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    Clinical Trial Results:
    Relative bioavailability and food effect study of two oral liquid formulations in comparison to a 1 mg tablet of riociguat to characterize its pharmacokinetic properties in healthy male and female adult subjects in a randomized, open label, 5 fold crossover design

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2011-001893-24
    Trial protocol
    		 DE  
    Global end of trial date
    21 May 2012

    Results information
    Results version number
    		 v2(current)
    This version publication date
    24 Jul 2016
    First version publication date
    05 Jul 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Review of results set after re-introduction of EudraCT

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY63-2521/14986
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01489488
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, D-51368, Germany,
    Public contact
    Bayer Clinical Trials Contact, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Bayer Clinical Trials Contact, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000718-PIP01-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 May 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study were to determine the oral bioavailability of the liquid formulations intended for pediatric use and any potential food effects in healthy adults.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representative. Participating subjects 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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jan 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    32
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at a single study center in Germany in healthy adult subjects between 09 January 2012 (first subject first visit) and 03 April 2012 (last subject last visit).

    Pre-assignment
    Screening details
    		 Out of a total of 32 randomized subjects, 30 subjects were treated with five riociguat doses, once in a crossover fashion during the respective intervention periods (1st, 2nd, 3rd, 4th, and 5th). The reasons for 2 ‘randomized but not treated’ subjects: one subject withdrew consent and the other revealed protocol violation.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment sequence A-B-C-D-E
    Arm description
    		 Single oral dose of 2.4 milligram (mg) riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg per milliliter [mg/mL], i.e. 16 mL) under fasting conditions (Treatment A) in the 1st intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL) under fed conditions (Treatment B) in the 2nd intervention period; followed by a single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL) under fasting conditions (Treatment C) in the 3rd intervention period; followed by single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL) under fasting conditions (Treatment D) in the 4th intervention period; and then single oral dose of riociguat immediate release (IR) tablet 1 mg under fasting conditions (Treatment E) in the 5th intervention period. A wash-out phase of at least 5 days was maintained between treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Suspension and effervescent granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment A: Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions. Treatment B: Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions. Treatment C: Single oral dose of 0.3 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions. Treatment D: Single oral dose of 0.15 mg riociguat (BAY63-2521) as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions.

    Investigational medicinal product name
    Riociguat, IR Tablet
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment E: Single oral dose of riociguat (BAY63-2521) IR tablet 1 mg, under fasting conditions.

    Arm title
    		 Treatment sequence B-C-E-A-D
    Arm description
    		 Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the first intervention period; followed by single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the second intervention period; followed by single oral dose of riociguat IR tablet 1 mg, under fasting conditions (Treatment E) in the third intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the fourth intervention period; and then single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat, IR Tablet
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment E: Single oral dose of riociguat (BAY63-2521) IR tablet 1 mg, under fasting conditions.

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Suspension and effervescent granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment A: Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions. Treatment B: Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions. Treatment C: Single oral dose of 0.3 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions. Treatment D: Single oral dose of 0.15 mg riociguat (BAY63-2521) as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions.

    Arm title
    		 Treatment sequence C-E-D-B-A
    Arm description
    		 Single oral dose of 0.3 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the first intervention period; followed by single oral dose of riociguat IR tablet 1 mg, under fasting conditions (Treatment E) in the second intervention period; followed by single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the third intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the fourth intervention period; and then single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Suspension and effervescent granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment A: Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions. Treatment B: Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions. Treatment C: Single oral dose of 0.3 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions. Treatment D: Single oral dose of 0.15 mg riociguat (BAY63-2521) as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions.

    Investigational medicinal product name
    Riociguat, IR Tablet
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment E: Single oral dose of riociguat (BAY63-2521) IR tablet 1 mg, under fasting conditions.

    Arm title
    		 Treatment sequence D-A-B-E-C
    Arm description
    		 Single oral dose of 0.15 mg riociguat (BAY63-2521) as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the first intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the second intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the third intervention period; followed by single oral dose of riociguat IR tablet 1 mg, under fasting conditions (Treatment E) in the fourth intervention period; and then single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Suspension and effervescent granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment A: Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions. Treatment B: Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions. Treatment C: Single oral dose of 0.3 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions. Treatment D: Single oral dose of 0.15 mg riociguat (BAY63-2521) as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions.

    Investigational medicinal product name
    Riociguat, IR Tablet
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment E: Single oral dose of riociguat (BAY63-2521) IR tablet 1 mg, under fasting conditions.

    Arm title
    		 Treatment sequence E-D-A-C-B
    Arm description
    		 Single oral dose of riociguat (BAY63-2521) IR tablet 1 mg, under fasting conditions (Treatment E) in the first intervention period; followed by single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the second intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the third intervention period; followed by single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the fourth intervention period; and then single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat, IR Tablet
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment E: Single oral dose of riociguat (BAY63-2521) IR tablet 1 mg, under fasting conditions.

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Suspension and effervescent granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment A: Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions. Treatment B: Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions. Treatment C: Single oral dose of 0.3 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions. Treatment D: Single oral dose of 0.15 mg riociguat (BAY63-2521) as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions.

    Number of subjects in period 1 [1]
    		Treatment sequence A-B-C-D-E Treatment sequence B-C-E-A-D Treatment sequence C-E-D-B-A Treatment sequence D-A-B-E-C Treatment sequence E-D-A-C-B
    Started
    6
    6
    6
    6
    6
    Received all 5 treatments
    6
    6
    6
    6
    6
    Completed
    6
    6
    6
    6
    6
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: All enrolled subjects were not treated with study drugs. As baseline included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment sequence A-B-C-D-E
    Reporting group description
    		 Single oral dose of 2.4 milligram (mg) riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg per milliliter [mg/mL], i.e. 16 mL) under fasting conditions (Treatment A) in the 1st intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL) under fed conditions (Treatment B) in the 2nd intervention period; followed by a single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL) under fasting conditions (Treatment C) in the 3rd intervention period; followed by single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL) under fasting conditions (Treatment D) in the 4th intervention period; and then single oral dose of riociguat immediate release (IR) tablet 1 mg under fasting conditions (Treatment E) in the 5th intervention period. A wash-out phase of at least 5 days was maintained between treatments.

    Reporting group title
    Treatment sequence B-C-E-A-D
    Reporting group description
    		 Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the first intervention period; followed by single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the second intervention period; followed by single oral dose of riociguat IR tablet 1 mg, under fasting conditions (Treatment E) in the third intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the fourth intervention period; and then single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.

    Reporting group title
    Treatment sequence C-E-D-B-A
    Reporting group description
    		 Single oral dose of 0.3 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the first intervention period; followed by single oral dose of riociguat IR tablet 1 mg, under fasting conditions (Treatment E) in the second intervention period; followed by single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the third intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the fourth intervention period; and then single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.

    Reporting group title
    Treatment sequence D-A-B-E-C
    Reporting group description
    		 Single oral dose of 0.15 mg riociguat (BAY63-2521) as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the first intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the second intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the third intervention period; followed by single oral dose of riociguat IR tablet 1 mg, under fasting conditions (Treatment E) in the fourth intervention period; and then single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.

    Reporting group title
    Treatment sequence E-D-A-C-B
    Reporting group description
    		 Single oral dose of riociguat (BAY63-2521) IR tablet 1 mg, under fasting conditions (Treatment E) in the first intervention period; followed by single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the second intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the third intervention period; followed by single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the fourth intervention period; and then single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.

    Reporting group values
    		 Treatment sequence A-B-C-D-E Treatment sequence B-C-E-A-D Treatment sequence C-E-D-B-A Treatment sequence D-A-B-E-C Treatment sequence E-D-A-C-B Total
    Number of subjects
    		 6 6 6 6 6 30
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.5 ( 6.1 ) 34.5 ( 7.1 ) 30.2 ( 5 ) 31.2 ( 5 ) 30.5 ( 8.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 3 3 3 3 15
        Male
    		 3 3 3 3 3 15

    End points

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    End points reporting groups
    Reporting group title
    Treatment sequence A-B-C-D-E
    Reporting group description
    		 Single oral dose of 2.4 milligram (mg) riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg per milliliter [mg/mL], i.e. 16 mL) under fasting conditions (Treatment A) in the 1st intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL) under fed conditions (Treatment B) in the 2nd intervention period; followed by a single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL) under fasting conditions (Treatment C) in the 3rd intervention period; followed by single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL) under fasting conditions (Treatment D) in the 4th intervention period; and then single oral dose of riociguat immediate release (IR) tablet 1 mg under fasting conditions (Treatment E) in the 5th intervention period. A wash-out phase of at least 5 days was maintained between treatments.

    Reporting group title
    Treatment sequence B-C-E-A-D
    Reporting group description
    		 Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the first intervention period; followed by single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the second intervention period; followed by single oral dose of riociguat IR tablet 1 mg, under fasting conditions (Treatment E) in the third intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the fourth intervention period; and then single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.

    Reporting group title
    Treatment sequence C-E-D-B-A
    Reporting group description
    		 Single oral dose of 0.3 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the first intervention period; followed by single oral dose of riociguat IR tablet 1 mg, under fasting conditions (Treatment E) in the second intervention period; followed by single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the third intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the fourth intervention period; and then single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.

    Reporting group title
    Treatment sequence D-A-B-E-C
    Reporting group description
    		 Single oral dose of 0.15 mg riociguat (BAY63-2521) as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the first intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the second intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the third intervention period; followed by single oral dose of riociguat IR tablet 1 mg, under fasting conditions (Treatment E) in the fourth intervention period; and then single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.

    Reporting group title
    Treatment sequence E-D-A-C-B
    Reporting group description
    		 Single oral dose of riociguat (BAY63-2521) IR tablet 1 mg, under fasting conditions (Treatment E) in the first intervention period; followed by single oral dose of 0.15 mg riociguat as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions (Treatment D) in the second intervention period; followed by single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions (Treatment A) in the third intervention period; followed by single oral dose of 0.3 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions (Treatment C) in the fourth intervention period; and then single oral dose of 2.4 mg riociguat as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions (Treatment B) in the fifth intervention period. A wash-out phase of at least 5 days was maintained between treatments.

    Subject analysis set title
    Riociguat (BAY63-2521) 2.4 mg suspension, fasted
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions in any intervention period.

    Subject analysis set title
    Riociguat (BAY63-2521) 2.4 mg suspension, fed
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions in any intervention period.

    Subject analysis set title
    Riociguat (BAY63-2521) 0.3 mg suspension, fasted
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single oral dose of 0.3 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions in any intervention period.

    Subject analysis set title
    Riociguat (BAY63-2521) 0.15 mg suspension, fasted
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single oral dose of 0.15 mg riociguat (BAY63-2521) as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions in any intervention period.

    Subject analysis set title
    Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Single oral dose of riociguat (BAY63-2521) IR tablet 1 mg, under fasting conditions in any intervention period.

    Subject analysis set title
    Pharmacokinetic (PK) analysis set (PKS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PKS included all subjects who completed all five periods of this trial with at least one valid PK profile.

    Primary: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose [1]
    End point description
    AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC is defined as area under concentration versus time curve from time 0 (pre-dose) to extrapolated infinite time. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Primary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [2]
    29 [3]
    29 [4]
    29 [5]
    29 [6]
    Units: microgram*hour per liter (mcg*h/L)
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 27, 25, 29)
    780.599 ( 48.68 )
    662.469 ( 45.03 )
    91.005 ( 43.4 )
    46.828 ( 59.49 )
    311.162 ( 46.41 )
        Analyte M1 (BAY60-4552) (N=29, 28, 16, 8, 29)
    555.013 ( 38.14 )
    513.447 ( 40.62 )
    77.78 ( 39.39 )
    45.735 ( 22 )
    237.386 ( 31.93 )
    Notes
    [2] - PKS
    [3] - PKS
    [4] - PKS
    [5] - PKS
    [6] - PKS
    No statistical analyses for this end point

    Primary: Maximum Observed Drug Concentration (Cmax) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Maximum Observed Drug Concentration (Cmax) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose [7]
    End point description
    Cmax refers to the highest measured drug concentration which is obtained by collecting a series of plasma samples and measuring the concentrations of drug in each sample. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Primary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [8]
    29 [9]
    29 [10]
    29 [11]
    29 [12]
    Units: microgram(s)/liter
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 29, 29, 29)
    78.0386 ( 31.3 )
    48.3776 ( 22.4 )
    9.7814 ( 32.93 )
    4.9024 ( 34.99 )
    35.8421 ( 29.55 )
        Analyte M1 (BAY60-4552) (N=29, 29, 29, 28, 29)
    19.44999 ( 42.64 )
    17.32912 ( 59.29 )
    2.37407 ( 53.44 )
    1.41143 ( 42.54 )
    8.90839 ( 48.75 )
    Notes
    [8] - PKS
    [9] - PKS
    [10] - PKS
    [11] - PKS
    [12] - PKS
    No statistical analyses for this end point

    Primary: Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose [13]
    End point description
    Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Primary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    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: EudraCT format does autoaddition of number of subjects analysed while reporting an explorative analysis of two treatment groups. Due to this format constrains, we have uploaded charts with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [14]
    29 [15]
    29 [16]
    29 [17]
    29 [18]
    Units: hour per liter
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 27, 25, 29)
    0.32525 ( 48.68 )
    0.276029 ( 45.03 )
    0.303351 ( 43.4 )
    0.312185 ( 59.49 )
    0.311162 ( 46.41 )
        Analyte M1 (BAY60-4552) (N=29, 28, 16, 8, 29)
    0.239183 ( 38.14 )
    0.22127 ( 40.62 )
    0.268155 ( 39.39 )
    0.315351 ( 22 )
    0.245524 ( 31.93 )
    Attachments
    		 AUC by D_Analyte_Statistical Analysis
    AUC by D_Riociguat_Statistical Analysis
    Notes
    [14] - PKS
    [15] - PKS
    [16] - PKS
    [17] - PKS
    [18] - PKS
    No statistical analyses for this end point

    Primary: Maximum Observed Drug Concentration Adjusted by Dose (Cmax/D) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Maximum Observed Drug Concentration Adjusted by Dose (Cmax/D) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose [19]
    End point description
    Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Primary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    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: EudraCT format does autoaddition of number of subjects analysed while reporting an explorative analysis of two treatment groups. Due to this format constrains, we have uploaded charts with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [20]
    29 [21]
    29 [22]
    29 [23]
    29 [24]
    Units: 1 per liter
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 29, 29, 29)
    0.032516 ( 31.3 )
    0.020157 ( 22.4 )
    0.032605 ( 32.93 )
    0.032683 ( 34.99 )
    0.035842 ( 29.55 )
        Analyte M1 (BAY60-4552) (N=29, 29, 29, 28, 29)
    0.008382 ( 42.64 )
    0.007468 ( 59.29 )
    0.008184 ( 53.44 )
    0.009732 ( 42.54 )
    0.009213 ( 48.75 )
    Attachments
    		 Cmax by D_Riociguat_Statistical Analysis
    Cmax by D_Analyte_Statistical analysis
    Notes
    [20] - PKS
    [21] - PKS
    [22] - PKS
    [23] - PKS
    [24] - PKS
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose per Kilogram Body Weight (AUC,norm) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose per Kilogram Body Weight (AUC,norm) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose
    End point description
    AUC is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption. AUCnorm is defined as AUC divided by dose per kg body weight. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Secondary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [25]
    29 [26]
    29 [27]
    29 [28]
    29 [29]
    Units: kilogram*hour per liter
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 27, 25, 29)
    21.9493 ( 52.4 )
    18.6276 ( 50.07 )
    20.73 ( 43.8 )
    20.9657 ( 58.75 )
    20.9986 ( 49.46 )
        Analyte M1 (BAy60-4552) (N=29, 28, 16, 8, 29)
    16.1411 ( 39.5 )
    14.8904 ( 37.9 )
    18.1793 ( 42.16 )
    20.4818 ( 22.27 )
    16.569 ( 33.11 )
    Notes
    [25] - PKS
    [26] - PKS
    [27] - PKS
    [28] - PKS
    [29] - PKS
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration Divided by Dose per Kilogram Body Weight (Cmax,norm) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Maximum Observed Plasma Concentration Divided by Dose per Kilogram Body Weight (Cmax,norm) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose
    End point description
    Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Cmax,norm is defined as Cmax divided by dose per kg body weight. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Secondary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [30]
    29 [31]
    29 [32]
    29 [33]
    29 [34]
    Units: kilogram per liter
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 29, 29, 29)
    2.19433 ( 31.33 )
    1.36031 ( 25.26 )
    2.2003 ( 29.91 )
    2.20556 ( 32.23 )
    2.41878 ( 28.06 )
        Analyte M1 (BAY60-4552) (N=29, 29, 29, 28, 29)
    0.56565 ( 38.01 )
    0.50397 ( 51.69 )
    0.55235 ( 48.93 )
    0.65492 ( 38.01 )
    0.62179 ( 43.25 )
    Notes
    [30] - PKS
    [31] - PKS
    [32] - PKS
    [33] - PKS
    [34] - PKS
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Drug Concentration in Plasma (tmax) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Time to Reach Maximum Drug Concentration in Plasma (tmax) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose
    End point description
    tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Secondary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [35]
    29 [36]
    29 [37]
    29 [38]
    29 [39]
    Units: hour
    median (full range (min-max))
        Riociguat (BAY63-2521) (N=29, 29, 29, 29, 29)
    1.5 (0.75 to 4)
    4 (3 to 12)
    1 (0.5 to 3)
    1 (0.5 to 4)
    1 (0.5 to 3)
        Analyte M1 (BAY60-4552) (N=29, 29, 29, 28, 29)
    12 (4 to 36)
    12 (4 to 24)
    12 (2 to 12.017)
    8 (2 to 12)
    12 (3 to 15)
    Notes
    [35] - PKS
    [36] - PKS
    [37] - PKS
    [38] - PKS
    [39] - PKS
    No statistical analyses for this end point

    Secondary: Terminal Half Life (t1/2) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Terminal Half Life (t1/2) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose
    End point description
    Half life associated with terminal slope refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in hours and derived from the terminal slope of the concentration versus time curve.Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Secondary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [40]
    29 [41]
    29 [42]
    29 [43]
    29 [44]
    Units: hour
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 27, 25, 29)
    9.1937 ( 41.09 )
    9.4197 ( 33.18 )
    7.8429 ( 39.25 )
    6.8434 ( 42.31 )
    7.9115 ( 43.17 )
        Analyte M1 (BAY60-4552) (N=29, 28, 16, 8, 29)
    14.5067 ( 25.81 )
    15.3798 ( 25.5 )
    16.6117 ( 36.58 )
    11.9893 ( 37.4 )
    14.4817 ( 33.58 )
    Notes
    [40] - PKS
    [41] - PKS
    [42] - PKS
    [43] - PKS
    [44] - PKS
    No statistical analyses for this end point

    Secondary: Mean Residence Time (MRT) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Mean Residence Time (MRT) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose
    End point description
    MRT is an average duration of the drug in the body, and is expressed in hours. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Secondary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [45]
    29 [46]
    29 [47]
    29 [48]
    29 [49]
    Units: hour
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 27, 25, 29)
    11.2926 ( 33.77 )
    13.3653 ( 30.97 )
    10.801 ( 32.53 )
    10.1044 ( 36.81 )
    10.3793 ( 37.6 )
        Analyte M1 (BAY60-4552) (N=29, 28, 16, 8, 29)
    26.426 ( 21.97 )
    28.752 ( 23.5 )
    27 ( 30.79 )
    21.019 ( 34.53 )
    25.791 ( 30.32 )
    Notes
    [45] - PKS
    [46] - PKS
    [47] - PKS
    [48] - PKS
    [49] - PKS
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose
    End point description
    AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-tlast) is defined as AUC from time zero to the last data point above the lower limit of quantification. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Secondary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [50]
    29 [51]
    29 [52]
    29 [53]
    29 [54]
    Units: mcg*h/L
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 29, 29, 29)
    767.0408 ( 48.98 )
    648.7076 ( 45.5 )
    81.6691 ( 45.56 )
    36.3776 ( 64.66 )
    298.7707 ( 47.65 )
        Analyte M1 (BAY60-4552) (N=29, 29, 29, 28, 29)
    524.0023 ( 38.21 )
    481.743 ( 40.72 )
    44.9594 ( 60.75 )
    18.7457 ( 76.77 )
    210.8965 ( 36.71 )
    Notes
    [50] - PKS
    [51] - PKS
    [52] - PKS
    [53] - PKS
    [54] - PKS
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration Divided by Dose per Kilogram Body Weight (AUC[0-tlast]norm) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration Divided by Dose per Kilogram Body Weight (AUC[0-tlast]norm) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose
    End point description
    AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-tlast),norm is defined as AUC from time zero to the last data point above the lower limit of quantification divided by dose per kg body weight. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Secondary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [55]
    29 [56]
    29 [57]
    29 [58]
    29 [59]
    Units: kilogram*hour per liter
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 29, 29, 29)
    21.568 ( 52.6 )
    18.2407 ( 50.5 )
    18.3713 ( 45.82 )
    16.3661 ( 66.1 )
    20.1623 ( 50.4 )
        Analyte M1 (BAY60-4552) (N=29, 29, 29, 28, 29)
    15.2392 ( 39.21 )
    14.0102 ( 37.87 )
    10.4602 ( 60.64 )
    8.6983 ( 74.02 )
    14.7201 ( 36.54 )
    Notes
    [55] - PKS
    [56] - PKS
    [57] - PKS
    [58] - PKS
    [59] - PKS
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration Divided by Dose (AUC[0-tlast]/D) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose

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    End point title
    		 Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration Divided by Dose (AUC[0-tlast]/D) of Riociguat and its Analyte M1 (BAY60-4552) After a Single Dose
    End point description
    AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-tlast)/D is defined as AUC from time zero to the last data point above the lower limit of quantification divided by dose. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In below table, "n" signifies the number of subjects that were evaluable in specified category of each group.
    End point type
    Secondary
    End point timeframe
    0 hour (pre-dose), 15, 30, 45 minutes; 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours post-dose
    End point values
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Number of subjects analysed
    29 [60]
    29 [61]
    29 [62]
    29 [63]
    29 [64]
    Units: hour per liter
    geometric mean (geometric coefficient of variation)
        Riociguat (BAY63-2521) (N=29, 29, 29, 29, 29)
    0.3196 ( 48.98 )
    0.270295 ( 45.5 )
    0.27223 ( 45.56 )
    0.242517 ( 64.66 )
    0.298771 ( 47.65 )
        Analyte M1 (BAY60-4552) (N=29, 29, 29, 28, 29)
    0.225819 ( 38.21 )
    0.207607 ( 40.72 )
    0.155002 ( 60.75 )
    0.129255 ( 76.77 )
    0.218126 ( 36.71 )
    Notes
    [60] - PKS
    [61] - PKS
    [62] - PKS
    [63] - PKS
    [64] - PKS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of informed consent signed until last follow-up visit
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Riociguat (BAY63-2521) 2.4 mg suspension, fasted
    Reporting group description
    		 Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fasting conditions in any intervention period.

    Reporting group title
    Riociguat (BAY63-2521) 2.4 mg suspension, fed
    Reporting group description
    		 Single oral dose of 2.4 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 16 mL), under fed conditions in any intervention period.

    Reporting group title
    Riociguat (BAY63-2521) 0.3 mg suspension, fasted
    Reporting group description
    		 Single oral dose of 0.3 mg riociguat (BAY63-2521) as pediatric high-concentration suspension (0.15 mg/mL, i.e. 2 mL), under fasting conditions in any intervention period.

    Reporting group title
    Riociguat (BAY63-2521) 0.15 mg suspension, fasted
    Reporting group description
    		 Single oral dose of 0.15 mg riociguat (BAY63-2521) as pediatric low-concentration suspension (0.03 mg/mL, i.e. 5 mL), under fasting conditions in any intervention period.

    Reporting group title
    Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Reporting group description
    		 Single oral dose of riociguat (BAY63-2521) IR tablet 1 mg, under fasting conditions in any intervention period.

    Serious adverse events
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Riociguat (BAY63-2521) 2.4 mg suspension, fasted Riociguat (BAY63-2521) 2.4 mg suspension, fed Riociguat (BAY63-2521) 0.3 mg suspension, fasted Riociguat (BAY63-2521) 0.15 mg suspension, fasted Riociguat (BAY63-2521) 1 mg IR tablet, fasted
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 30 (66.67%)
    19 / 30 (63.33%)
    18 / 30 (60.00%)
    17 / 30 (56.67%)
    17 / 30 (56.67%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Asthenia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Discomfort
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    3 / 30 (10.00%)
    3 / 30 (10.00%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    4 / 30 (13.33%)
         occurrences all number
    3
    3
    3
    2
    4
    Feeling hot
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Catheter site pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nasal obstruction
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    2
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    2
    3
    1
    1
    1
    Headache
         subjects affected / exposed
    14 / 30 (46.67%)
    14 / 30 (46.67%)
    14 / 30 (46.67%)
    10 / 30 (33.33%)
    10 / 30 (33.33%)
         occurrences all number
    16
    16
    18
    12
    11
    Sinus headache
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    5
    2
    0
    0
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    0
    2
    Erythema of eyelid
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Gingival bleeding
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    4
    1
    1
    1
    0
    Toothache
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Occurrence of "±” in relation with geometric CV(%) is auto-generated and cannot be deleted. Decimal places were automatically truncated if last decimal equals zero.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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