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    Clinical Trial Results:
    Efficacy and Safety of gadoPIClenol for CenTral NervoUs System (CNS) Magnetic REsonance Imaging (MRI) (PICTURE trial)

    Summary
    EudraCT number
    		 2018-003988-54
    Trial protocol
    		 FR   BE   DE   HU   ES   IT  
    Global end of trial date
    11 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Nov 2021
    First version publication date
    25 Nov 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GDX-44-010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03996447
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Guerbet
    Sponsor organisation address
    B.P. 57400, CdG Cedex, France, 95943
    Public contact
    Jing Hao, MD, Guerbet, +33 (0)1 45 91 51 76 , jing.hao@guerbet.com
    Scientific contact
    Jing Hao, MD, Guerbet, +33 (0)1 45 91 51 76 , jing.hao@guerbet.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
    23 Mar 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - To demonstrate the superiority of gadopiclenol-enhanced MRI at 0.05 mmol/kg body weight compared to unenhanced MRI for patient referred for contrast-enhanced MRI of CNS, in terms of 3 lesion visualization co-primary criteria using the patient as his/her own control. - To demonstrate the non-inferiority of gadopiclenol at 0.05 mmol/kg compared to gadobutrol at 0.1 mmol/kg in terms of 3 lesion visualization co-primary criteria for patient referred for contrast-enhanced MRI of CNS.
    Protection of trial subjects
    This trial has been conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, that are consistent with Good Clinical Practice (GCP) according to International Conference on Harmonisation (ICH) guidelines and with the applicable regional/local regulations of the country in which the trial was conducted. The safety of subjects was assessed over 1 day follow-up period after each MRI visit, for vital signs, injection site tolerance, clinical laboratory parameters and monitoring of adverse events. For patients enrolled in France: a safety follow-up contact between 7 and 14 days after the last IMP injection was performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Apr 2019
    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
    United States: 46
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Poland: 29
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 104
    Country: Number of subjects enrolled
    Italy: 23
    Worldwide total number of subjects
    256
    EEA total number of subjects
    176
    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)
    164
    From 65 to 84 years
    92
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 260 [1]
    Number of subjects completed
    		 256

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen failure: 4
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of patients presented in the Pre-assignment period (260) is the number of screened patients. Among these patients, 256 were randomized.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Arm title
    		 Overall population
    Arm description
    		 All patients who received at least one injection of one of the 2 contrast agents.
    Arm type
    		 Experimental

    Investigational medicinal product name
    gadopiclenol
    Investigational medicinal product code
    Other name
    P03277
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    single intravenous bolus injection at 0.05 mmol/kg. The recommended injection rate was 2 mL/second followed by a saline flush via manual injection or power injector.

    Investigational medicinal product name
    gadobutrol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single intravenous bolus injection at 0.1 mmol/kg. The recommended injection rate was 2 mL/second followed by a saline flush via manual injection or power injector.

    Number of subjects in period 1
    		Overall population
    Started
    256
    Completed
    242
    Not completed
    14
         Adverse event other than COVID-19
    4
         Consent withdrawn by subject
    4
         COVID-19 pandemic preventing protocol follow-up
    3
         Inclusion/non-inclusion criteria not met/met
    1
         Other reason
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial (overall period) Total
    Number of subjects
    		 256 256
    Age categorical
    Units: Subjects
        18-64 years
    		 164 164
        ≥ 65 years
    		 92 92
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.2 ( 13.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 137 137
        Male
    		 119 119

    End points

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    End points reporting groups
    Reporting group title
    Overall population
    Reporting group description
    		 All patients who received at least one injection of one of the 2 contrast agents.

    Subject analysis set title
    FAS1 Paired images
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set 1 (FAS1): all patients who have both Pre and Paired images with gadopiclenol assessable for primary criteria 1 for at least one matching lesion for at least one off-site reader

    Subject analysis set title
    FAS1 Pre images
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set 1 (FAS1): all patients who have both Pre and Paired images with gadopiclenol assessable for primary criteria 1 for at least one matching lesion for at least one off-site reader

    Subject analysis set title
    PPS2 Gadopiclenol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol Set 2 (PPS2): all patients from Full Analysis Set 2 (FAS 2) who have no major protocol deviations for primary criteria 2 FAS 2: all patients who have Paired images for both gadopiclenol and gadobutrol assessable for primary criteria 2 for at least one matching lesion for at least one off-site reader

    Subject analysis set title
    PPS2 Gadobutrol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol Set 2 (PPS2): all patients from Full Analysis Set 2 (FAS 2) who have no major protocol deviations for primary criteria 2 FAS 2: all patients who have Paired images for both gadopiclenol and gadobutrol assessable for primary criteria 2 for at least one matching lesion for at least one off-site reader

    Primary: lesion visualization criteria for gadopiclenol-enhanced MRI compared to unenhanced MRI (off-site read)

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    End point title
    		 lesion visualization criteria for gadopiclenol-enhanced MRI compared to unenhanced MRI (off-site read)
    End point description
    The lesion visualization criteria were based on 3 co-primary criteria: border delineation, internal morphology and degree of contrast enhancement, assessed on the images acquired during the MRI performed with gadopiclenol. Data presented are the differences in mean of scores for border delineation, internal morphology and degree of contrast enhancement.
    End point type
    Primary
    End point timeframe
    1 day procedure
    End point values
    		 FAS1 Paired images FAS1 Pre images
    Number of subjects analysed
    239
    239
    Units: None
    least squares mean (standard error)
        Border delineation - Reader 1
    3.90 ( 0.02 )
    2.08 ( 0.02 )
        Border delineation - Reader 2
    3.64 ( 0.04 )
    1.74 ( 0.04 )
        Border delineation - Reader 3
    3.97 ( 0.03 )
    2.61 ( 0.03 )
        Internal morphology - Reader 1
    3.92 ( 0.03 )
    1.66 ( 0.03 )
        Internal morphology - Reader 2
    3.65 ( 0.03 )
    1.88 ( 0.03 )
        Internal morphology - Reader 3
    3.97 ( 0.04 )
    2.01 ( 0.04 )
        Degree of contrast enhancement - Reader 1
    3.77 ( 0.03 )
    1.00 ( 0.03 )
        Degree of contrast enhancement - Reader 2
    3.58 ( 0.03 )
    1.00 ( 0.03 )
        Degree of contrast enhancement - Reader 3
    3.90 ( 0.02 )
    1.00 ( 0.02 )
    Statistical analysis title
    		 Border delineation - Reader 1
    Statistical analysis description
    The Null hypothesis is rejected if the difference [“Paired” scores mean – “Pre” scores mean] is significantly different from zero with a type 1 error set at 0.025.
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.76
         upper limit
    		 1.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Statistical analysis title
    		 Border delineation - Reader 2
    Statistical analysis description
    The Null hypothesis is rejected if the difference [“Paired” scores mean – “Pre” scores mean] is significantly different from zero with a type 1 error set at 0.025.
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.81
         upper limit
    		 2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Statistical analysis title
    		 Border delineation - Reader 3
    Statistical analysis description
    The Null hypothesis is rejected if the difference [“Paired” scores mean – “Pre” scores mean] is significantly different from zero with a type 1 error set at 0.025.
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.29
         upper limit
    		 1.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Statistical analysis title
    		 Internal morphology - Reader 1
    Statistical analysis description
    The Null hypothesis is rejected if the difference [“Paired” scores mean – “Pre” scores mean] is significantly different from zero with a type 1 error set at 0.025.
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.2
         upper limit
    		 2.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Statistical analysis title
    		 Internal morphology - Reader 2
    Statistical analysis description
    The Null hypothesis is rejected if the difference [“Paired” scores mean – “Pre” scores mean] is significantly different from zero with a type 1 error set at 0.025.
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.69
         upper limit
    		 1.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Statistical analysis title
    		 Internal morphology - Reader 3
    Statistical analysis description
    The Null hypothesis is rejected if the difference [“Paired” scores mean – “Pre” scores mean] is significantly different from zero with a type 1 error set at 0.025.
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.85
         upper limit
    		 2.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Statistical analysis title
    		 Degree of contrast enhancement - Reader 1
    Statistical analysis description
    The Null hypothesis is rejected if the difference [“Paired” scores mean – “Pre” scores mean] is significantly different from zero with a type 1 error set at 0.025.
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.69
         upper limit
    		 2.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Statistical analysis title
    		 Degree of contrast enhancement - Reader 2
    Statistical analysis description
    The Null hypothesis is rejected if the difference [“Paired” scores mean – “Pre” scores mean] is significantly different from zero with a type 1 error set at 0.025.
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.49
         upper limit
    		 2.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Statistical analysis title
    		 Degree of contrast enhancement - Reader 3
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.84
         upper limit
    		 2.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03

    Primary: Lesion visualization criteria for gadopiclenol compared to gadobutrol (off-site read)

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    End point title
    		 Lesion visualization criteria for gadopiclenol compared to gadobutrol (off-site read)
    End point description
    The lesion visualization criteria were based on 3 co-primary criteria: border delineation, internal morphology and degree of contrast enhancement, assessed on the images acquired during the MRI performed with gadopiclenol and those performed with gadobutrol. Data presented are the differences in mean of scores for border delineation, internal morphology and degree of contrast enhancement.
    End point type
    Primary
    End point timeframe
    Data from two different MRI (with gadopiclenol and gadobutrol) performed at an interval of 2 to 14 days
    End point values
    		 PPS2 Gadopiclenol PPS2 Gadobutrol
    Number of subjects analysed
    236
    236
    Units: None
    least squares mean (standard error)
        Border delineation - Reader 1
    3.91 ( 0.02 )
    3.93 ( 0.02 )
        Border delineation - Reader 2
    3.64 ( 0.04 )
    3.60 ( 0.04 )
        Border delineation - Reader 3
    3.97 ( 0.01 )
    3.95 ( 0.01 )
        Internal morphology - Reader 1
    3.93 ( 0.02 )
    3.93 ( 0.02 )
        Internal morphology - Reader 2
    3.64 ( 0.04 )
    3.62 ( 0.04 )
        Internal morphology - Reader 3
    3.97 ( 0.02 )
    3.92 ( 0.02 )
        Degree of contrast enhancement - Reader 1
    3.78 ( 0.04 )
    3.77 ( 0.04 )
        Degree of contrast enhancement - Reader 2
    3.57 ( 0.04 )
    3.52 ( 0.04 )
        Degree of contrast enhancement - Reader 3
    3.89 ( 0.03 )
    3.81 ( 0.03 )
    Statistical analysis title
    		 Border delineation - Reader 1
    Statistical analysis description
    The Null hypothesis is rejected if the 2-sided 95% Confidence Interval (CI) for the difference [gadopiclenol scores mean – gadobutrol scores mean] had its lower limit above -0.35
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Statistical analysis title
    		 Border delineation - Reader 2
    Statistical analysis description
    The Null hypothesis is rejected if the 2-sided 95% Confidence Interval (CI) for the difference [gadopiclenol scores mean – gadobutrol scores mean] had its lower limit above -0.35
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Statistical analysis title
    		 Border delineation - Reader 3
    Statistical analysis description
    The Null hypothesis is rejected if the 2-sided 95% Confidence Interval (CI) for the difference [gadopiclenol scores mean – gadobutrol scores mean] had its lower limit above -0.35
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Statistical analysis title
    		 Internal morphology - Reader 1
    Statistical analysis description
    The Null hypothesis is rejected if the 2-sided 95% Confidence Interval (CI) for the difference [gadopiclenol scores mean – gadobutrol scores mean] had its lower limit above -0.35
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Statistical analysis title
    		 Internal morphology - Reader 2
    Statistical analysis description
    The Null hypothesis is rejected if the 2-sided 95% Confidence Interval (CI) for the difference [gadopiclenol scores mean – gadobutrol scores mean] had its lower limit above -0.35
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Statistical analysis title
    		 Internal morphology - Reader 3
    Statistical analysis description
    The Null hypothesis is rejected if the 2-sided 95% Confidence Interval (CI) for the difference [gadopiclenol scores mean – gadobutrol scores mean] had its lower limit above -0.35
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Statistical analysis title
    		 Degree of contrast enhancement - Reader 1
    Statistical analysis description
    The Null hypothesis is rejected if the 2-sided 95% Confidence Interval (CI) for the difference [gadopiclenol scores mean – gadobutrol scores mean] had its lower limit above -0.35
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Statistical analysis title
    		 Degree of contrast enhancement - Reader 2
    Statistical analysis description
    The Null hypothesis is rejected if the 2-sided 95% Confidence Interval (CI) for the difference [gadopiclenol scores mean – gadobutrol scores mean] had its lower limit above -0.35
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Notes
    [1] - The Null hypothesis is rejected if the 2-sided 95% Confidence Interval (CI) for the difference [gadopiclenol scores mean – gadobutrol scores mean] had its lower limit above -0.35
    Statistical analysis title
    		 Degree of contrast enhancement - Reader 3
    Statistical analysis description
    The Null hypothesis is rejected if the 2-sided 95% Confidence Interval (CI) for the difference [gadopiclenol scores mean – gadobutrol scores mean] had its lower limit above -0.35
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from informed consent signature up to one day after the second MRI. For patients enrolled in France: a safety follow-up contact between 7 and 14 days after the last IMP injection was performed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Safety Set - Gadopiclenol
    Reporting group description
    		 All patients having received at least one injection of gadopiclenol regardless of the quantity

    Reporting group title
    Safety Set - Gadobutrol
    Reporting group description
    		 All patients having received at least one injection of gadobutrol regardless of the quantity

    Serious adverse events
    		 Safety Set - Gadopiclenol Safety Set - Gadobutrol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    General physical health deterioration
    Additional description: Worsening General Condition Leading To Fatal Respiratory Failure Not related to contrast
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety Set - Gadopiclenol Safety Set - Gadobutrol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 247 (14.57%)
    42 / 245 (17.14%)
    Vascular disorders
    Pallor
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    5 / 247 (2.02%)
    5 / 245 (2.04%)
         occurrences all number
    5
    5
    Injection site bruising
         subjects affected / exposed
    3 / 247 (1.21%)
    3 / 245 (1.22%)
         occurrences all number
    3
    3
    Injection site erythema
         subjects affected / exposed
    1 / 247 (0.40%)
    3 / 245 (1.22%)
         occurrences all number
    1
    3
    Injection site coldness
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 245 (0.41%)
         occurrences all number
    2
    1
    Injection site warmth
         subjects affected / exposed
    1 / 247 (0.40%)
    2 / 245 (0.82%)
         occurrences all number
    1
    2
    Injection site haematoma
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 245 (0.41%)
         occurrences all number
    1
    1
    Injection site haemorrhage
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 245 (0.82%)
         occurrences all number
    0
    2
    Injection site paraesthesia
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 245 (0.41%)
         occurrences all number
    1
    1
    Vessel puncture site haemorrhage
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 245 (0.82%)
         occurrences all number
    0
    5
    Asthenia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Drug ineffective
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Feeling hot
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Injection site discomfort
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Injection site extravasation
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Injection site hypoaesthesia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Injection site oedema
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Claustrophobia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 247 (0.40%)
    5 / 245 (2.04%)
         occurrences all number
    1
    5
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count increased
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Incorrect dose administered
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 245 (0.41%)
         occurrences all number
    2
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 247 (0.81%)
    5 / 245 (2.04%)
         occurrences all number
    2
    5
    Dizziness
         subjects affected / exposed
    5 / 247 (2.02%)
    1 / 245 (0.41%)
         occurrences all number
    5
    1
    Dysgeusia
         subjects affected / exposed
    1 / 247 (0.40%)
    2 / 245 (0.82%)
         occurrences all number
    1
    2
    Partial seizures
         subjects affected / exposed
    1 / 247 (0.40%)
    2 / 245 (0.82%)
         occurrences all number
    1
    2
    Blood and lymphatic system disorders
    Anaemia macrocytic
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Eye disorders
    Scleral haemorrhage
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 247 (1.62%)
    1 / 245 (0.41%)
         occurrences all number
    4
    1
    Paraesthesia oral
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 245 (0.41%)
         occurrences all number
    1
    1
    Erythema
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 245 (0.41%)
         occurrences all number
    1
    1
    Ecchymosis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Rash macular
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Myofascial pain syndrome
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (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.
    None reported
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