Riociguat nei bambini con ipertensione arteriosa polmonare (PAH) (PATENT-CHILD)

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.

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.

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).

Mean change in heart rate from baseline is reported.

Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline are reported.

Mean change in respiratory rate from baseline is reported.

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.

Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.

Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.

Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

Estimated right atrial pressure was measured by echocardiography.

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.

Pericardial effusion was measured by echocardiography.

Pulmonary artery acceleration time was measured by echocardiography.

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.

Right ventricular cardiac output was measured by echocardiography.

Right atrial diastolic area was measured by echocardiography.

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.

Right atrial systolic area was measured by echocardiography.

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.

Right ventricular fractional area change was measured by echocardiography.

Right ventricular diastolic area was measured by echocardiography.

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.

Right ventricular systolic area was measured by echocardiography.

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.

Systolic pulmonary artery pressure was measured by echocardiography.

Tricuspid annular plane systolic excursion (TAPSE) was measured by echocardiography.

Tricuspid regurgitation peak velocity was measured by echocardiography.

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).

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).

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".

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".

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".

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".

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).

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).

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".

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".