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    Clinical Trial Results:
    Single-dose, open-label, randomized, 2-way crossover bioequivalence study of 20 mg granules for oral suspension rivaroxaban versus 20 mg tablets rivaroxaban under fed condition in healthy subjects

    Summary
    EudraCT number
    		 2017-000609-18
    Trial protocol
    		 DE  
    Global end of trial date
    27 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Sep 2018
    First version publication date
    06 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY59-7939/19366
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    27 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to establish bioequivalence with respect to area under concentration versus time curve from zero to infinity after single dose administration (AUC), AUC from time zero to the last data point (AUC[0-tlast]) and maximum observed drug concentration (Cmax) of 20 milligrams (mg) granules for oral suspension versus 20 mg tablets rivaroxaban (BAY59-7939, Xarelto) when administered as single oral dose under fed conditions.
    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. 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
    04 Jul 2017
    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: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at one study center in Germany, between 04 July 2017 (first subject first visit) and 04 September 2017 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall, 68 subjects were enrolled, of these 38 subjects were screen failures: 2 subjects withdrew consent, 6 subjects were qualified but not needed and 30 subjects failed screening. A total of 30 subjects were randomized and received at least one dose of rivaroxaban.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment A-B
    Arm description
    		 Subjects received a single oral dose of 20 mg rivaroxaban tablet in the fed state on Day 1 (Treatment A) during treatment period 1; followed by a single oral dose of 20 mg rivaroxaban oral suspension in the fed state on Day 1 (Treatment B) during treatment period 2. A wash-out period of at least 7 days was maintained between the treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    BAY59-7939
    Other name
    Xarelto
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of 20 mg rivaroxaban tablet in the fed state on Day 1 (Treatment A).

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    BAY59-7939
    Other name
    Xarelto
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of 20 mg rivaroxaban oral suspension in the fed state on Day 1 (Treatment B).

    Arm title
    		 Treatment B-A
    Arm description
    		 Subjects received a single oral dose of 20 mg rivaroxaban oral suspension in the fed state on Day 1 (Treatment B) during treatment period 1; followed by a single oral dose of 20 mg rivaroxaban tablet in the fed state on Day 1 (Treatment A) during treatment period 2. A wash-out period of at least 7 days was maintained between the treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    BAY59-7939
    Other name
    Xarelto
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of 20 mg rivaroxaban oral suspension in the fed state on Day 1 (Treatment B).

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    BAY59-7939
    Other name
    Xarelto
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of 20 mg rivaroxaban tablet in the fed state on Day 1 (Treatment A).

    Number of subjects in period 1
    		Treatment A-B Treatment B-A
    Started
    15
    15
    Completed
    14
    14
    Not completed
    1
    1
         Withdrawal by subject
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment A-B
    Reporting group description
    		 Subjects received a single oral dose of 20 mg rivaroxaban tablet in the fed state on Day 1 (Treatment A) during treatment period 1; followed by a single oral dose of 20 mg rivaroxaban oral suspension in the fed state on Day 1 (Treatment B) during treatment period 2. A wash-out period of at least 7 days was maintained between the treatments.

    Reporting group title
    Treatment B-A
    Reporting group description
    		 Subjects received a single oral dose of 20 mg rivaroxaban oral suspension in the fed state on Day 1 (Treatment B) during treatment period 1; followed by a single oral dose of 20 mg rivaroxaban tablet in the fed state on Day 1 (Treatment A) during treatment period 2. A wash-out period of at least 7 days was maintained between the treatments.

    Reporting group values
    		 Treatment A-B Treatment B-A Total
    Number of subjects
    		 15 15 30
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.3 ( 11.2 ) 38.5 ( 12.0 ) -
    Gender Categorical
    Units: Subjects
        Male
    		 15 15 30

    End points

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    End points reporting groups
    Reporting group title
    Treatment A-B
    Reporting group description
    		 Subjects received a single oral dose of 20 mg rivaroxaban tablet in the fed state on Day 1 (Treatment A) during treatment period 1; followed by a single oral dose of 20 mg rivaroxaban oral suspension in the fed state on Day 1 (Treatment B) during treatment period 2. A wash-out period of at least 7 days was maintained between the treatments.

    Reporting group title
    Treatment B-A
    Reporting group description
    		 Subjects received a single oral dose of 20 mg rivaroxaban oral suspension in the fed state on Day 1 (Treatment B) during treatment period 1; followed by a single oral dose of 20 mg rivaroxaban tablet in the fed state on Day 1 (Treatment A) during treatment period 2. A wash-out period of at least 7 days was maintained between the treatments.

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF included all subjects who received at least one dose of the study medication (N=30).

    Subject analysis set title
    Pharmacokinetic Analysis Set (PKS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PKS included all subjects who completed all treatment periods, and for whom valid sets of pharmacokinetic samples were taken (N=28).

    Subject analysis set title
    20 mg Rivaroxaban tablet (Treatment A)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a single oral dose of 20 mg rivaroxaban tablet in the fed state on Day 1 during either of the treatment periods (N=29).

    Subject analysis set title
    20 mg Rivaroxaban oral suspension (Treatment B)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a single oral dose of 20 mg rivaroxaban granules for oral suspension in the fed state on Day 1 during either of the treatment periods (N=30).

    Primary: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma After Single Dose Administration

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    End point title
    		 Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma After Single Dose Administration
    End point description
    Area under the concentration versus time curve from zero to infinity of rivaroxaban in plasma after single dose administration was measured. Geometric mean and geometric coefficient of variation were reported.
    End point type
    Primary
    End point timeframe
    pre dose (0 hour) up to 72 hours post dose
    End point values
    		 20 mg Rivaroxaban tablet (Treatment A) 20 mg Rivaroxaban oral suspension (Treatment B)
    Number of subjects analysed
    28 [1]
    28 [2]
    Units: microgram*hour per liter (mcg*h/L)
        geometric mean (geometric coefficient of variation)
    2600 ( 28.7 )
    2560 ( 30.5 )
    Notes
    [1] - PKS
    [2] - PKS
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Logarithms of AUC were analyzed using analysis of variance (ANOVA) including sequence, subject (sequence), period, and treatment effects. Based on these analyses point estimates (Least squares [LS] mean) and 90% confidence intervals (CIs) for the treatment ratio: 20 mg granules for oral suspension/tablet were calculated by re- transformation of the logarithmic results given by the ANOVA. Database auto-calculates total number of subjects erroneously, analyzed number of subjects was 28.
    Comparison groups
    20 mg Rivaroxaban oral suspension (Treatment B) v 20 mg Rivaroxaban tablet (Treatment A)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean
    Point estimate
    0.9843
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9433
         upper limit
    		 1.0271

    Primary: Area Under the Concentration Versus Time Curve From Time Zero to the Last Data Point Greater Than (>) Lower Limit Of Quantification (LLOQ) (AUC[0-tlast]) of Rivaroxaban in Plasma After Single Dose Administration

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    End point title
    		 Area Under the Concentration Versus Time Curve From Time Zero to the Last Data Point Greater Than (>) Lower Limit Of Quantification (LLOQ) (AUC[0-tlast]) of Rivaroxaban in Plasma After Single Dose Administration
    End point description
    Area under the concentration versus time curve from time zero to the last data point greater than (>) lower limit of quantification of rivaroxaban in plasma after single dose administration was measured. Geometric mean and percentage geometric coefficient of variation were reported.
    End point type
    Primary
    End point timeframe
    pre dose (0 hour) up to 72 hours post dose
    End point values
    		 20 mg Rivaroxaban tablet (Treatment A) 20 mg Rivaroxaban oral suspension (Treatment B)
    Number of subjects analysed
    28 [3]
    28 [4]
    Units: microgram*hour per liter (mcg*h/L)
        geometric mean (geometric coefficient of variation)
    2570 ( 28.6 )
    2540 ( 30.6 )
    Notes
    [3] - PKS
    [4] - PKS
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Logarithms of AUC(0-tlast) were analyzed using ANOVA including sequence, subject (sequence), period, and treatment effects. Based on these analyses point estimates (LS mean) and 90 % CIs for the treatment ratio: 20 mg granules for oral suspension/tablet were calculated by re- transformation of the logarithmic results given by the ANOVA. Database auto-calculates total number of subjects erroneously, analyzed number of subjects was 28.
    Comparison groups
    20 mg Rivaroxaban oral suspension (Treatment B) v 20 mg Rivaroxaban tablet (Treatment A)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean
    Point estimate
    0.9869
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.946
         upper limit
    		 1.0295

    Primary: Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma After Single Dose Administration

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    End point title
    		 Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma After Single Dose Administration
    End point description
    Maximum observed drug concentration of rivaroxaban in plasma after single dose administration was measured. Geometric mean and geometric coefficient of variation were reported.
    End point type
    Primary
    End point timeframe
    pre dose (0 hour) up to 72 hours post dose
    End point values
    		 20 mg Rivaroxaban tablet (Treatment A) 20 mg Rivaroxaban oral suspension (Treatment B)
    Number of subjects analysed
    28 [5]
    28 [6]
    Units: microgram per liter (mcg/L)
        geometric mean (geometric coefficient of variation)
    343 ( 27.1 )
    302 ( 24.0 )
    Notes
    [5] - PKS
    [6] - PKS
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Logarithms of Cmax were analyzed using ANOVA including sequence, subject (sequence), period, and treatment effects. Based on these analyses point estimates (LS mean) and 90% CIs for the treatment ratio: 20 mg granules for oral suspension/tablet were calculated by re- transformation of the logarithmic results given by the ANOVA. Database auto-calculates total number of subjects erroneously, analyzed number of subjects was 28.
    Comparison groups
    20 mg Rivaroxaban oral suspension (Treatment B) v 20 mg Rivaroxaban tablet (Treatment A)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean
    Point estimate
    0.8822
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8146
         upper limit
    		 0.9554

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. AEs that started or worsened after first administration of study medication up to 14 days after end of treatment with study medication were considered to be treatment emergent (TE).
    End point type
    Secondary
    End point timeframe
    from start of study drug administration up to 14 days after last study drug administration
    End point values
    		 20 mg Rivaroxaban tablet (Treatment A) 20 mg Rivaroxaban oral suspension (Treatment B)
    Number of subjects analysed
    29 [7]
    30 [8]
    Units: count of subjects
    5
    2
    Notes
    [7] - SAF with evaluable number of subjects for this specific end point
    [8] - SAF
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from start of study drug administration until 14 days after the last study drug administration
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    20 mg Rivaroxaban oral suspension
    Reporting group description
    		 Subjects received a single oral dose of 20 mg rivaroxaban granules for oral suspension in the fed state on Day 1 during either of the treatment periods.

    Reporting group title
    20 mg Rivaroxaban tablet
    Reporting group description
    		 Subjects received a single oral dose of 20 mg rivaroxaban tablet in the fed state on Day 1 during either of the treatment periods.

    Serious adverse events
    		 20 mg Rivaroxaban oral suspension 20 mg Rivaroxaban tablet
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 20 mg Rivaroxaban oral suspension 20 mg Rivaroxaban tablet
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 30 (6.67%)
    5 / 29 (17.24%)
    Investigations
    Lipase increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Vascular access site haematoma
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Infections and infestations
    Otitis media
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences all number
    1
    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. Decimal places were automatically truncated if last decimals is equals to 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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