Clinical Trial Results:
Open-label, individual dose titration study to evaluate safety, tolerability and pharmacokinetics of riociguat in children from 6 to less than 18 years of age with pulmonary arterial hypertension (PAH)
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Summary
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EudraCT number |
2014-003952-29 |
Trial protocol |
HU IT GB DE ES PL Outside EU/EEA BE RO |
Global end of trial date |
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Sep 2020
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First version publication date |
19 Sep 2020
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
15681
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02562235 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bayer AG
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Sponsor organisation address |
Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
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Public contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Scientific contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000718-PIP01-09 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Interim
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Date of interim/final analysis |
07 Mar 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Mar 2020
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Global end of trial reached? |
No
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General information about the trial
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Main objective of the trial |
The primary objective was to evaluate safety, tolerability and pharmacokinetics of oral riociguat treatment
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Protection of trial subjects |
The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects or their legally authorized representative. Subjects or legal representatives signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
Subjects must be on standard of care PAH medications, allowing Endothelin Receptor Antagonists (ERA) and/or Prostacyclin Analogues (PCA), for at least 12 weeks prior to baseline visit. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Oct 2015
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Safety | ||
Long term follow-up duration |
11 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Taiwan: 2
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Country: Number of subjects enrolled |
Germany: 5
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Country: Number of subjects enrolled |
Hungary: 2
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Country: Number of subjects enrolled |
Italy: 3
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Country: Number of subjects enrolled |
Japan: 6
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Country: Number of subjects enrolled |
Mexico: 4
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Country: Number of subjects enrolled |
Poland: 2
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Worldwide total number of subjects |
24
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EEA total number of subjects |
12
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
6
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Adolescents (12-17 years) |
18
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Study was conducted at multiple centers in 9 countries or regions between 29-Oct-2015 (first subject first visit) and 07-Mar-2020 (last subject last visit of main study part). | ||||||||||
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Pre-assignment
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Screening details |
A total of 26 subjects were screened. Of them, 2 subjects were screening failures and 24 subjects received study treatment. | ||||||||||
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Period 1
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Period 1 title |
Baseline and main treatment period (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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Riociguat >=6 to <18 years | ||||||||||
Arm description |
Subjects with age >=6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 0.5 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 of the dose for safety reasons was allowed at any time. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Riociguat
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Investigational medicinal product code |
BAY63-2521
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Other name |
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Pharmaceutical forms |
Granules for oral suspension, Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
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.
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Baseline characteristics reporting groups
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Reporting group title |
Riociguat >=6 to <18 years
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Reporting group description |
Subjects with age >=6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 0.5 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 of the dose for safety reasons was allowed at any time. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Riociguat >=6 to <18 years
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Reporting group description |
Subjects with age >=6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 0.5 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 of the dose for safety reasons was allowed at any time. | ||
Subject analysis set title |
Safety analysis set (SAF)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subject who was assigned to receive study medication and had received at least one dose of the study medication.
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Subject analysis set title |
Riociguat 0.5 mg or equivalent - PK
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who received riociguat at 0.5 mg or body weight-adjusted dose equivalent to the exposure of 0.5 mg dose in adults at the day of PK measurement
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Subject analysis set title |
Riociguat 1.0 mg or equivalent - PK
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who received riociguat at 1.0 mg or body weight-adjusted dose equivalent to the exposure of 1.0 mg dose in adults at the day of PK measurement
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Subject analysis set title |
Riociguat 2.0 mg or equivalent - PK
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who received riociguat at 2.0 mg or body weight-adjusted dose equivalent to the exposure of 2.0 mg dose in adults at the day of PK measurement
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Subject analysis set title |
Riociguat 2.5 mg or equivalent - PK
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who received riociguat at 2.5 mg or body weight-adjusted dose equivalent to the exposure of 2.5 mg dose in adults at the day of PK measurement
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End point title |
Number of subjects with any treatment-emergent adverse events [1] | ||||||||||
End point description |
An adverse event (AE), including AE in relation to a medical device (i.e. Raumedic dosing pipette), is any untoward medical occurrence in a subject 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).
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End point type |
Primary
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End point timeframe |
From start of study drug up to 2 days after the last dose of study drug in the main study part, up to 24 weeks plus/minus 5 days.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [2] - SAF |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Change in heart rate from baseline [3] | ||||||||
End point description |
Mean change in heart rate from baseline is reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [4] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in blood pressure from baseline [5] | ||||||||||||
End point description |
Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline are reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [6] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in respiratory rate from baseline [7] | ||||||||
End point description |
Mean change in respiratory rate from baseline by age subgroups (≥6 to <12 years and ≥12 to <18 years) were reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [8] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with transitions from baseline in bone age compared to chronological age [9] | ||||||||||||||||||||
End point description |
X-ray of left hand was performed for each subject and bone age was determined centrally by a specialist. For each subject, 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 subjects who transitioned to another category different from baseline was calculated and reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [10] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change in hematology parameters (platelets) from baseline [11] | ||||||||
End point description |
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline were reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [12] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in hematology parameters (lymphocytes/leucocytes ratio) from baseline [13] | ||||||||
End point description |
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline were reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [14] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in hematology parameters (neutrophils/leucocytes ratio) from baseline [15] | ||||||||
End point description |
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline were reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [16] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in clinical chemistry (alanine aminotransferase) from baseline [17] | ||||||||
End point description |
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [18] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in clinical chemistry (aspartate aminotransferase) from baseline [19] | ||||||||
End point description |
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [20] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in clinical chemistry (eGFR) from baseline [21] | ||||||||
End point description |
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported. eGFR = estimated glomerular filtration rate
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [22] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in clinical chemistry (sodium) from baseline [23] | ||||||||
End point description |
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [24] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in clinical chemistry (blood urea nitrogen) from baseline [25] | ||||||||
End point description |
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [26] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in clinical chemistry (urea) from baseline [27] | ||||||||
End point description |
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
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End point type |
Primary
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End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
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| Notes [27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
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| Notes [28] - Subjects in SAF with evaluable data |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in clinical chemistry (gamma glutamyl transferase) from baseline [29] | ||||||||
End point description |
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
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End point type |
Primary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
| Notes [29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
|||||||||
|
|||||||||
| Notes [30] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Plasma concentration of riociguat at Week 0 [31] | ||||||||||||
End point description |
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) were reported. W = Week. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)
|
||||||||||||
| Notes [31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
|||||||||||||
|
|||||||||||||
| Notes [32] - Subjects in SAF with evaluable data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Plasma concentration of riociguat at Week 4 [33] | ||||||||||||||||
End point description |
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) were reported. "99999" denotes that value was not calculated due to very low number of subjects. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Week 4 (pre-dose)
|
||||||||||||||||
| Notes [33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
|||||||||||||||||
|
|||||||||||||||||
| Notes [34] - Subjects in SAF with evaluable data [35] - Subjects in SAF with evaluable data [36] - SAF |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Plasma concentration of riociguat at Week 8 [37] | ||||||||||||||||||||||||||||||
End point description |
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) were reported. "99999" denotes that value was not calculated due to very low number of subjects. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
|
||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||
End point timeframe |
Week 8 (pre-dose)
|
||||||||||||||||||||||||||||||
| Notes [37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
|||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| Notes [38] - Subjects in SAF with evaluable data [39] - Subjects in SAF with evaluable data [40] - Subjects in SAF with evaluable data [41] - Subjects in SAF with evaluable data |
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||
End point title |
Plasma concentration of BAY60-4552 at Week 0 [42] | ||||||||||||
End point description |
BAY60-4552 is riociguat's active metabolite. 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) were reported. W = Week; n = number of subjects. "99999" denotes that value was not calculated due to very low number of subjects.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)
|
||||||||||||
| Notes [42] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
|||||||||||||
|
|||||||||||||
| Notes [43] - Subjects in SAF with evaluable data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Plasma concentration of BAY60-4552 at Week 4 [44] | ||||||||||||||||
End point description |
BAY60-4552 is riociguat's active metabolite. 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) were reported. "99999" denotes that value was not calculated due to very low number of subjects. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Week 4 (pre-dose)
|
||||||||||||||||
| Notes [44] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
|||||||||||||||||
|
|||||||||||||||||
| Notes [45] - Subjects in SAF with evaluable data [46] - Subjects in SAF with evaluable data [47] - Subjects in SAF with evaluable data |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||
End point title |
Plasma concentration of BAY60-4552 at Week 8 [48] | ||||||||||||||||||||
End point description |
BAY60-4552 is riociguat's active metabolite. 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) were reported. "99999" denotes that value was not calculated due to very low number of subjects. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Week 8 (pre-dose)
|
||||||||||||||||||||
| Notes [48] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics. |
|||||||||||||||||||||
|
|||||||||||||||||||||
| Notes [49] - Subjects in SAF with evaluable data [50] - Subjects in SAF with evaluable data [51] - Subjects in SAF with evaluable data [52] - Subjects in SAF with evaluable data |
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||
End point title |
Change in 6-minute walking distance from baseline | ||||||||
End point description |
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.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [53] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||
End point title |
Number of subjects with change in WHO functional class from baseline | ||||||||||||||||||||
End point description |
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 subjects per change in number of classes was reported.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||||||||||||||
|
|||||||||||||||||||||
| Notes [54] - Subjects in SAF with evaluable data |
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||
End point title |
Change in NT-proBNP from baseline | ||||||||
End point description |
Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the subjects. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [55] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in BNP from baseline | ||||||||
End point description |
Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the subjects. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [56] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Change in quality of life evaluated by SF-10 questionnaire from baseline | ||||||||||||
End point description |
SF-10 is a parent-completed health survey for children that contains 10 questions adapted from the Child Health Questionnaire. It is scored to produce physical and psychosocial health summary measures. Each of the 10 questions responses is scored with a point value from 1 to 6 (1 is the worst possible condition and 6 is the best possible condition). The SF-10 physical and psychosocial measures are scored such that higher scores indicate more favorable functioning.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||||||
|
|||||||||||||
| Notes [57] - Subjects in SAF with evaluable data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||
End point title |
Change in quality of life evaluated by PedsQL scale | ||||||||||||||
End point description |
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.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||||||||
|
|||||||||||||||
| Notes [58] - Subjects in SAF with evaluable data |
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||
End point title |
Number of subjects with clinical worsening | ||||||
End point description |
Clinical worsening was defined as: hospitalization for right heart failure, death, lung transplantation, Pott’s anastomosis and atrioseptostomy, worsening of PAH symptoms, which must include either an increase in WHO functional class or appearance/worsening symptoms of right heart failure and need for additional PAH therapy.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Up to Week 24 (plus/minus 5 days)
|
||||||
|
|||||||
| Notes [59] - SAF |
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||
End point title |
Change in estimated right atrial pressure from baseline | ||||||||
End point description |
Estimated right atrial pressure was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [60] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in left ventricular eccentricity index from baseline | ||||||||
End point description |
Left ventricular eccentricity index was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [61] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in pericardial effusion from baseline | ||||||||
End point description |
Pericardial effusion was measured by echocardiography. "99999" denotes that value was not calculated due to very low number of subjects.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [62] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in pulmonary artery acceleration time from baseline | ||||||||
End point description |
Pulmonary artery acceleration time was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [63] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right ventricular cardiac index from baseline | ||||||||
End point description |
Rright ventricular cardiac index was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [64] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right ventricular cardiac output from baseline | ||||||||
End point description |
Right ventricular cardiac output was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [65] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right atrial diastolic area from baseline | ||||||||
End point description |
Right atrial diastolic area was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [66] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right atrial diastolic area index from baseline | ||||||||
End point description |
Right atrial diastolic area index was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [67] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right atrial systolic area from baseline | ||||||||
End point description |
Right atrial systolic area was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [68] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right atrial systolic area index from baseline | ||||||||
End point description |
Right atrial systolic area index was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [69] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right ventricular fractional area change from baseline | ||||||||
End point description |
Right ventricular fractional area change was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [70] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right ventricular diastolic area from baseline | ||||||||
End point description |
Right ventricular diastolic area was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [71] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right ventricular diastolic area index from baseline | ||||||||
End point description |
Right ventricular diastolic area index was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [72] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right ventricular systolic area from baseline | ||||||||
End point description |
Right ventricular systolic area was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [73] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in right ventricular systolic area index from baseline | ||||||||
End point description |
Right ventricular systolic area index was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [74] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in systolic pulmonary artery pressure from baseline | ||||||||
End point description |
Systolic pulmonary artery pressure was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [75] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in tricuspid annular plane systolic excursion from baseline | ||||||||
End point description |
Tricuspid annular plane systolic excursion (TAPSE) was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [76] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in tricuspid regurgitation peak velocity from baseline | ||||||||
End point description |
Ttricuspid regurgitation peak velocity was measured by echocardiography.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 24 (plus/minus 5 days)
|
||||||||
|
|||||||||
| Notes [77] - Subjects in SAF with evaluable data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||
End point title |
Taste and texture (Questions 1 to 4) of the oral suspension of Riociguat at Week 0 | ||||||||||||||||||||||||||||||||||||||
End point description |
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Questions 1 to 4 were reported in this endpoint. Questions 1 and 2 were asked before the subjects received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Subjects were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
|
||||||||||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||||||||||
End point timeframe |
At the beginning of the treatment (Week 0)
|
||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||
| Notes [78] - Subjects in SAF with assessment |
|||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||
End point title |
Taste and texture (Questions 1 to 4) the oral suspension of Riociguat at Week 24 | ||||||||||||||||||||||||||||||||||||||
End point description |
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Qusestions 1 to 4 were reported in this endpoint. Questions 1 and 2 were asked before the subjects received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Subjects were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
|
||||||||||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||||||||||
End point timeframe |
Week 24 (plus/minus 5 days)
|
||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||
| Notes [79] - Subjects in SAF with assessment |
|||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Taste and texture (Question 5) of the oral suspension of Riociguat at Week 0 | ||||||||||||||||||
End point description |
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 5 "Taste of the drink" was reported in this endpoint. Question 5 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity".
|
||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||
End point timeframe |
At the beginning of the treatment (Week 0)
|
||||||||||||||||||
|
|||||||||||||||||||
| Notes [80] - Subjects in SAF with assessment |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||||||
End point title |
Taste and texture (Question 5) of the oral suspension of Riociguat at Week 24 | ||||||||||||||||||||||||||||
End point description |
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 5 "Taste of the drink" was reported in this endpoint. Question 5 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity".
|
||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||
End point timeframe |
Week 24 (plus/minus 5 days)
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
| Notes [81] - Subjects in SAF with assessment |
|||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Taste and texture (Question 6) of the oral suspension of Riociguat at Week 0 | ||||||||||||||||
End point description |
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 6 "Drink feels in mouth" was reported in this endpoint. Question 6 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy".
|
||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||
End point timeframe |
At the beginning of the treatment (Week 0)
|
||||||||||||||||
|
|||||||||||||||||
| Notes [82] - Subjects in SAF with assessment |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||
End point title |
Taste and texture (Question 6) of the oral suspension of Riociguat in mouth at Week 24 | ||||||||||||||||||||||||||||
End point description |
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 6 "Drink feels in mouth" was reported in this endpoint. Question 6 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy".
|
||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||
End point timeframe |
Week 24 (plus/minus 5 days)
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
| Notes [83] - Subjects in SAF with assessment |
|||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||
|
|||||||||||||
End point title |
Taste and texture (Question 7) of the oral suspension of Riociguat in mouth at Week 0 | ||||||||||||
End point description |
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 7 "Did you like the taste after swallowing" was reported in this endpoint. Question 7 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
At the beginning of the treatment (Week 0)
|
||||||||||||
|
|||||||||||||
| Notes [84] - Subjects in SAF with assessment |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Taste and texture (Question 7) of the oral suspension of Riociguat in mouth at Week 24 | ||||||||||||
End point description |
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 7 "Did you like the taste after swallowing" was reported in this endpoint. Question 7 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Week 24 (plus/minus 5 days)
|
||||||||||||
|
|||||||||||||
| Notes [85] - Subjects in SAF with assessment |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||
End point title |
Expression assessment on the taste and texture of oral suspension of Riociguat - Week 0 | ||||||||||||||
End point description |
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".
|
||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||
End point timeframe |
At the beginning of the treatment (Week 0)
|
||||||||||||||
|
|||||||||||||||
| Notes [86] - Subjects in SAF with assessment |
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Expression assessment on the taste and texture of oral suspension of Riociguat - Week 24 | ||||||||||||||
End point description |
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".
|
||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||
End point timeframe |
Week 24 (plus/minus 5 days)
|
||||||||||||||
|
|||||||||||||||
| Notes [87] - Subjects in SAF with assessment |
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
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Timeframe for reporting adverse events |
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.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.1
|
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|
Reporting groups
|
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Reporting group title |
Riociguat >=6 to <18 years
|
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Reporting group description |
Subjects with age >=6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 0.5 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 of the dose for safety reasons was allowed at any time. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
24 Nov 2015 |
Amendment 3 introduced the following changes: The wording describing the LTE part of the study was changed (“study” was replaced with “phase” and “optional” was added) to clarify that the subjects can volunteer to participate in the LTE, which is a part of this study. Clarification of primary completion and end of study. Pharmacodynamics was deleted from primary objective. Addition of a safety follow up visit for subjects participating in the LTE phase. |
||
31 May 2016 |
Amendment 5 introduced the following changes: The collection of the following parameters: GGT, UA, T-Bil, Alb, Na, K, Ca, and P at visit 0, 5 and 9 were added for safety reasons. Addition of the statement that all laboratory parameters are recorded to the eCRF when obtained as medically required according to a local package insert of bosentan or medical practice at any time. The collection of RHC parameters in the eCRF was included. The echocardiography parameter of right heart dimensions was introduced in the study and all Echo parameters were listed as main secondary variables. Central reading of the echocardiographic parameters were added. Taste and texture was downgraded from secondary efficacy endpoint to other endpoint. |
||
09 Jan 2017 |
Amendment 6 introduced the following changes: A new exclusion criterion “patients with pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP)” was added. The study population was broadened to include patients treated with PAH medications including ERA (besides bosentan), PCAs or combination of these. Parents and patients questionnaires were added. Exclusion criteria were changed regarding the pretreatment with PDE5 inhibitors. Clarification that pretreatment with PDE5i was allowed but up to 3 three days prior to start of riociguat treatment (Visit 1) was added. BNP was added as an alternative for NT-proBNP. |
||
13 Mar 2018 |
Amendment 9 introduced the following changes: The inclusion of patients with ostium secundum atrial septal defect ≤1 cm without hemodynamic alterations was allowed. The inclusion of patients with patent foramen ovale ≤1 cm was allowed. The definition of “effective” methods was added in inclusion criterion 7. |
||
23 Aug 2019 |
Amendment 12 introduced the following changes: Description of the pregnancy testing (to be performed in 4-weekly intervals starting at Visit 1 until 4 weeks after the patient stopped intake of study drug) in the optional LTE phase was added. The conditions for transitioning into the optional LTE phase was clarified. The dosing recommendation for patients with body weight ≥12 to <14 kg was added. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| 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. | |||
