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| ID | Type | Description | Link |
|---|---|---|---|
| 2014-003952-29 | EudraCT Number |
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| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Riociguat | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Drug | 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. |
| 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. |
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Taste and Texture (Questions 1 to 4) of the Oral Suspension of Riociguat at Week 0 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Questions 1 to 4 are reported in this endpoint. Questions 1 and 2 were asked before the participants received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Participants were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer). |
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)
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
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
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)
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| Name | Affiliation | Role |
|---|---|---|
| Bayer Study Director | Bayer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| ClÃnica Imbanaco S.A.S | Cali | Valle del Cauca Department | 760042 | Colombia | ||
| Universitätsklinikum Heidelberg |
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| Label | URL |
|---|---|
| Click here to find information about studies related to Bayer Healthcare products conducted in Europe | View source |
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Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.
Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.
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A total of 26 participants were screened. Of them, 2 participants were screening failures and 24 participants received study treatment.
Study was conducted at multiple centers in 9 countries or regions between 29-Oct-2015 (first participant first visit) and 07-Mar-2020 (last participant last visit of main study part). The long-term extension part of the study is ongoing.
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| ID | Title | Description |
|---|---|---|
| FG000 | Riociguat >=6 to <18 Years | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Safety analysis set (SAF): All participants who were assigned to receive study medication and had received at least one dose of the study medication.
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| ID | Title | Description |
|---|---|---|
| BG000 | Riociguat >=6 to <18 Years | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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). | Safety analysis set (SAF) | Posted | Count of Participants | Participants | 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. |
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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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Riociguat >=6 to <18 Years | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pain of skin | Skin and subcutaneous tissue disorders | MedDRA 22.1 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pyrexia | General disorders | MedDRA 22.1 | Non-systematic Assessment |
The results should be interpreted with caution due to the limited number of subjects. The number of subjects with clinical worsening events was too low to produce valid Kaplan-Meier estimates for the time to clinical worsening.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Therapeutic Area Head | Bayer | 1-888-8422937 | clinical-trials-contact@bayer.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 20, 2020 | Mar 4, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 17, 2020 | Mar 4, 2021 | SAP_001.pdf |
| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| D000081029 | Pulmonary Arterial Hypertension |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| C542595 | riociguat |
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|
| 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) |
| 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) |
| At the beginning of the treatment (Week 0) |
| Taste and Texture (Questions 1 to 4) the Oral Suspension of Riociguat at Week 24 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Questions 1 to 4 are reported in this endpoint. Questions 1 and 2 were asked before the participants received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Participants were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer). | Week 24 (plus/minus 5 days) |
| Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 0 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 5 "Taste of the drink" is reported in this endpoint. Question 5 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity". | At the beginning of the treatment (Week 0) |
| Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 24 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 5 "Taste of the drink" is reported in this endpoint. Question 5 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity". | Week 24 (plus/minus 5 days) |
| Taste and Texture (Question 6) of the Oral Suspension of Riociguat at Week 0 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 6 "Drink feels in mouth" is reported in this endpoint. Question 6 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy". | At the beginning of the treatment (Week 0) |
| Taste and Texture (Question 6) of the Oral Suspension of Riociguat in Mouth at Week 24 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 6 "Drink feels in mouth" is reported in this endpoint. Question 6 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy". | Week 24 (plus/minus 5 days) |
| Taste and Texture (Question 7) of the Oral Suspension of Riociguat in Mouth at Week 0 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 7 "Did you like the taste after swallowing" is reported in this endpoint. Question 7 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer). | At the beginning of the treatment (Week 0) |
| Taste and Texture (Question 7) of the Oral Suspension of Riociguat in Mouth at Week 24 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 7 "Did you like the taste after swallowing" is reported in this endpoint. Question 7 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer). | Week 24 (plus/minus 5 days) |
| Expression Assessment on the Taste and Texture of Oral Suspension of Riociguat - Week 0 | The facial expression of the subjects concerning appearance, smell and taste of the suspension of Riociguat was captured by the investigators as "comfortable", "indifferent" and "displeased". | At the beginning of the treatment (Week 0) |
| Expression Assessment on the Taste and Texture of Oral Suspension of Riociguat - Week 24 | The facial expression of the subjects concerning appearance, smell and taste of the suspension of Riociguat was captured by the investigators as "comfortable", "indifferent" and "displeased". | Week 24 (plus/minus 5 days) |
| Heidelberg |
| Baden-Wurttemberg |
| 69115 |
| Germany |
| Universitätsklinikum Ulm | Ulm | Baden-Wurttemberg | 89075 | Germany |
| Deutsches Herzzentrum der Charité (DHZC) | Berlin | 13353 | Germany |
| Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ | Szeged | Csongrád-Csanád | 6720 | Hungary |
| Gottsegen Gyorgy Orszagos Kardiovaszkularis Intezet | Budapest | 1096 | Hungary |
| Azienda Ospedale-Università di Padova - UOC Cardiologia Pediatrica | Padova | Veneto | 35128 | Italy |
| Aichi Children's Health and Medical Center | ÅŒbu | Aichi-ken | 474-8710 | Japan |
| The University of Osaka Hospital | Suita | Osaka | 565-0871 | Japan |
| National Cerebral and Cardiovascular Center | Suita | Osaka | 565-8565 | Japan |
| Keio University Hospital | Shinjuku-ku | Tokyo | 160-8582 | Japan |
| Instituto Nacional de CardiologÃa "Ignacio Chávez" | México D.F. | Mexico City | 14080 | Mexico |
| Operadora de Hospitales Angeles S. A. de C. V. | Huixquilucan | 52763 | Mexico |
| Wojewodzki Szpital Specjalistyczny - Wroclaw | Wroclaw | 51-124 | Poland |
| Veterans General Hospital | Kaohsiung City | 813414 | Taiwan |
| Hacettepe Universitesi Tip Fakultesi | Ankara | 06230 | Turkey (Türkiye) |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| 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, bone age was compared to chronological age and assessed as as "delayed, in accordance or advanced". | Count of Participants | Participants |
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| WHO functional class | 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. | Count of Participants | Participants |
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| Heart rate | Mean | Standard Deviation | Beats per minute (BPM) |
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| Diastolic blood pressure | Mean | Standard Deviation | millimetre of mercury (mmHg) |
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| Systolic blood pressure | Mean | Standard Deviation | millimetre of mercury (mmHg) |
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| Respiratory Rate | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Breath per minute |
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| 6-minute walking distance | 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. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Meter |
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| N-terminal prohormone brain-type natriuretic peptide | 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. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Picograms per milliliter (pg/mL) |
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| Brain-type natriuretic peptide | 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. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Picograms per milliliter (pg/mL) |
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| Quality of life evaluated by SF-10 questionnaire physical summary score | 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 higher scores indicate more favorable functioning. | Mean | Standard Deviation | Scores on a scale |
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| Quality of life evaluated by SF-10 questionnaire psychosocial summary score | 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 psychosocial measure is 8.8 to 62.3 scores and higher scores indicate more favorable functioning. | Mean | Standard Deviation | Scores on a scale |
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| Quality of life evaluated by PedsQL total scale score | 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, physical health summary score (physical functioning) and psychosocial health summary score (emotional, social and school functioning). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Scores on a scale |
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| Quality of life evaluated by PedsQL physical health summary score | 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, physical health summary score (physical functioning) and psychosocial health summary score (emotional, social and school functioning). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Scores on a scale |
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| Quality of life evaluated by PedsQL psychosocial health summary score | PedsQL Generic Core Scales were designed to 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, physical health summary score (physical functioning) and psychosocial health summary score (emotional, social and school functioning). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Scores on a scale |
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| Estimate right atrial pressure | Estimate right atrial pressure was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | millimetre of mercury (mmHg) |
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| Left ventricular eccentricity index | Left ventricular (LV) eccentricity index (EI) is defined as the ratio of the LV long axis to the LV transverse diameter, measured at end systole and end diastole by echocardiography. The value of EI > 1.0 is abnormal and suggests right ventricle (RV) overload. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Ratio |
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| Pulmonary artery acceleration time | Pulmonary artery acceleration time was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Millisecond (msec) |
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| Right ventricular cardiac index | 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. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Liter/minute/square meter (L/min/m^2) |
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| Right ventricular cardiac output | Right ventricular cardiac output was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Liter per minute (L/min) |
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| Right atrial diastolic area | Right atrial diastolic area was measured by echocardiography. Number of subjects with right atrial diastolic area data at baseline: n=18 | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Square centimeter (cm^2) |
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| Right atrial diastolic area index | 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. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Ratio |
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| Right atrial systolic area | Right atrial systolic area was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Square centimeter (cm^2) |
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| Right atrial systolic area index | 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. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Ratio |
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| Right ventricular fractional area change | Right ventricular fractional area change was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Percentage (%) |
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| Right ventricular diastolic area | Right ventricular diastolic area was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Square centimeter (cm^2) |
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| Right ventricular diastolic area index | 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. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Ratio |
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| Right ventricular systolic area | Right ventricular systolic area was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Square centimeter (cm^2) |
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| Right ventricular systolic area index | 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. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Ratio |
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| Systolic pulmonary artery pressure | Systolic pulmonary artery pressure was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | millimetre of mercury (mmHg) |
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| Tricuspid annular plane systolic excursion | Tricuspid annular plane systolic excursion was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Millimeter (mm) |
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| Tricuspid regurgitation peak velocity | Tricuspid regurgitation peak velocity was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Meter/second (m/s) |
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| Pericardial effusion | Pericardial effusion was measured by echocardiography. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Millimeter (mm) |
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| Platelets | Hematology parameters were collected and analyzed. | Mean | Standard Deviation | Giga platelets per liter |
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| Lymphocytes/leucocytes ratio | Hematology parameters were collected and analyzed. | Mean | Standard Deviation | Percentage of leucocytes in blood |
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| Neutrophils/leucocytes ratio | Hematology parameters were collected and analyzed. | Mean | Standard Deviation | Percentage of leucocytes in blood |
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| Alanine aminotransferase | Clinical chemistry parameters were collected and analyzed. | Mean | Standard Deviation | Units per liter (U/L) |
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| Aspartate aminotransferase | Clinical chemistry parameters were collected and analyzed. | Mean | Standard Deviation | Units per liter (U/L) |
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| Urea | Clinical chemistry parameters were collected and analyzed. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | microgram per deciliter (mg/dL) |
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| Gamma glutamyl transferase | Clinical chemistry parameters were collected and analyzed. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | Units per liter (U/L) |
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| Blood urea nitrogen | Clinical chemistry parameters were collected and analyzed. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | microgram per deciliter (mg/dL) |
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| Estimated Glomerular Filtration Rate (eGFR) | Clinical chemistry parameters were collected and analyzed. | Mean | Standard Deviation | milliliter/minute/1.73 square meter |
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| Sodium | Clinical chemistry parameters were collected and analyzed. | Participants in SAF with evaluable data for this measurement | Mean | Standard Deviation | millimole per Liter (mmol/L) |
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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. |
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| Primary | Change in Heart Rate From Baseline | Mean change in heart rate from baseline is reported. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Beats per minute (BPM) | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | Change in Blood Pressure From Baseline | Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline are reported. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | millimetre of mercury (mmHg) | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | Change in Respiratory Rate From Baseline | Mean change in respiratory rate from baseline is reported. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Breath per minute | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Count of Participants | Participants | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Giga platelets per Liter | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Percentage of leucocytes in blood | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Percentage of leucocytes in blood | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Units per liter (U/L) | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Units per liter (U/L) | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | millimole per Liter (mmol/L) | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | microgram per deciliter (mg/dL) | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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 | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | milliliter/minute/1.73 square meter | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | microgram per deciliter (mg/dL) | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Units per liter (U/L) | Baseline and Week 24 (plus/minus 5 days) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per liter (mcg/L) | Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per liter (mcg/L) | Week 4 (pre-dose) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per liter (mcg/L) | Week 8 (pre-dose) |
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| Primary | 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 | Participants in safety analysis set (SAF) with evaluable data | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per liter (mcg/L) | Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per liter (mcg/L) | Week 4 (pre-dose) |
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| Primary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per liter (mcg/L) | Week 8 (pre-dose) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Meter | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Count of Participants | Participants | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | picograms per milliliter (pg/mL) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Picograms per milliliter (pg/mL) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Scores on a scale | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Scores on a scale | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Count of Participants | Participants | Up to Week 24 (plus/minus 5 days) |
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| Secondary | Change in Estimated Right Atrial Pressure From Baseline | Estimated right atrial pressure was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | millimetre of mercury (mmHg) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Ratio | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | Change in Pericardial Effusion From Baseline | Pericardial effusion was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Millimeter (mm) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | Change in Pulmonary Artery Acceleration Time From Baseline | Pulmonary artery acceleration time was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Millisecond (msec) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Liter/minute/square meter (L/min/m^2) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | Change in Right Ventricular Cardiac Output From Baseline | Right ventricular cardiac output was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Liter per minute (L/min) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | Change in Right Atrial Diastolic Area From Baseline | Right atrial diastolic area was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Square centimeter (cm^2) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Ratio | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | Change in Right Atrial Systolic Area From Baseline | Right atrial systolic area was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Square centimeter (cm^2) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Ratio | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | Change in Right Ventricular Fractional Area Change From Baseline | Right ventricular fractional area change was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Percentage (%) of area | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | Change in Right Ventricular Diastolic Area From Baseline | Right ventricular diastolic area was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Square centimeter (cm^2) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Ratio | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | Change in Right Ventricular Systolic Area From Baseline | Right ventricular systolic area was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Square centimeter (cm^2) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | 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. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Ratio | Baseline and Week 24 (plus/minus 5 days) |
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|
| Secondary | Change in Systolic Pulmonary Artery Pressure From Baseline | Systolic pulmonary artery pressure was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | millimetre of mercury (mmHg) | Baseline and Week 24 (plus/minus 5 days) |
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|
| Secondary | Change in Tricuspid Annular Plane Systolic Excursion From Baseline | Tricuspid annular plane systolic excursion (TAPSE) was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Millimeter (mm) | Baseline and Week 24 (plus/minus 5 days) |
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| Secondary | Change in Tricuspid Regurgitation Peak Velocity From Baseline | Tricuspid regurgitation peak velocity was measured by echocardiography. | Participants in safety analysis set (SAF) with evaluable data | Posted | Mean | Standard Deviation | Meter/second (m/s) | Baseline and Week 24 (plus/minus 5 days) |
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| Other Pre-specified | Taste and Texture (Questions 1 to 4) of the Oral Suspension of Riociguat at Week 0 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Questions 1 to 4 are reported in this endpoint. Questions 1 and 2 were asked before the participants received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Participants were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer). | Participants in safety analysis set (SAF) with evaluable data | Posted | Count of Participants | Participants | At the beginning of the treatment (Week 0) |
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| Other Pre-specified | Taste and Texture (Questions 1 to 4) the Oral Suspension of Riociguat at Week 24 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Questions 1 to 4 are reported in this endpoint. Questions 1 and 2 were asked before the participants received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Participants were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer). | Participants in safety analysis set (SAF) with evaluable data | Posted | Count of Participants | Participants | Week 24 (plus/minus 5 days) |
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|
| Other Pre-specified | Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 0 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 5 "Taste of the drink" is reported in this endpoint. Question 5 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity". | Participants in safety analysis set (SAF) with evaluable data | Posted | Count of Participants | Participants | At the beginning of the treatment (Week 0) |
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| Other Pre-specified | Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 24 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 5 "Taste of the drink" is reported in this endpoint. Question 5 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity". | Participants in safety analysis set (SAF) with evaluable data | Posted | Count of Participants | Participants | Week 24 (plus/minus 5 days) |
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| Other Pre-specified | Taste and Texture (Question 6) of the Oral Suspension of Riociguat at Week 0 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 6 "Drink feels in mouth" is reported in this endpoint. Question 6 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy". | Participants in safety analysis set (SAF) with evaluable data | Posted | Count of Participants | Participants | At the beginning of the treatment (Week 0) |
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| Other Pre-specified | Taste and Texture (Question 6) of the Oral Suspension of Riociguat in Mouth at Week 24 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 6 "Drink feels in mouth" is reported in this endpoint. Question 6 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy". | Participants in safety analysis set (SAF) with assessment | Posted | Count of Participants | Participants | Week 24 (plus/minus 5 days) |
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| Other Pre-specified | Taste and Texture (Question 7) of the Oral Suspension of Riociguat in Mouth at Week 0 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 7 "Did you like the taste after swallowing" is reported in this endpoint. Question 7 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer). | Participants in safety analysis set (SAF) with assessment | Posted | Count of Participants | Participants | At the beginning of the treatment (Week 0) |
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|
|
| Other Pre-specified | Taste and Texture (Question 7) of the Oral Suspension of Riociguat in Mouth at Week 24 | To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 7 "Did you like the taste after swallowing" is reported in this endpoint. Question 7 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer). | Participants in safety analysis set (SAF) with assessment | Posted | Count of Participants | Participants | Week 24 (plus/minus 5 days) |
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| Other Pre-specified | Expression Assessment on the Taste and Texture of Oral Suspension of Riociguat - Week 0 | The facial expression of the subjects concerning appearance, smell and taste of the suspension of Riociguat was captured by the investigators as "comfortable", "indifferent" and "displeased". | Participants in safety analysis set (SAF) with assessment | Posted | Count of Participants | Participants | At the beginning of the treatment (Week 0) |
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| Other Pre-specified | Expression Assessment on the Taste and Texture of Oral Suspension of Riociguat - Week 24 | The facial expression of the subjects concerning appearance, smell and taste of the suspension of Riociguat was captured by the investigators as "comfortable", "indifferent" and "displeased". | Participants in safety analysis set (SAF) with assessment | Posted | Count of Participants | Participants | Week 24 (plus/minus 5 days) |
|
|
|
| 0 |
| 24 |
| 4 |
| 24 |
| 15 |
| 24 |
| Skin swelling | Skin and subcutaneous tissue disorders | MedDRA 22.1 | Non-systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 22.1 | Non-systematic Assessment |
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| Right ventricular failure | Cardiac disorders | MedDRA 22.1 | Non-systematic Assessment |
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| Vascular device infection | Infections and infestations | MedDRA 22.1 | Non-systematic Assessment |
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| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA 22.1 | Non-systematic Assessment |
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| Gastroenteritis | Infections and infestations | MedDRA 22.1 | Non-systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 22.1 | Non-systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 22.1 | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 22.1 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 22.1 | Non-systematic Assessment |
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| Hypotension | Vascular disorders | MedDRA 22.1 | Non-systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA 22.1 | Non-systematic Assessment |
|
Most restricted agreement: CTA Japan; Embargo time mentioned. Hospital shall obtain prior written consent of Sponsor if PI intends to publish the information obtained from study externally such as in a professional society or association.
| D002318 |
| Cardiovascular Diseases |
| Title | Measurements |
|---|---|
|
| Transitioned from In Accordance to Advanced |
|
| Transitioned from In Accordance to Missing |
|
| Transitioned from Advanced to Delayed |
|
| Transitioned from Advanced to In Accordance |
|
| 0 classes |
|
| 1 classes |
|
| 2 classes |
|
| 3 classes |
|
|
| Missing |
|
| Like the smell of the drink |
|
| Like the drink |
|
| Like to drink again |
|
| Missing |
|
| Like the smell of the drink |
|
| Like the drink |
|
| Like to drink again |
|
| Sour |
|
| Bitter |
|
| Salty |
|
| Disgusting |
|
| Fruity |
|
| Sour |
|
| Bitter |
|
| Salty |
|
| Disgusting |
|
| Fruity |
|
| Sticky |
|
| Gooey |
|
| Slimy |
|
| Creamy |
|
| Sticky |
|
| Gooey |
|
| Slimy |
|
| Creamy |
|
| Missing |
|
| Missing |
|