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    Clinical Trial Results:
    Efficacy and safety of gadopiclenol for body magnetic resonance imaging (MRI) (The PROMISE trial)

    Summary
    EudraCT number
    		 2018-003946-18
    Trial protocol
    		 FR   HU   BG   DE   ES   IT  
    Global end of trial date
    09 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Dec 2021
    First version publication date
    24 Dec 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GDX-44-011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03986138
    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 145915176, jing.hao@guerbet.com
    Scientific contact
    Jing Hao, MD, GUERBET, +33 145915176, 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
    31 May 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective 1: To demonstrate the superiority of gadopiclenol-enhanced MRI at 0.05 mmol/kg body weight compared to unenhanced MRI for patients referred for contrast-enhanced MRI of body regions, in terms of 3 lesion visualization co-primary criteria (border delineation, internal morphology and degree of contrast enhancement) using the patient as his/her own control. Primary objective 2: 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 (border delineation, internal morphology, degree of contrast enhancement) for patients referred for contrast-enhanced MRI of body regions.
    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
    27 Aug 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
    Korea, Democratic People's Republic of: 46
    Country: Number of subjects enrolled
    Mexico: 31
    Country: Number of subjects enrolled
    Ukraine: 17
    Country: Number of subjects enrolled
    United States: 49
    Country: Number of subjects enrolled
    Poland: 75
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Bulgaria: 11
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 51
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    304
    EEA total number of subjects
    161
    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)
    202
    From 65 to 84 years
    101
    85 years and over
    1

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 324 [1]
    Number of subjects completed
    		 304

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Received first contrast agent but not randomized: 1
    Reason: Number of subjects
    		 screen failure: 19
    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 (324) is the number of screened patients. Among these patients, 304 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
    		 Investigator, Monitor, Data analyst, Subject, 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 injection rate was depending on scanned organ/region and a saline flush should follow, preferably via a 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 injection rate was depending on scanned organ/region and a saline flush should follow, preferably via a power injector.

    Number of subjects in period 1
    		Overall population
    Started
    304
    Completed
    275
    Not completed
    29
         Adverse event other than COVID-19
    2
         COVID-19 pandemic preventing protocol follow-up
    2
         Consent withdrawn by subject
    11
         COVID-19
    1
         Other reason
    12
         Discovery of an unacceptable risk to the patient
    1

    Baseline characteristics

    		 Close Top of page
    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
    		 304 304
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 202 202
        From 65-84 years
    		 101 101
        85 years and over
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.29 ± 12.93 -
    Gender categorical
    Units: Subjects
        Female
    		 180 180
        Male
    		 124 124

    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.
    End point type
    Primary
    End point timeframe
    1 day procedure
    End point values
    		 FAS1 Paired images FAS1 Pre images
    Number of subjects analysed
    278
    278
    Units: None
    least squares mean (standard error)
        Border delineation - Reader 1
    3.79 ± 0.03
    2.26 ± 0.03
        Border delineation - Reader 2
    3.48 ± 0.06
    3.01 ± 0.06
        Border delineation - Reader 3
    3.49 ± 0.03
    1.78 ± 0.03
        Internal morphology - Reader 1
    3.80 ± 0.02
    1.99 ± 0.02
        Internal morphology - Reader 2
    3.75 ± 0.05
    3.22 ± 0.05
        Internal morphology - Reader 3
    3.72 ± 0.03
    1.69 ± 0.03
        Degree of contrast enhancement - Reader 1
    3.64 ± 0.03
    1.00 ± 0.03
        Degree of contrast enhancement - Reader 2
    2.82 ± 0.05
    1.00 ± 0.05
        Degree of contrast enhancement - Reader 3
    3.33 ± 0.03
    1.00 ± 0.03
    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
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.46
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    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
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    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
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.65
         upper limit
    		 1.78
    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
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.76
         upper limit
    		 1.87
    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
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Statistical analysis title
    		 Internal morphology - Reader 3
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.95
         upper limit
    		 2.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Statistical analysis title
    		 Degree of contrast enhancement - Reader 1
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.56
         upper limit
    		 2.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Statistical analysis title
    		 Degree of contrast enhancement - Reader 2
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    556
    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
    		 1.68
         upper limit
    		 1.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Statistical analysis title
    		 Degree of contrast enhancement - Reader 3
    Comparison groups
    FAS1 Paired images v FAS1 Pre images
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.26
         upper limit
    		 2.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04

    Primary: Lesion visualization criteria for gadopiclenol compared to gadobutrol (offsite read)

    		 Close Top of page
    End point title
    		 Lesion visualization criteria for gadopiclenol compared to gadobutrol (offsite 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.
    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
    260
    260
    Units: None
    least squares mean (standard error)
        Border delineation - Reader 1
    3.82 ± 0.02
    3.81 ± 0.02
        Border delineation - Reader 2
    3.56 ± 0.05
    3.53 ± 0.05
        Border delineation - Reader 3
    3.53 ± 0.03
    3.57 ± 0.03
        Internal morphology - Reader 1
    3.83 ± 0.02
    3.83 ± 0.02
        Internal morphology - Reader 2
    3.75 ± 0.04
    3.75 ± 0.04
        Internal morphology - Reader 3
    3.74 ± 0.03
    3.77 ± 0.03
        Degree of contrast enhancement - Reader 1
    3.69 ± 0.04
    3.68 ± 0.04
        Degree of contrast enhancement - Reader 2
    2.88 ± 0.07
    2.86 ± 0.07
        Degree of contrast enhancement - Reader 3
    3.35 ± 0.04
    3.37 ± 0.04
    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
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    520
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.05
    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 2-sided 95% Confidence Interval (CI) for the difference.
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    520
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.1
    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.
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    520
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    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.
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    520
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Statistical analysis title
    		 Internal morphology - Reader 2
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    520
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.07
    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 2-sided 95% Confidence Interval (CI) for the difference.
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    520
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.02
    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.
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    520
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.09
    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 2-sided 95% Confidence Interval (CI) for the difference.
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    520
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    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.
    Comparison groups
    PPS2 Gadopiclenol v PPS2 Gadobutrol
    Number of subjects included in analysis
    520
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.04
    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
    3 / 288 (1.04%)
    0 / 290 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    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
    49 / 288 (17.01%)
    58 / 290 (20.00%)
    Surgical and medical procedures
    Central venous catheterisation
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    5 / 288 (1.74%)
    7 / 290 (2.41%)
         occurrences all number
    5
    7
    Injection site bruising
         subjects affected / exposed
    3 / 288 (1.04%)
    1 / 290 (0.34%)
         occurrences all number
    3
    1
    Fatigue
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 290 (0.34%)
         occurrences all number
    1
    1
    Injection site discomfort
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 290 (0.34%)
         occurrences all number
    1
    1
    Injection site erythema
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 290 (0.69%)
         occurrences all number
    0
    2
    Injection site haemorrhage
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 290 (0.69%)
         occurrences all number
    0
    2
    Pain
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 290 (0.69%)
         occurrences all number
    0
    2
    Asthenia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Extravasation
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Infusion site pain
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Injection site haematoma
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Injection site inflammation
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Injection site pruritus
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Injection site warmth
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 290 (0.34%)
         occurrences all number
    1
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 290 (0.34%)
         occurrences all number
    1
    1
    Swelling
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Contrast media reaction
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Drug hypersensitivity
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 290 (0.34%)
         occurrences all number
    2
    1
    Epistaxis
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 290 (0.69%)
         occurrences all number
    0
    2
    Dyspnoea
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 290 (0.69%)
         occurrences all number
    0
    2
    Investigations
    Blood pressure increased
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 290 (0.69%)
         occurrences all number
    2
    2
    Cystatin C increased
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 290 (0.34%)
         occurrences all number
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Paracentesis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Incorrect dosage administered
         subjects affected / exposed
    5 / 288 (1.74%)
    4 / 290 (1.38%)
         occurrences all number
    5
    4
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 288 (5.56%)
    4 / 290 (1.38%)
         occurrences all number
    17
    4
    Dizziness
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 290 (0.34%)
         occurrences all number
    1
    1
    Dysgeusia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 288 (0.69%)
    3 / 290 (1.03%)
         occurrences all number
    2
    3
    Neutropenia
         subjects affected / exposed
    1 / 288 (0.35%)
    4 / 290 (1.38%)
         occurrences all number
    1
    4
    Leukopenia
         subjects affected / exposed
    0 / 288 (0.00%)
    3 / 290 (1.03%)
         occurrences all number
    0
    3
    Thrombocytopenia
         subjects affected / exposed
    0 / 288 (0.00%)
    3 / 290 (1.03%)
         occurrences all number
    0
    3
    Lymphopenia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Monocytopenia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Eye disorders
    Swelling of eyelid
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 288 (1.74%)
    4 / 290 (1.38%)
         occurrences all number
    5
    4
    Dry mouth
         subjects affected / exposed
    3 / 288 (1.04%)
    3 / 290 (1.03%)
         occurrences all number
    3
    3
    Diarrhoea
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 290 (0.69%)
         occurrences all number
    2
    2
    Vomiting
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 290 (0.69%)
         occurrences all number
    1
    2
    Abdominal pain
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 290 (0.34%)
         occurrences all number
    1
    1
    Abdominal distension
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Enteritis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Dermatitis allergic
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Nephropathy
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 290 (0.34%)
         occurrences all number
    1
    1
    Renal impairment
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 290 (0.69%)
         occurrences all number
    0
    2
    Acute kidney injury
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Renal failure
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 290 (0.34%)
         occurrences all number
    2
    1
    Back pain
         subjects affected / exposed
    0 / 288 (0.00%)
    3 / 290 (1.03%)
         occurrences all number
    0
    3
    Muscle spasms
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Pain in jaw
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 290 (0.34%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 290 (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
    30 Jun 2020
    The anticipated actual rate of non-evaluable patients was estimated to be higher than initially planned: the revised hypothesis for the non-evaluable patient rate was about 33% instead of 20%. This increase in drop-out rate was due in part to the Covid-19 pandemic impact on enrollment of patients and/or compliance with protocol, but also to the variety and complexity of organs in this study. Therefore, to secure the target 200 evaluable patients needed for sufficient statistical power to meet both study primary objectives, the sample size had to be increased from 250 to 300 enrolled patients.

    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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