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    Clinical Trial Results:
    Multicenter, single-blind, adaptive dose finding study of single intravenous injections of BAY 1747846 with corresponding blinded read in adult participants with known or highly suspected CNS lesions referred for contrast-enhanced MRI of the CNS

    Summary
    EudraCT number
    		 2019-001560-30
    Trial protocol
    		 DE   BG  
    Global end of trial date
    14 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Dec 2023
    First version publication date
    25 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1747846/20241
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04307186
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, +49 30 300139003, 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
    14 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To identify a dose of gadoquatrane for further development that has an overall diagnostic preference rate similar to that of the comparator gadobutrol at 5 min post injection.
    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
    18 Nov 2020
    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
    Bulgaria: 9
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Japan: 22
    Country: Number of subjects enrolled
    United States: 13
    Worldwide total number of subjects
    57
    EEA total number of subjects
    22
    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)
    39
    From 65 to 84 years
    16
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 17 study centers in 4 countries between 18-Nov-2020 (first subject first visit) and 6-Sep-2022 (last subject last visit).

    Pre-assignment
    Screening details
    		 Of the 62 screened subjects 5 were screening failures, resulting in 57 subjects assigned to treatment who started with gadobutrol.

    Period 1
    Period 1 title
    Period 1 - Gadobutrol
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Gadobutrol + Gadoquatrane
    Arm description
    		 Subjects received one intravenous (IV) injection of gadobutrol 0.1 millimole(s) gadolinium/kilogram body weight (mmol Gd/kg bw) during treatment Period 1 and one IV injection of gadoquatrane (BAY1747846) 0.04 mmol Gd/kg bw during treatment Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadoquatrane
    Investigational medicinal product code
    BAY1747846
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Solution for IV injection, 0.04 mmol Gd/kg bw

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    Other name
    Gadovist/Gadavist
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Solution for IV injection, 0.1 mmol Gd/kg bw

    Number of subjects in period 1
    		Gadobutrol + Gadoquatrane
    Started
    57
    Completed
    56
    Not completed
    1
         Consent withdrawn by subject
    1
    Period 2
    Period 2 title
    Washout 3-14 days
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Gadobutrol + Gadoquatrane
    Arm description
    		 Subjects received one intravenous (IV) injection of gadobutrol 0.1 millimole(s) gadolinium/kilogram body weight (mmol Gd/kg bw) during treatment Period 1 and one IV injection of gadoquatrane (BAY1747846) 0.04 mmol Gd/kg bw during treatment Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    Other name
    Gadovist/Gadavist
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Solution for IV injection, 0.1 mmol Gd/kg bw

    Investigational medicinal product name
    Gadoquatrane
    Investigational medicinal product code
    BAY1747846
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Solution for IV injection, 0.04 mmol Gd/kg bw

    Number of subjects in period 2
    		Gadobutrol + Gadoquatrane
    Started
    56
    Completed
    53
    Not completed
    3
         Consent withdrawn by subject
    1
         Pre-specified withdrawal criterion met
    1
         Progressive disease
    1
    Period 3
    Period 3 title
    Period 2 - Gadoquatrane
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Gadobutrol + Gadoquatrane
    Arm description
    		 Subjects received one intravenous (IV) injection of gadobutrol 0.1 millimole(s) gadolinium/kilogram body weight (mmol Gd/kg bw) during treatment Period 1 and one IV injection of gadoquatrane (BAY1747846) 0.04 mmol Gd/kg bw during treatment Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    Other name
    Gadovist/Gadavist
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Solution for IV injection, 0.1 mmol Gd/kg bw

    Investigational medicinal product name
    Gadoquatrane
    Investigational medicinal product code
    BAY1747846
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Solution for IV injection, 0.04 mmol Gd/kg bw

    Number of subjects in period 3
    		Gadobutrol + Gadoquatrane
    Started
    53
    Completed
    52
    Not completed
    1
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gadobutrol + Gadoquatrane
    Reporting group description
    		 Subjects received one intravenous (IV) injection of gadobutrol 0.1 millimole(s) gadolinium/kilogram body weight (mmol Gd/kg bw) during treatment Period 1 and one IV injection of gadoquatrane (BAY1747846) 0.04 mmol Gd/kg bw during treatment Period 2.

    Reporting group values
    		 Gadobutrol + Gadoquatrane Total
    Number of subjects
    		 57 57
    Age Categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 39 39
        From 65-84 years
    		 16 16
        85 years and over
    		 2 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.9 ( 13.6 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 34 34
        Male
    		 23 23
    Race
    Units: Subjects
        Asian
    		 23 23
        Black or African American
    		 1 1
        White
    		 32 32
        More than one race
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Gadobutrol + Gadoquatrane
    Reporting group description
    		 Subjects received one intravenous (IV) injection of gadobutrol 0.1 millimole(s) gadolinium/kilogram body weight (mmol Gd/kg bw) during treatment Period 1 and one IV injection of gadoquatrane (BAY1747846) 0.04 mmol Gd/kg bw during treatment Period 2.
    Reporting group title
    Gadobutrol + Gadoquatrane
    Reporting group description
    		 Subjects received one intravenous (IV) injection of gadobutrol 0.1 millimole(s) gadolinium/kilogram body weight (mmol Gd/kg bw) during treatment Period 1 and one IV injection of gadoquatrane (BAY1747846) 0.04 mmol Gd/kg bw during treatment Period 2.
    Reporting group title
    Gadobutrol + Gadoquatrane
    Reporting group description
    		 Subjects received one intravenous (IV) injection of gadobutrol 0.1 millimole(s) gadolinium/kilogram body weight (mmol Gd/kg bw) during treatment Period 1 and one IV injection of gadoquatrane (BAY1747846) 0.04 mmol Gd/kg bw during treatment Period 2.

    Subject analysis set title
    Gadobutrol post-contrast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    MR images were taken 5 min after receiving IV injection of gadobutrol.

    Subject analysis set title
    Gadoquatrane post-contrast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    MR images were taken 5 min after receiving IV injection of gadoquatrane.

    Subject analysis set title
    Gadobutrol pre-contrast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    MR images were taken before receiving IV injection of gadobutrol.

    Subject analysis set title
    Gadobutrol combined pre- and post-contrast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Evaluation of the combined MR image sets taken before and 5 min after receiving IV injection of gadobutrol.

    Subject analysis set title
    Gadoquatrane pre-contrast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    MR images were taken before receiving IV injection of gadoquatrane.

    Subject analysis set title
    Gadoquatrane combined pre- and post-contrast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Evaluation of the combined MR image sets taken before and 5 min after receiving IV injection of gadoquatrane.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who have completed magnetic resonance (MR) image datasets that qualify for blinded read.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received any dose of study intervention

    Primary: Overall diagnostic preference

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    End point title
    		 Overall diagnostic preference [1]
    End point description
    Overall diagnostic preference using a matched pairs approach was evaluated by 3 blinded readers using an ordinal 5-point scale (greatly prefer gadoquatrane, prefer gadoquatrane, no preference, prefer gadobutrol, greatly prefer gadobutrol). Percentage of participants and the respective Wald confidence intervals (CI) for image preference were reported for each of the 3 readers based on the 3-point preference scale (1=greatly prefer/prefer gadoquatrane, 0=no preference, -1=greatly prefer/prefer gadobutrol). If 2 or 3 readers reach the same conclusion on the recommended action (e.g. no dose adjustment needed), then this will be the recommended action taken.
    End point type
    Primary
    End point timeframe
    At 5 minute post each injection
    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: Statistical analyses were provided as an attachment
    End point values
    		 Gadobutrol + Gadoquatrane
    Number of subjects analysed
    50 [2]
    Units: Percentage of subjects
    number (confidence interval 95%)
        Reader 1 (1)
    10 (1.68 to 18.32)
        Reader 1 (0)
    34 (20.87 to 47.13)
        Reader 1 (-1)
    56 (42.24 to 69.76)
        Reader 2 (1)
    26 (13.84 to 38.16)
        Reader 2 (0)
    42 (28.32 to 55.68)
        Reader 2 (-1)
    32 (19.07 to 44.93)
        Reader 3 (1)
    30 (17.30 to 42.70)
        Reader 3 (0)
    28 (15.55 to 40.45)
        Reader 3 (-1)
    42 (28.32 to 55.68)
    Attachments
    		 Untitled (Filename: 20241_Statistical Analyses_Primary.pdf)
    Notes
    [2] - FAS
    No statistical analyses for this end point

    Secondary: Sum of lesion visualization parameters on post-contrast images

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    End point title
    		 Sum of lesion visualization parameters on post-contrast images
    End point description
    The 3 lesion visualization parameters (border delineation/degree of contrast enhancement/internal morphology) were combined by adding them up for each participant and each blinded reader, leading to only one variable on an ordinal 11-point scale (the higher values represent a better lesion visualization). Average reader was the mean of the 3 blinded readers averages of the scores per participant. Lesion border delineation: measured on a 4-point scale (1=None [no/unclear delineation of the lesion boundaries] to 4=Excellent [clear and complete delineation]). Degree of lesion contrast enhancement: measured on a 4-point scale (1=No [lesion is not enhanced] to 4=Excellent [lesion is clearly and brightly enhanced]). Lesion internal morphology: measured on a 3-point scale (1=Poor [structure and internal morphology of the lesion is poorly visible] to 3=Good [structure and internal morphology of the lesion is sufficiently visible]).
    End point type
    Secondary
    End point timeframe
    At 5 minute post each injection
    End point values
    		 Gadobutrol post-contrast Gadoquatrane post-contrast
    Number of subjects analysed
    50 [3]
    50 [4]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Reader 1 (n=49,49)
    9.95 ( 1.447 )
    9.67 ( 1.541 )
        Reader 2 (n=50,50)
    7.67 ( 1.292 )
    7.49 ( 1.406 )
        Reader 3 (n=50,49)
    9.28 ( 1.877 )
    9.65 ( 1.598 )
        Average reader (n=49,49)
    9.00 ( 1.294 )
    8.94 ( 1.229 )
    Notes
    [3] - FAS
    [4] - FAS
    Statistical analysis title
    		 Average reader
    Statistical analysis description
    The non-inferiority of gadoquatrane versus gadobutrol was evaluated using CIs based on the t-distribution. A non-inferiority margin of 1 was used, i.e. meaning that a 95% two-sided CI for the mean difference gadoquatrane minus gadobutrol score must exclude the value -1. Number of subjects in this analysis is 49.
    Comparison groups
    Gadoquatrane post-contrast v Gadobutrol post-contrast
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001 [5]
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.13
    Notes
    [5] - P-Value was calculated. Non-inferiority was achieved with a one-sided p-value lower than 0.025.

    Secondary: Lesion visualization parameter border delineation on pre-contrast and combined pre- and post-contrast images

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    End point title
    		 Lesion visualization parameter border delineation on pre-contrast and combined pre- and post-contrast images
    End point description
    Lesion border delineation: up to 5 of the largest lesions were selected and scored using a 4-point scale (1=None [no/unclear delineation of the lesion boundaries] to 4=Excellent [clear and complete delineation]; the higher values represent a better lesion border delineation). Average reader was the mean of the 3 blinded readers averages of the scores per participant.
    End point type
    Secondary
    End point timeframe
    At pre-injection and 5 minute post each injection
    End point values
    		 Gadobutrol pre-contrast Gadobutrol combined pre- and post-contrast Gadoquatrane pre-contrast Gadoquatrane combined pre- and post-contrast
    Number of subjects analysed
    50 [6]
    50 [7]
    50 [8]
    50 [9]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Reader 1 (n=46,46,43,43)
    1.83 ( 0.701 )
    3.39 ( 0.936 )
    1.88 ( 0.698 )
    3.28 ( 0.970 )
        Reader 2 (n=44,44,44,44)
    1.70 ( 0.509 )
    2.45 ( 0.589 )
    1.67 ( 0.469 )
    2.39 ( 0.576 )
        Reader 3 (n=40,40,41,41)
    1.98 ( 0.423 )
    3.28 ( 0.751 )
    1.87 ( 0.403 )
    3.21 ( 0.873 )
        Average reader (n=39,39,39,39)
    1.82 ( 0.438 )
    3.02 ( 0.614 )
    1.81 ( 0.394 )
    2.91 ( 0.609 )
    Notes
    [6] - FAS
    [7] - FAS
    [8] - FAS
    [9] - FAS
    Statistical analysis title
    		 Average Reader - gadoquatrane
    Statistical analysis description
    95% two-sided CIs based on a t-distribution for the difference of combined pre- and post-contrast minus pre-contrast scores. Parameter estimate was the descriptive comparison of the result following gadobutrol with the result following gadoquatrane. Number of subjects in this analysis is 39.
    Comparison groups
    Gadoquatrane combined pre- and post-contrast v Gadoquatrane pre-contrast
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.25
    Statistical analysis title
    		 Average Reader - gadobutrol
    Statistical analysis description
    95% two-sided CIs based on a t-distribution for the difference of combined pre- and post-contrast minus pre-contrast scores. Parameter estimate was the descriptive comparison of the result following gadobutrol with the result following gadoquatrane. Number of subjects in this analysis is 39.
    Comparison groups
    Gadobutrol combined pre- and post-contrast v Gadobutrol pre-contrast
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 1.34

    Secondary: Lesion visualization parameter contrast enhancement on pre-contrast and combined pre- and post-contrast images

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    End point title
    		 Lesion visualization parameter contrast enhancement on pre-contrast and combined pre- and post-contrast images
    End point description
    Degree of lesion contrast enhancement: up to the 5 largest lesions were selected and scored using a 4-point scale (1=No [lesion is not enhanced] to 4=Excellent [lesion is clearly and brightly enhanced]; the higher values represent a better degree of lesion contrast enhancement). Average reader was the mean of the 3 blinded readers averages of the scores per participant.
    End point type
    Secondary
    End point timeframe
    At pre-injection and 5 minute post each injection
    End point values
    		 Gadobutrol pre-contrast Gadobutrol combined pre- and post-contrast Gadoquatrane pre-contrast Gadoquatrane combined pre- and post-contrast
    Number of subjects analysed
    50 [10]
    50 [11]
    50 [12]
    50 [13]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Reader 1 (n=46,46,43,43)
    1.00 ( 0.000 )
    3.24 ( 0.917 )
    1.00 ( 0.000 )
    3.20 ( 0.825 )
        Reader 2 (n=44,44,44,44)
    1.00 ( 0.000 )
    2.50 ( 0.629 )
    1.00 ( 0.000 )
    2.57 ( 0.587 )
        Reader 3 (n=40,40,41,41)
    1.00 ( 0.000 )
    3.55 ( 0.904 )
    0.99 ( 0.078 )
    3.49 ( 0.925 )
        Average Reader (n=39,39,39,39)
    1.00 ( 0.000 )
    3.07 ( 0.638 )
    1.00 ( 0.027 )
    3.05 ( 0.600 )
    Notes
    [10] - FAS
    [11] - FAS
    [12] - FAS
    [13] - FAS
    Statistical analysis title
    		 Average Reader - gadoquatrane
    Statistical analysis description
    95% two-sided CIs based on a t-distribution for the difference of combined pre- and post-contrast minus pre-contrast scores. Parameter estimate was the descriptive comparison of the result following gadobutrol with the result following gadoquatrane. Number of subjects in this analysis is 39.
    Comparison groups
    Gadoquatrane combined pre- and post-contrast v Gadoquatrane pre-contrast
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.86
         upper limit
    		 2.25
    Statistical analysis title
    		 Average Reader - gadobutrol
    Statistical analysis description
    95% two-sided CIs based on a t-distribution for the difference of combined pre- and post-contrast minus pre-contrast scores. Parameter estimate was the descriptive comparison of the result following gadobutrol with the result following gadoquatrane. Number of subjects in this analysis is 39.
    Comparison groups
    Gadobutrol combined pre- and post-contrast v Gadobutrol pre-contrast
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.87
         upper limit
    		 2.28

    Secondary: Lesion visualization parameter internal morphology on pre-contrast and combined pre- and post-contrast images

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    End point title
    		 Lesion visualization parameter internal morphology on pre-contrast and combined pre- and post-contrast images
    End point description
    Lesion internal morphology: up to 5 of the largest lesions were selected and scored using a 3-point scale (1=Poor [structure and internal morphology of the lesion is poorly visible] to 3=Good [structure and internal morphology of the lesion is sufficiently visible]; the higher values represent a better lesion internal morphology). Average reader was the mean of the 3 blinded readers averages of the scores per participant.
    End point type
    Secondary
    End point timeframe
    At pre-injection and 5 minute post each injection
    End point values
    		 Gadobutrol pre-contrast Gadobutrol combined pre- and post-contrast Gadoquatrane pre-contrast Gadoquatrane combined pre- and post-contrast
    Number of subjects analysed
    50 [14]
    50 [15]
    50 [16]
    50 [17]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Reader 1 (n=46,46,43,43)
    1.27 ( 0.444 )
    2.62 ( 0.693 )
    1.40 ( 0.484 )
    2.58 ( 0.655 )
        Reader 2 (n=44,44,44,44)
    1.05 ( 0.185 )
    2.13 ( 0.598 )
    1.05 ( 0.211 )
    2.11 ( 0.689 )
        Reader 3 (n=40,40,41,41)
    1.05 ( 0.221 )
    2.45 ( 0.677 )
    1.04 ( 0.234 )
    2.44 ( 0.673 )
        Average Reader (n=39,39,39,39)
    1.13 ( 0.194 )
    2.39 ( 0.493 )
    1.16 ( 0.218 )
    2.35 ( 0.500 )
    Notes
    [14] - FAS
    [15] - FAS
    [16] - FAS
    [17] - FAS
    Statistical analysis title
    		 Average Reader - gadoquatrane
    Statistical analysis description
    95% two-sided CIs based on a t-distribution for the difference of combined pre- and post-contrast minus pre-contrast scores. Parameter estimate was the descriptive comparison of the result following gadobutrol with the result following gadoquatrane. Number of subjects in this analysis is 39.
    Comparison groups
    Gadoquatrane combined pre- and post-contrast v Gadoquatrane pre-contrast
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 1.32
    Statistical analysis title
    		 Average Reader - gadobutrol
    Statistical analysis description
    95% two-sided CIs based on a t-distribution for the difference of combined pre- and post-contrast minus pre-contrast scores. Parameter estimate was the descriptive comparison of the result following gadobutrol with the result following gadoquatrane. Number of subjects in this analysis is 39.
    Comparison groups
    Gadobutrol combined pre- and post-contrast v Gadobutrol pre-contrast
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 1.43

    Secondary: Number of lesions on pre-contrast and combined pre- and post-contrast images

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    End point title
    		 Number of lesions on pre-contrast and combined pre- and post-contrast images
    End point description
    The 3 blinded readers recorded the total number of lesions for each pre-contrast and combined pre- and post-contrast magnetic resonance image set separately. The numbers of subjects by number of detected lesions were reported. For Reader 2, the number of subjects analyzed for each reporting groups are: 48, 49, 49, 49.
    End point type
    Secondary
    End point timeframe
    At pre-injection and 5 minute post injection
    End point values
    		 Gadobutrol pre-contrast Gadobutrol combined pre- and post-contrast Gadoquatrane pre-contrast Gadoquatrane combined pre- and post-contrast
    Number of subjects analysed
    50 [18]
    50 [19]
    50 [20]
    50 [21]
    Units: Subjects
        Reader 1 (Nr. of lesions=0)
    4
    1
    7
    1
        Reader 1 (Nr. of lesions=1)
    43
    40
    40
    41
        Reader 1 (Nr. of lesions=2)
    3
    7
    1
    6
        Reader 1 (Nr. of lesions=3)
    0
    2
    2
    2
        Reader 2 (Nr. of lesions=0)
    4
    0
    5
    0
        Reader 2 (Nr. of lesions=1)
    42
    43
    42
    43
        Reader 2 (Nr. of lesions=2)
    0
    3
    0
    3
        Reader 2 (Nr. of lesions=3)
    2
    3
    2
    3
        Reader 3 (Nr. of lesions=0)
    10
    1
    9
    1
        Reader 3 (Nr. of lesions=1)
    40
    41
    40
    42
        Reader 3 (Nr. of lesions=2)
    0
    7
    1
    4
        Reader 3 (Nr. of lesions=3)
    0
    1
    0
    1
        Reader 3 (Nr. of lesions=4)
    0
    0
    0
    2
    Notes
    [18] - FAS
    [19] - FAS
    [20] - FAS
    [21] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events tables: up to the 24 h ± 4 h follow-up time point following Gadobutrol or Gadoquatrane injection. Adverse event reporting for the deaths (all causes): after signing informed consent up to the last contact per participant, up to 36 days.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Gadoquatrane
    Reporting group description
    		 Subjects received one intravenous (IV) injection of gadoquatrane (BAY1747846) 0.04 millimole(s) gadolinium/kilogram body weight (mmol Gd/kg bw) during treatment Period 2.

    Reporting group title
    Gadobutrol
    Reporting group description
    		 Subjects received one IV injection of gadobutrol 0.1 mmol Gd/kg bw during treatment Period 1.

    Serious adverse events
    		 Gadoquatrane Gadobutrol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 57 (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
    		 Gadoquatrane Gadobutrol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 57 (5.26%)
    General disorders and administration site conditions
    Injection site bruising
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 57 (1.75%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 57 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 57 (1.75%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jul 2021
    Incorporated an interim analysis to facilitate the planning of future phases of development. Furthermore the inclusion criterion pertaining to eGFR at baseline was clarified and two exclusion criteria were adapted.
    06 Jan 2022
    To fulfill the FDA request to add secondary endpoints to the study (lesion visualization parameters and number of lesions).

    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.
    None reported
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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
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