The possible range for the physical measure is -10.9 to 57.2 scores and the possible range for the psychosocial measure is 8.8 to 62.3 scores. Higher scores indicate more favorable functioning. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Quality of Life Evaluated by PedsQL Scale | The PedsQL Generic Core Scales were designed to measure health-related quality of life in children and adolescents. It has 4 dimensions: physical functioning, emotional functioning, social functioning and school functioning. 3 Summary Scores of PedsQL were calculated from the scales including total scale score (23 questions), physical health summary score (physical functioning, 8 questions) and psychosocial health summary score (emotional, social and school functioning, 15 questions). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life. | Baseline and Week 24 (plus/minus 5 days) | 
| Number of Subjects With Clinical Worsening | Clinical worsening was defined as: hospitalization for right heart failure, death, lung transplantation, Pott's anastomosis and atrioseptostomy, worsening of pulmonary arterial hypertension (PAH) symptoms, which must include either an increase in World Health Organization (WHO) functional class or appearance/worsening symptoms of right heart failure and need for additional PAH therapy. | Up to Week 24 (plus/minus 5 days) | 
| Change in Estimated Right Atrial Pressure From Baseline | Estimated right atrial pressure was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Left Ventricular Eccentricity Index From Baseline | Left ventricular (LV) eccentricity index (EI) was measured by echocardiography and defined as the ratio of the LV anteroposterior dimension to the septolateral dimension in the parasternal short-axis window by echocardiography. The value of EI greater than 1.0 is abnormal and suggests right ventricle (RV) overload. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Pericardial Effusion From Baseline | Pericardial effusion was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Pulmonary Artery Acceleration Time From Baseline | Pulmonary artery acceleration time was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Ventricular Cardiac Index From Baseline | Right ventricle (RV) cardiac index (CI) was measured by echocardiography and calculated by dividing the cardiac output (stroke volume × heart rate) by the body surface area. The change in RV CI should not be understood solely but associated with other conditions of the participants. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Ventricular Cardiac Output From Baseline | Right ventricular cardiac output was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Atrial Diastolic Area From Baseline | Right atrial diastolic area was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Atrial Diastolic Area Index From Baseline | Right atrial (RA) diastolic area index was measured by echocardiography and calculated by dividing the RA area at end-diastole by the body surface area. The RA area index is a reflection of RA volume at end-diastole. The change in the index should not be understood solely but associated with other conditions of the participants. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Atrial Systolic Area From Baseline | Right atrial systolic area was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Atrial Systolic Area Index From Baseline | Right atrial (RA) systolic area index was measured by echocardiography and calculated by dividing the RA area at end-systole by the body surface area. The RA area index is a reflection of RA volume at end-systole. The change in the index should not be understood solely but associated with other conditions of the participants. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Ventricular Fractional Area Change From Baseline | Right ventricular fractional area change was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Ventricular Diastolic Area From Baseline | Right ventricular diastolic area was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Ventricular Diastolic Area Index From Baseline | Right ventricular (RV) diastolic area index was measured by echocardiography and calculated by dividing the RV area at end-diastole by the body surface area. The RV area index is a reflection of RV volume at end-diastole. The change in the index should not be understood solely but associated with other conditions of the participants. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Ventricular Systolic Area From Baseline | Right ventricular systolic area was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Right Ventricular Systolic Area Index From Baseline | Right ventricular (RV) systolic area index was measured by echocardiography and calculated by dividing the RV area at end-systole by the body surface area. The RV area index is a reflection of RV volume at end-systole. The change in the index should not be understood solely but associated with other conditions of the participants. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Systolic Pulmonary Artery Pressure From Baseline | Systolic pulmonary artery pressure was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Tricuspid Annular Plane Systolic Excursion From Baseline | Tricuspid annular plane systolic excursion (TAPSE) was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 
| Change in Tricuspid Regurgitation Peak Velocity From Baseline | Tricuspid regurgitation peak velocity was measured by echocardiography. | Baseline and Week 24 (plus/minus 5 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary arterial hypertension