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    Clinical Trial Results:
    LowEr Administered Dose with highEr Relaxivity: Gadovist vs Dotarem (LEADER 75)

    Summary
    EudraCT number
    		 2018-000690-78
    Trial protocol
    		 FR   GB   IT  
    Global end of trial date
    26 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jun 2021
    First version publication date
    05 Jun 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY86-4875/19773
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03602339
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, 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
    26 May 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate non-inferiority of gadobutrol-enhanced central nervous system (CNS) imaging (0.075 mmol/kg body weight [BW]) compared to gadoterate-enhanced CNS imaging (0.1 mmol/kg BW) based on the blinded read for 3 lesion visualization parameters (degree of lesion contrast enhancement, assessment of lesion border delineation, internal morphology of lesions).
    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. Only after the subject voluntarily signed the informed consent form was he/she able to enter the study. If the subject was not capable of providing a signature, an oral statement of consent could have been given in the presence of a witness. Each subject was assured of the right to 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
    14 Nov 2018
    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
    France: 16
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Italy: 39
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Switzerland: 15
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    157
    EEA total number of subjects
    88
    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)
    94
    From 65 to 84 years
    62
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at multiple centers in 7 countries between 14 November 2018 (first subject first visit) and 13 March 2020 (last subject last visit).

    Pre-assignment
    Screening details
    		 From 166 subjects screened, 9 subjects were sceening failure and a total of 157 subjects were enrolled, 157 received study drug for period 1 however 142 received study drug for period 2.

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

    Arms
    Arm title
    		 Gadoterate 0.1 mmol/kg BW-Gadobutrol 0.075 mmol/kg BW
    Arm description
    		 Subjects received gadoterate at the standard dose of 0.1 mmol/kg body weight (BW) by single intravenous (IV) injection in period 1 and gadobutrol at a dose of 0.075 mmol/kg BW by single IV injection in period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gadoterate
    Investigational medicinal product code
    Other name
    Dotarem, Clariscan
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects administrered gadoterate at the dose of 0.1 mmol per kg body weight by single IV injection.

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    BAY86-4875
    Other name
    Gadovist, Gadavist
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects administered gadobutrol at the dose of 0.075 mmol per kg body weight by single IV (intravenous) injection.

    Number of subjects in period 1
    		Gadoterate 0.1 mmol/kg BW-Gadobutrol 0.075 mmol/kg BW
    Started
    157
    Completed period 1 (Gadoterate)
    155
    Started period 2 (Gadobutrol)
    142
    Completed
    142
    Not completed
    15
         Consent withdrawn by subject
    9
         Physician decision
    2
         Other reason
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gadoterate 0.1 mmol/kg BW-Gadobutrol 0.075 mmol/kg BW
    Reporting group description
    		 Subjects received gadoterate at the standard dose of 0.1 mmol/kg body weight (BW) by single intravenous (IV) injection in period 1 and gadobutrol at a dose of 0.075 mmol/kg BW by single IV injection in period 2.

    Reporting group values
    		 Gadoterate 0.1 mmol/kg BW-Gadobutrol 0.075 mmol/kg BW Total
    Number of subjects
    		 157 157
    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)
    		 94 94
        From 65-84 years
    		 62 62
        85 years and over
    		 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.9 ( 13.3 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 71 71
        Male
    		 86 86
    Race
    Units: Subjects
        Multiple
    		 0 0
        White
    		 109 109
        Black or African American
    		 2 2
        Asian
    		 27 27
        American Indian or Alaska Native
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Not Reported
    		 19 19
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 106 106
        Hispanic or Latino
    		 32 32
        Not reported
    		 19 19
    Subject analysis sets

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects for whom electronic case report form (eCRF) entries and images are available for unenhanced MRI, combined unenhanced and gadobutrol enhanced MRI, and combined unenhanced and gadoterate enhanced MRI.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAF included all enrolled subjects who received at least 1 study treatment administration.

    Subject analysis set title
    Gadoterate 0.1 mmol/kg BW
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received gadoterate at the standard dose of 0.1 mmol/kg body weight (BW) by single intravenous (IV) injection.

    Subject analysis set title
    Gadobutrol 0.075 mmol/kg BW
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received gadobutrol at a dose of 0.075 mmol/kg BW by single intravenous (IV) injection.

    Subject analysis sets values
    		 Full analysis set (FAS) Safety analysis set (SAF) Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects
    141
    157
    156
    143
    Age Categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    88
    94
    93
    90
        From 65-84 years
    52
    62
    62
    52
        85 years and over
    1
    1
    1
    1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Gender Categorical
    Units: Subjects
        Female
        Male
    Race
    Units: Subjects
        Multiple
        White
        Black or African American
        Asian
        American Indian or Alaska Native
        Native Hawaiian or Other Pacific Islander
        Not Reported
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
        Hispanic or Latino
        Not reported

    End points

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    End points reporting groups
    Reporting group title
    Gadoterate 0.1 mmol/kg BW-Gadobutrol 0.075 mmol/kg BW
    Reporting group description
    		 Subjects received gadoterate at the standard dose of 0.1 mmol/kg body weight (BW) by single intravenous (IV) injection in period 1 and gadobutrol at a dose of 0.075 mmol/kg BW by single IV injection in period 2.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects for whom electronic case report form (eCRF) entries and images are available for unenhanced MRI, combined unenhanced and gadobutrol enhanced MRI, and combined unenhanced and gadoterate enhanced MRI.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAF included all enrolled subjects who received at least 1 study treatment administration.

    Subject analysis set title
    Gadoterate 0.1 mmol/kg BW
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received gadoterate at the standard dose of 0.1 mmol/kg body weight (BW) by single intravenous (IV) injection.

    Subject analysis set title
    Gadobutrol 0.075 mmol/kg BW
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received gadobutrol at a dose of 0.075 mmol/kg BW by single intravenous (IV) injection.

    Primary: Degree of lesion contrast enhancement

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    End point title
    		 Degree of lesion contrast enhancement
    End point description
    Degree of lesion contrast enhancement is assessed by 3 blinded Readers (Full Analysis Set). Results are presented as the Average Reader score. Blinded Readers scored up to 5 lesions using image sequences and a 4-point scale (1 - No = Lesion not enhanced; 2 - Moderate = Lesion weakly enhanced; 3 - Good = Lesion clearly enhanced; 4 - Excellent = Lesion clearly and brightly enhanced).
    End point type
    Primary
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    141
    141
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Unenhanced
    0.884 ( 0.252 )
    0.863 ( 0.201 )
        Combined unenhanced/enhanced
    3.007 ( 0.813 )
    2.979 ( 0.837 )
    Statistical analysis title
    		 Degree of lesion contrast enhancement
    Statistical analysis description
    Difference (gadobutrol minus unenhanced) - (gadoterate minus unenhanced)
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.455
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.347
         upper limit
    		 0.562
    Notes
    [1] - The score to evaluate the non-inferiority is calculated for each subject as (combined unenhanced/gadobutrol-enhanced - unenhanced) - 0.8*(combined unenhanced/gadoterate-enhanced - unenhanced). The non-inferiority for gadobutrol is achieved if the one-sided p-value for "H0: (gadobutrol minus unenhanced) - 0.8*(gadoterate minus unenhanced) ≤ 0" is lower than 0.025.

    Primary: Lesion border delineation

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    End point title
    		 Lesion border delineation
    End point description
    Lesion border delineation is assessed by 3 blinded Readers (Full Analysis Set). Results are presented as the Average Reader score. Blinded Readers scored the delineation of up to 5 lesions using image sequences and a 4-point scale (1 - None = No or unclear delineation; 2 - Moderate = Partial delineation; 3 - Good = Almost clear, but incomplete delineation; 4 - Excellent = Clear and complete delineation).
    End point type
    Primary
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    141
    141
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Unenhanced
    2.279 ( 0.820 )
    2.278 ( 0.864 )
        Combined unenhanced/enhanced
    3.096 ( 0.781 )
    3.099 ( 0.828 )
    Statistical analysis title
    		 Lesion border delineation
    Statistical analysis description
    Difference (gadobutrol minus unenhanced) - (gadoterate minus unenhanced)
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.0151
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.017
         upper limit
    		 0.342
    Notes
    [2] - The score to evaluate the non-inferiority is calculated for each subject as (combined unenhanced/gadobutrol-enhanced - unenhanced) - 0.8*(combined unenhanced/gadoterate-enhanced - unenhanced). The non-inferiority for gadobutrol is achieved if the one-sided p-value for "H0: (gadobutrol minus unenhanced) - 0.8*(gadoterate minus unenhanced) ≤ 0" is lower than 0.025.

    Primary: Lesion internal morphology

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    End point title
    		 Lesion internal morphology
    End point description
    Lesion internal morphology is assessed by 3 blinded Readers (Full Analysis Set). Results are presented as the Average Reader score. Blinded Readers scored the structure and internal morphology of up to 5 lesions using image sequences and a 3-point scale (1 - Poor = Poor visibility; 2 - Moderate = Partial visibility; 3 - Good = Sufficient visibility)
    End point type
    Primary
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    141
    141
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Unenhanced
    1.835 ( 0.620 )
    1.823 ( 0.589 )
        Combined unenhanced/enhanced
    2.503 ( 0.496 )
    2.484 ( 0.545 )
    Statistical analysis title
    		 Lesion internal morphology
    Statistical analysis description
    Difference (gadobutrol minus unenhanced) - (gadoterate minus unenhanced)
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.01
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.024
         upper limit
    		 0.275
    Notes
    [3] - The score to evaluate the non-inferiority is calculated for each subject as (combined unenhanced/gadobutrol-enhanced - unenhanced) - 0.8*(combined unenhanced/gadoterate-enhanced - unenhanced). The non-inferiority for gadobutrol is achieved if the one-sided p-value for "H0: (gadobutrol minus unenhanced) - 0.8*(gadoterate minus unenhanced) ≤ 0" is lower than 0.025.

    Secondary: Number of lesions identified

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    End point title
    		 Number of lesions identified
    End point description
    Number of lesions identified (up to 10) detected by 3 blinded Readers. The mean (SD) number lesions in the Average Reader for gadobutrol and gadoterate in the Full Analysis Set was reported below.
    End point type
    Secondary
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    141 [4]
    141 [5]
    Units: Number of lesions identified
        arithmetic mean (standard deviation)
    2.064 ( 2.254 )
    2.137 ( 2.327 )
    Notes
    [4] - combined unenhanced/enhanced
    [5] - combined unenhanced/enhanced
    Statistical analysis title
    		 Number of lesions identified
    Statistical analysis description
    Difference (Gadobutrol - Gadoterate)
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.073
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.176
    Notes
    [6] - Non-inferiority margin is defined as 0.35. If the lower limit of the 95% CI is >-0.35, then non-inferiority is achieved.

    Secondary: Detection of malignant disease

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    End point title
    		 Detection of malignant disease
    End point description
    The 3 blinded Readers had to evaluate if the diagnosis resulting from the combined images was malignant disease or not. Each blinded Reader provided a malignant yes/no response. This was compared to the final diagnosis provided by the Investigator. The majority of Readers (2 or 3 Readers agree) was used to calculate sensitivity, specificity, and accuracy - eg. Final Diagnosis - Malignant (Reader 1-yes, Reader 2-no, Reader 3-yes --- Majority Reader yes) - this would be a match for sensitivity. The percentage of sensitivity, specificity, and accuracy of detection of malignant disease detected by 3 blinded Readers, gadobutrol versus gadoterate (Full Analysis Set) is reported below for Majority Readers.
    End point type
    Secondary
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    141
    141
    Units: Percentage (%)
    number (not applicable)
        Accuracy
    70.2
    70.2
        Sensitivity
    58.7
    58.7
        Specificity
    91.8
    91.8
    Statistical analysis title
    		 Detection of malignant disease
    Statistical analysis description
    Accuracy Difference (Gadobutrol - Gadoterate)
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Difference (Gadobutrol - Gadoterate)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 3.4
    Notes
    [7] - Non-inferiority margin = 10%, if the lower limit of the confidence interval > -10%, then non-inferiority is achieved. The 95% confidence intervals are based on McNemar's test.
    Statistical analysis title
    		 Detection of malignant disease
    Statistical analysis description
    Sensitivity Difference (Gadobutrol - Gadoterate)
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Difference (Gadobutrol - Gadoterate)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.22
         upper limit
    		 5.22
    Notes
    [8] - Non-inferiority margin = 10%, if the lower limit of the confidence interval > -10%, then non-inferiority is achieved. The 95% confidence intervals are based on McNemar's test.
    Statistical analysis title
    		 Detection of malignant disease
    Statistical analysis description
    Specificity Difference (Gadobutrol - Gadoterate)
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 Difference (Gadobutrol - Gadoterate)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [9] - Non-inferiority margin = 10%, if the lower limit of the confidence interval > -10%, then non-inferiority is achieved. The 95% confidence intervals are based on McNemar's test. No continuity correction for calculation of the confidence interval was included. Zero cells lead to degenerated confidence interval.

    Secondary: Confidence in diagnosis

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    End point title
    		 Confidence in diagnosis
    End point description
    Diagnostic confidence detected by 3 blinded Readers, gadobutrol vs gadoterate (Full Analysis Set). Blinded Readers rated their confidence in diagnosis according to a 4-point scale (1 - Not confident; 2 - Somewhat confident; 3 - Confident; 4 - Very confident). Results for the Average Reader are reported below.
    End point type
    Secondary
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    141 [10]
    141 [11]
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    3.272 ( 0.567 )
    3.348 ( 0.591 )
    Notes
    [10] - combined unenhanced/enhanced
    [11] - combined unenhanced/enhanced
    Statistical analysis title
    		 Diagnostic confidence
    Statistical analysis description
    Difference (Gadobutrol - Gadoterate)
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.076
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.011
         upper limit
    		 0.14

    Secondary: Image quality

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    End point title
    		 Image quality
    End point description
    Comparison of image quality between gadobutrol and gadoterate detected by 3 blinded Readers (Full Analysis Set). Blinded Readers assessed the image quality of gadobutrol- and gadoterate-enhanced images (randomly assigned as left [L] and right [R] image positions) according to a 5-point scale (1- Image R is worse; 2 - Image R is slightly worse; 3- Image R is similar; 4 - Image R is slightly better; 5 - Image R is better). After unblinding of data, the above codes were translated into the following scale: -2 = Gadobutrol image set is worse ; -1 = Gadobutrol image set is slightly worse ; 0 = Image sets are the same ; 1 = Gadobutrol image set is slightly better; 2 = Gadobutrol image set is better. Results for the Average Reader are reported below. Statistical Analysis: two sided 95%-CI for the Average Reader is [-0.10;0.11], p= 0.9149 (Wilcoxon signed-rank test).
    End point type
    Secondary
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW-Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    141
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    0.00 ( 0.61 )
    No statistical analyses for this end point

    Secondary: Contrast enhancement utilizing an exploratory overall contrast enhancement estimation algorithm

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    End point title
    		 Contrast enhancement utilizing an exploratory overall contrast enhancement estimation algorithm
    End point description
    Comparison of contrast enhancement utilizing an overall contrast enhancement estimation algorithm (Full Analysis Set). The exploratory algorithm analyzed the overall enhancement by comparing the axial T1w (longitudinal relaxation time-weighted) enhanced images to the T1w unenhanced images.
    End point type
    Secondary
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    88
    89
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Relative score
    0.19894 ( 0.09905 )
    0.18564 ( 0.09028 )
        Full image score
    0.05604 ( 0.08581 )
    0.05573 ( 0.08036 )
        Dice score
    0.92984 ( 0.04293 )
    0.92991 ( 0.05216 )
    Statistical analysis title
    		 Overall contrast enhancement estimation algorithm
    Statistical analysis description
    Difference (Gadobutrol-Gadoterate) for Relative score
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01968
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03491
         upper limit
    		 -0.00445
    Statistical analysis title
    		 Overall contrast enhancement estimation algorithm
    Statistical analysis description
    Difference (Gadobutrol-Gadoterate) for Full image score
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.00586
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.00589
         upper limit
    		 0.01762
    Statistical analysis title
    		 Overall contrast enhancement estimation algorithm
    Statistical analysis description
    Difference (Gadobutrol-Gadoterate) for Dice score
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.00139
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.00471
         upper limit
    		 0.00749

    Secondary: Number of subjects with treatment-emergent adverse events

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    End point title
    		 Number of subjects with treatment-emergent adverse events
    End point description
    Number of subjects with treatment-emergent adverse events (TEAEs) (Safety Analysis Set). TEAEs are defined as any AEs that increase in intensity or that are newly developed during the TE period for Study Period 1 or Study Period 2, where TE period for Study Period 1 goes from the first study drug administration in Study Period 1 to 24 hours post-injection, and TE period for Study Period 2 from the first study drug administration in Study Period 2 to 24 hours post-injection.
    End point type
    Secondary
    End point timeframe
    From the first study drug administration up to 24 hours post injection
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    156
    143
    Units: Participants
        Any TEAE
    4
    1
        Any study drug-related TEAE
    2
    1
        Any TEAE related to the protocol
    0
    0
        Any TEAE leading to discontinuation
    0
    0
        Any TESAE
    0
    0
        TEAE with outcome death
    0
    0
    No statistical analyses for this end point

    Post-hoc: Comparison of degree of lesion contrast enhancement detected by blinded Readers for combined image sets - Equivalence Test

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    End point title
    		 Comparison of degree of lesion contrast enhancement detected by blinded Readers for combined image sets - Equivalence Test
    End point description
    Comparison of degree of lesion contrast enhancement detected by blinded Readers for combined image sets - Equivalence Test (Full Analysis Set). Results are presented as the average Reader score. Blinded Readers scored up to 5 lesions using image sequences and a 4-point scale (1 - No = Lesion not enhanced; 2 - Moderate = Lesion weakly enhanced; 3 - Good = Lesion clearly enhanced; 4 - Excellent = Lesion clearly and brightly enhanced).
    End point type
    Post-hoc
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    141
    141
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Combined unenhanced/enhanced
    3.007 ( 0.813 )
    2.979 ( 0.837 )
    Statistical analysis title
    		 Equivalence Test
    Statistical analysis description
    An equivalence test was calculated using the two one-sided t-tests (TOST) procedure with null hypotheses H01: (gadobutrol - gadoterate) ≤ -0.05 * (gadoterate), and H02: (gadobutrol - gadoterate) ≥ +0.05 * (gadoterate).
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.0049 [12]
    Method
    		 Two one-sided t-tests (TOST)
    Confidence interval
    Notes
    [12] - The overall p-value was calculated as max(p1, p2) where p1 and p2 are the results of null hypotheses H01 and H02 respectively.

    Post-hoc: Comparison of border delineation detected by blinded Readers for combined image sets - Equivalence Test

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    End point title
    		 Comparison of border delineation detected by blinded Readers for combined image sets - Equivalence Test
    End point description
    Comparison of border delineation detected by blinded Readers for combined image sets - Equivalence Test (Full Analysis Set). Results are presented as the Average Reader score. Blinded Readers scored the delineation of up to 5 lesions using image sequences and a 4-point scale (1 - None = No or unclear delineation; 2 - Moderate = Partial delineation; 3 - Good = Almost clear, but incomplete delineation; 4 - Excellent = Clear and complete delineation).
    End point type
    Post-hoc
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    141
    141
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Combined unenhanced/enhanced
    3.096 ( 0.781 )
    3.099 ( 0.828 )
    Statistical analysis title
    		 Equivalence Test
    Statistical analysis description
    An equivalence test was calculated using the two one-sided t-tests (TOST) procedure with null hypotheses H01: (gadobutrol - gadoterate) ≤ -0.05 * (gadoterate) and H02: (gadobutrol - gadoterate) ≥ +0.05 * (gadoterate).
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.0013 [13]
    Method
    		 Two one-sided t-tests (TOST)
    Confidence interval
    Notes
    [13] - The overall p-value was calculated as max(p1, p2) where p1 and p2 are the results of null hypotheses H01 and H02 respectively.

    Post-hoc: Comparison of internal morphology detected by blinded Readers for combined image sets - Equivalence Test

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    End point title
    		 Comparison of internal morphology detected by blinded Readers for combined image sets - Equivalence Test
    End point description
    Comparison of internal morphology detected by blinded Readers for combined image sets - Equivalence Test (Full Analysis Set). Results are presented as the average Reader score. Blinded Readers scored the structure and internal morphology of up to 5 lesions using image sequences and a 3-point scale (1 - Poor = Poor visibility; 2 - Moderate = Partial visibility; 3 - Good = Sufficient visibility).
    End point type
    Post-hoc
    End point timeframe
    Up to 20 days
    End point values
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Number of subjects analysed
    141
    141
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Combined unenhanced/enhanced
    2.503 ( 0.496 )
    2.484 ( 0.545 )
    Statistical analysis title
    		 Equivalence Test
    Statistical analysis description
    An equivalence test was calculated using the two one-sided t-tests (TOST) procedure with null hypotheses H01: (gadobutrol - gadoterate) ≤ -0.05 * (gadoterate) and H02: (gadobutrol - gadoterate) ≥ +0.05 * (gadoterate).
    Comparison groups
    Gadoterate 0.1 mmol/kg BW v Gadobutrol 0.075 mmol/kg BW
    Number of subjects included in analysis
    282
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.0065 [14]
    Method
    		 Two one-sided t-tests (TOST)
    Confidence interval
    Notes
    [14] - The overall p-value was calculated as max(p1, p2) where p1 and p2 are the results of null hypotheses H01 and H02 respectively.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug administration up to 24 hours post injection
    Adverse event reporting additional description
    1 out of 157 subjects received gadobutrol instead of gadoterate in study period 1. This subject dropped out. 156 subjects received gadoterate and 143 subjects received gadobutrol. 142 subjects received both doses. Of the 142, 1 subject's dose extravasated and could not be adequately imaged and was removed from the efficacy population.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Gadoterate 0.1 mmol/kg BW
    Reporting group description
    		 Participants received gadoterate at the standard dose of 0.1 mmol/kg body weight (BW) by single intravenous (IV) injection.

    Reporting group title
    Gadobutrol 0.075 mmol/kg BW
    Reporting group description
    		 Participants received gadobutrol at a dose of 0.075 mmol/kg BW by single IV injection.

    Serious adverse events
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 143 (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
    		 Gadoterate 0.1 mmol/kg BW Gadobutrol 0.075 mmol/kg BW
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 156 (2.56%)
    1 / 143 (0.70%)
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 143 (0.70%)
         occurrences all number
    0
    1
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 143 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 143 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 143 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 143 (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? Yes
    Date
    Amendment
    25 Mar 2019
    The following is the overview of changes to the study as per Amendment 1: - Changes in MRI field strength were made to permit either the previously specified 1.5T or the newer 3.0T field strength and to provide greater flexibility based on the study center’s available MRI equipment. - Recommended Pulse sequences were added (T1w spin echo/fast spin echo acquisition should be performed in 2D mode). - Quantitative contrast enhancement estimation, “up to 10 lesions” was removed since the estimation algorithm was not applied to a single lesion or up to 10 lesions, as it was a result of software evaluation for a complete image. - Confidence in diagnosis was modified to clarify that frequency tables for confidence responses were not to be constructed for unenhanced MRI alone. - Analysis of safety variables: Reference to McNemar’s tests and/or related CIs were removed, reflecting a changed analysis plan.

    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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