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    Clinical Trial Results:
    P03277 Dose Finding Study in Central Nervous System (CNS) Magnetic Resonance Imaging (MRI)

    Summary
    EudraCT number
    		 2014-003576-23
    Trial protocol
    		 BE   CZ   HU   IT  
    Global end of trial date
    23 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2019
    First version publication date
    01 Mar 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GDX-44-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02633501
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 123673
    Sponsors
    Sponsor organisation name
    Guerbet
    Sponsor organisation address
    BP 57400, Roissy CDG Cedex, France, 95943
    Public contact
    Jing HAO, Head of Medical Affairs & Clinical Development, GUERBET, +33 145915000, jing.hao@guerbet.com
    Scientific contact
    Jing HAO, Head of Medical Affairs & Clinical Development, GUERBET, +33 145915000, 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 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine a safe and effective dose of P03277 based on a comparison of Contrast to Noise Ratio (CNR) between several doses, 0.025, 0.05, 0.1, 0.2 mmol/kg, of P03277 and gadobenate dimeglumine (MultiHance®) at 0.1 mmol/kg.
    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, ECG, injection site tolerance, clinical laboratory parameters and monitoring of adverse events.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2016
    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
    Poland: 13
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Hungary: 90
    Country: Number of subjects enrolled
    Mexico: 93
    Country: Number of subjects enrolled
    United States: 55
    Country: Number of subjects enrolled
    Korea, Republic of: 29
    Country: Number of subjects enrolled
    Italy: 23
    Worldwide total number of subjects
    312
    EEA total number of subjects
    135
    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)
    231
    From 65 to 84 years
    79
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 312
    Intermediate milestone: Number of subjects
    Randomization: 280
    Number of subjects completed
    		 272

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 11
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 Various reasons: 26
    Reason: Number of subjects
    		 Adverse event, serious fatal: 1
    Reason: Number of subjects
    		 Adverse event, non-fatal: 1
    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, Assessor, Subject

    Arms
    Arm title
    		 Overall population
    Arm description
    		 All subjects who had received at least one injection of contrast agent, regardless of the quantity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    P03277
    Investigational medicinal product code
    Other name
    Gadopiclenol
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    One of the four doses (0.025, 0.05, 0.1 or 0.2 mmol/kg body weight) in a single intravenous injection.

    Investigational medicinal product name
    Gadobenate dimeglumine
    Investigational medicinal product code
    Other name
    MultiHance
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.1 mmol/kg body weight in a single intravenous injection.

    Number of subjects in period 1 [1]
    		Overall population
    Started
    272
    Completed
    238
    Not completed
    34
         Consent withdrawn by subject
    9
         Adverse event, non-fatal
    2
         Other reasons
    20
         Lost to follow-up
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Among the 312 screened subjects, 32 subjects were screening failure mainly due to not fulfillment of inclusion criteria/ presence of non-inclusion criteria or due to consent withdrawal. Therefore 280 subjects were randomized. Eight randomized subjects were prematurely withdrawn before receiving the first contrast agent administration (2 for withdrawal of subject's consent, 1 for adverse event and 5 for other reason).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall population
    Reporting group description
    		 All subjects who had received at least one injection of contrast agent, regardless of the quantity.

    Reporting group values
    		 Overall population Total
    Number of subjects
    		 272 272
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 53.8 ± 13.6 -
    Gender categorical
    Units: Subjects
        Female
    		 159 159
        Male
    		 113 113

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Overall population
    Reporting group description
    		 All subjects who had received at least one injection of contrast agent, regardless of the quantity.

    Subject analysis set title
    P03277 0.2 mmol/kg - Reader 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.1 mmol/kg - Reader 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.05 mmol/kg - Reader 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.025 mmol/kg - Reader 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.2 mmol/kg - Reader 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.1 mmol/kg - Reader 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.05 mmol/kg - Reader 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.025 mmol/kg - Reader 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.2 mmol/kg - Reader 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.1 mmol/kg - Reader 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.05 mmol/kg - Reader 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    P03277 0.025 mmol/kg - Reader 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.2 mmol/kg) - Reader 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.1 mmol/kg) - Reader 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.05 mmol/kg) - Reader 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.025 mmol/kg) - Reader 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.1 mmol/kg) - Reader 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.05 mmol/kg) - Reader 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.025 mmol/kg) - Reader 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.2 mmol/kg) - Reader 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.1 mmol/kg) - Reader 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.05 mmol/kg) - Reader 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.025 mmol/kg) - Reader 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Subject analysis set title
    Gadobenate dimeglumine (P03277 0.2 mmol/kg) - Reader 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set included all subjects who have a Contrast-to-Noise Ratio (CNR) from both enhanced and unenhanced measurements derivable from one MRI by at least one off-site blinded reader and who had no major protocol deviations throughout their whole study period.

    Primary: Contrast-to-Noise Ratio (CNR)

    		 Close Top of page
    End point title
    		 Contrast-to-Noise Ratio (CNR)
    End point description
    The Contrast-to-Noise Ratio (CNR) was calculated from the signal intensity measurement of maximum 3 enhanced lesions by 3 independent blinded readers.
    End point type
    Primary
    End point timeframe
    1 day procedure
    End point values
    		 P03277 0.2 mmol/kg - Reader 1 P03277 0.1 mmol/kg - Reader 1 P03277 0.05 mmol/kg - Reader 1 P03277 0.025 mmol/kg - Reader 1 P03277 0.2 mmol/kg - Reader 2 P03277 0.1 mmol/kg - Reader 2 P03277 0.05 mmol/kg - Reader 2 P03277 0.025 mmol/kg - Reader 2 P03277 0.2 mmol/kg - Reader 3 P03277 0.1 mmol/kg - Reader 3 P03277 0.05 mmol/kg - Reader 3 P03277 0.025 mmol/kg - Reader 3 Gadobenate dimeglumine (P03277 0.2 mmol/kg) - Reader 1 Gadobenate dimeglumine (P03277 0.1 mmol/kg) - Reader 1 Gadobenate dimeglumine (P03277 0.05 mmol/kg) - Reader 1 Gadobenate dimeglumine (P03277 0.025 mmol/kg) - Reader 1 Gadobenate dimeglumine (P03277 0.1 mmol/kg) - Reader 2 Gadobenate dimeglumine (P03277 0.05 mmol/kg) - Reader 2 Gadobenate dimeglumine (P03277 0.025 mmol/kg) - Reader 2 Gadobenate dimeglumine (P03277 0.2 mmol/kg) - Reader 3 Gadobenate dimeglumine (P03277 0.1 mmol/kg) - Reader 3 Gadobenate dimeglumine (P03277 0.05 mmol/kg) - Reader 3 Gadobenate dimeglumine (P03277 0.025 mmol/kg) - Reader 3 Gadobenate dimeglumine (P03277 0.2 mmol/kg) - Reader 2
    Number of subjects analysed
    44
    51
    56
    54
    41
    43
    47
    44
    42
    45
    51
    49
    44
    51
    56
    54
    43
    47
    44
    42
    45
    51
    49
    41
    Units: None
        least squares mean (standard error)
    49.99 ± 7.96
    35.94 ± 2.71
    31.78 ± 3.58
    21.13 ± 2.65
    103.18 ± 10.94
    72.17 ± 6.29
    51.02 ± 5.09
    43.15 ± 7.57
    125.08 ± 14.08
    94.17 ± 7.99
    67.05 ± 6.43
    46.74 ± 10.04
    35.55 ± 7.96
    27.28 ± 2.71
    29.60 ± 3.58
    31.72 ± 2.65
    52.79 ± 6.29
    49.11 ± 5.09
    57.29 ± 7.57
    73.12 ± 14.08
    64.94 ± 7.99
    64.58 ± 6.43
    70.70 ± 10.04
    64.81 ± 10.94
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 44. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.2 mmol/kg - Reader 1 v Gadobenate dimeglumine (P03277 0.2 mmol/kg) - Reader 1
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    14.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.64
         upper limit
    		 21.25
    Notes
    [1] - Superiority confirmed
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 51. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.1 mmol/kg - Reader 1 v Gadobenate dimeglumine (P03277 0.1 mmol/kg) - Reader 1
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    8.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.52
         upper limit
    		 13.79
    Notes
    [2] - Superiority confirmed
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 56. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.05 mmol/kg - Reader 1 v Gadobenate dimeglumine (P03277 0.05 mmol/kg) - Reader 1
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1858 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    2.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.67
         upper limit
    		 7.03
    Notes
    [3] - Superiority not confirmed
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 54. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.025 mmol/kg - Reader 1 v Gadobenate dimeglumine (P03277 0.025 mmol/kg) - Reader 1
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -10.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.59
         upper limit
    		 -6.58
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 41. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.2 mmol/kg - Reader 2 v Gadobenate dimeglumine (P03277 0.2 mmol/kg) - Reader 2
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    38.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.62
         upper limit
    		 58.12
    Notes
    [4] - Superiority confirmed
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 43. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.1 mmol/kg - Reader 2 v Gadobenate dimeglumine (P03277 0.1 mmol/kg) - Reader 2
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    19.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.42
         upper limit
    		 27.34
    Notes
    [5] - Superiority confirmed
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 47. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.05 mmol/kg - Reader 2 v Gadobenate dimeglumine (P03277 0.05 mmol/kg) - Reader 2
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3384 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.28
         upper limit
    		 11.1
    Notes
    [6] - Superiority not confirmed
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 44. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.025 mmol/kg - Reader 2 v Gadobenate dimeglumine (P03277 0.025 mmol/kg) - Reader 2
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -14.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.33
         upper limit
    		 -4.95
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 42. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.2 mmol/kg - Reader 3 v Gadobenate dimeglumine (P03277 0.2 mmol/kg) - Reader 3
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    51.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 30.36
         upper limit
    		 73.55
    Notes
    [7] - Superiority confirmed
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 45. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.1 mmol/kg - Reader 3 v Gadobenate dimeglumine (P03277 0.1 mmol/kg) - Reader 3
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    29.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.05
         upper limit
    		 42.41
    Notes
    [8] - Superiority confirmed
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 51. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.05 mmol/kg - Reader 3 v Gadobenate dimeglumine (P03277 0.05 mmol/kg) - Reader 3
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3249 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    2.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.39
         upper limit
    		 13.32
    Notes
    [9] - Superiority not confirmed
    Statistical analysis title
    		 Mixed Models - Holm's Step-Down Method
    Statistical analysis description
    The number of subjects analyzed was 49. The difference in CNR was calculated as follow: CNR (P03277) - CNR (gadobenate dimeglumine).
    Comparison groups
    P03277 0.025 mmol/kg - Reader 3 v Gadobenate dimeglumine (P03277 0.025 mmol/kg) - Reader 3
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -23.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.78
         upper limit
    		 -14.13

    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.
    Adverse event reporting additional description
    Post-injection adverse events are reported below.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    P03277 all doses
    Reporting group description
    		 Subjects who received one injection of P03277 regardless of the injection order versus gadobenate dimeglumine.

    Reporting group title
    Gadobenate dimeglumine
    Reporting group description
    		 Subjects who received one injection of gadobenate dimeglumine regardless of the injection order versus P03277.

    Serious adverse events
    		 P03277 all doses Gadobenate dimeglumine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 256 (0.78%)
    2 / 256 (0.78%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood creatine increased
    Additional description: After injection of P03277 at 0.1 mmol/kg
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
    Additional description: After injection of P03277 at 0.2 mmol/kg
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Meningioma Surgery
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 P03277 all doses Gadobenate dimeglumine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 256 (24.61%)
    57 / 256 (22.27%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 256 (0.39%)
         occurrences all number
    1
    1
    Peripheral coldness
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    2
    0
    Flushing
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    14 / 256 (5.47%)
    9 / 256 (3.52%)
         occurrences all number
    17
    9
    Injection site coldness
         subjects affected / exposed
    2 / 256 (0.78%)
    4 / 256 (1.56%)
         occurrences all number
    2
    4
    Fatigue
         subjects affected / exposed
    4 / 256 (1.56%)
    1 / 256 (0.39%)
         occurrences all number
    4
    1
    Injection site warmth
         subjects affected / exposed
    1 / 256 (0.39%)
    3 / 256 (1.17%)
         occurrences all number
    1
    3
    Feeling hot
         subjects affected / exposed
    0 / 256 (0.00%)
    2 / 256 (0.78%)
         occurrences all number
    0
    3
    Infusion site extravasation
         subjects affected / exposed
    0 / 256 (0.00%)
    2 / 256 (0.78%)
         occurrences all number
    0
    2
    Injection site oedema
         subjects affected / exposed
    2 / 256 (0.78%)
    0 / 256 (0.00%)
         occurrences all number
    2
    0
    Chills
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 256 (0.39%)
         occurrences all number
    1
    1
    Injection site bruising
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Injection site erythema
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Injection site haematoma
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Injection site inflammation
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Injection site paraesthesia
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Injection site reaction
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Sensation of foreign body
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 256 (0.39%)
         occurrences all number
    1
    1
    Investigations
    Blood pressure increased
         subjects affected / exposed
    3 / 256 (1.17%)
    2 / 256 (0.78%)
         occurrences all number
    3
    2
    Blood creatine increased
         subjects affected / exposed
    0 / 256 (0.00%)
    2 / 256 (0.78%)
         occurrences all number
    0
    2
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 256 (0.39%)
    2 / 256 (0.78%)
         occurrences all number
    1
    2
    Blood urea increased
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    2
    Electrocardiogram QT interval abnormal
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Urobilinogen urine
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    2
    0
    Palpitations
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Sinus arrhythmia
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 256 (2.73%)
    6 / 256 (2.34%)
         occurrences all number
    7
    6
    Dizziness
         subjects affected / exposed
    2 / 256 (0.78%)
    4 / 256 (1.56%)
         occurrences all number
    2
    7
    Seizure
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 256 (0.39%)
         occurrences all number
    1
    1
    Dysgeusia
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Lymphocytosis
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 256 (0.39%)
         occurrences all number
    1
    1
    Ear pain
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Eye disorders
    Eye irritation
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Periorbital oedema
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 256 (0.39%)
    9 / 256 (3.52%)
         occurrences all number
    1
    9
    Diarrhoea
         subjects affected / exposed
    3 / 256 (1.17%)
    0 / 256 (0.00%)
         occurrences all number
    3
    0
    Vomiting
         subjects affected / exposed
    2 / 256 (0.78%)
    1 / 256 (0.39%)
         occurrences all number
    2
    2
    Abdominal pain
         subjects affected / exposed
    1 / 256 (0.39%)
    1 / 256 (0.39%)
         occurrences all number
    1
    1
    Abdominal discomfort
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Glossitis
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 256 (0.39%)
    2 / 256 (0.78%)
         occurrences all number
    1
    3
    Cold sweat
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Erythema
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    5 / 256 (1.95%)
    4 / 256 (1.56%)
         occurrences all number
    5
    4
    Bilirubinuria
         subjects affected / exposed
    2 / 256 (0.78%)
    2 / 256 (0.78%)
         occurrences all number
    2
    2
    Glycosuria
         subjects affected / exposed
    1 / 256 (0.39%)
    2 / 256 (0.78%)
         occurrences all number
    1
    2
    Haematuria
         subjects affected / exposed
    1 / 256 (0.39%)
    2 / 256 (0.78%)
         occurrences all number
    1
    2
    Haemoglobinuria
         subjects affected / exposed
    1 / 256 (0.39%)
    2 / 256 (0.78%)
         occurrences all number
    1
    2
    Proteinuria
         subjects affected / exposed
    3 / 256 (1.17%)
    0 / 256 (0.00%)
         occurrences all number
    3
    0
    Ketonuria
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Nitrituria
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 256 (1.17%)
    0 / 256 (0.00%)
         occurrences all number
    3
    0
    Influenza
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 256 (0.78%)
    1 / 256 (0.39%)
         occurrences all number
    2
    1
    Diabetes mellitus
         subjects affected / exposed
    0 / 256 (0.00%)
    1 / 256 (0.39%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 256 (0.39%)
    0 / 256 (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
    11 Jul 2016
    Exclusion of subject presenting with acute relapse of multiple sclerosis Deletion of eGFR evaluation at visit 1 New biochemistry dosage; cystatin C and triglycerides Clarification that radiologist or neuro-radiologist could be involved in the study Update on ECG description Adverse event definition clarification Unusual failure in efficacy deleted from collection of adverse event description Addition of a subject stopping rule related to cystatin C and clarification of the serum creatinine value stopping rule Clarification of technical adequacy of images

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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