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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
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.
Clínica Imbanaco S.A.S
Cali, Valle del Cauca Department, Colombia
Universitätsklinikum Heidelberg
Heidelberg, Baden-Wurttemberg, Germany
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).
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Week 24 (plus/minus 5 days)
Change in Respiratory Rate From Baseline
Mean change in respiratory rate from baseline is reported.
Time frame: 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.
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Universitätsklinikum Ulm
Ulm, Baden-Wurttemberg, Germany
Deutsches Herzzentrum der Charité (DHZC)
Berlin, Germany
Gottsegen Gyorgy Orszagos Kardiovaszkularis Intezet
Budapest, Hungary
SZTE ÁOK Szent Györgyi Albert Klinikai Kozpont
Szeged, Hungary
Azienda Ospedale-Università di Padova - UOC Cardiologia Pediatrica
Padua, Veneto, Italy
Aichi Children's Health and Medical Center
Ōbu, Aichi-ken, Japan
The University of Osaka Hospital
Suita, Osaka, Japan
National Cerebral and Cardiovascular Center
Suita, Osaka, Japan
...and 6 more locations
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: Week 8 (pre-dose)
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to Week 24 (plus/minus 5 days)
Change in Estimated Right Atrial Pressure From Baseline
Estimated right atrial pressure was measured by echocardiography.
Time frame: 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.
Time frame: Baseline and Week 24 (plus/minus 5 days)
Change in Pericardial Effusion From Baseline
Pericardial effusion was measured by echocardiography.
Time frame: Baseline and Week 24 (plus/minus 5 days)
Change in Pulmonary Artery Acceleration Time From Baseline
Pulmonary artery acceleration time was measured by echocardiography.
Time frame: 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.
Time frame: Baseline and Week 24 (plus/minus 5 days)
Change in Right Ventricular Cardiac Output From Baseline
Right ventricular cardiac output was measured by echocardiography.
Time frame: Baseline and Week 24 (plus/minus 5 days)
Change in Right Atrial Diastolic Area From Baseline
Right atrial diastolic area was measured by echocardiography.
Time frame: 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.
Time frame: Baseline and Week 24 (plus/minus 5 days)
Change in Right Atrial Systolic Area From Baseline
Right atrial systolic area was measured by echocardiography.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and Week 24 (plus/minus 5 days)
Change in Right Ventricular Diastolic Area From Baseline
Right ventricular diastolic area was measured by echocardiography.
Time frame: 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.
Time frame: Baseline and Week 24 (plus/minus 5 days)
Change in Right Ventricular Systolic Area From Baseline
Right ventricular systolic area was measured by echocardiography.
Time frame: 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.
Time frame: Baseline and Week 24 (plus/minus 5 days)
Change in Systolic Pulmonary Artery Pressure From Baseline
Systolic pulmonary artery pressure was measured by echocardiography.
Time frame: 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.
Time frame: Baseline and Week 24 (plus/minus 5 days)
Change in Tricuspid Regurgitation Peak Velocity From Baseline
Tricuspid regurgitation peak velocity was measured by echocardiography.
Time frame: Baseline and Week 24 (plus/minus 5 days)