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    Clinical Trial Results:
    A Phase IV, Double-Blind, Multi-Center Randomized, Crossover Study to Compare 0.1 mmol/kg of ProHance® with 0.1 mmol/kg of Gadovist®/Gadavist™ in Magnetic Resonance Imaging (MRI) of the Brain (TRUTH)

    Summary
    EudraCT number
    		 2011-006135-29
    Trial protocol
    		 CZ   IT  
    Global end of trial date
    03 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2020
    First version publication date
    23 Oct 2020
    Other versions
    Summary report(s)
    		 Study PH-107 Publication

    Trial information

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    Trial identification
    Sponsor protocol code
    PH-107
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01613417
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bracco Diagnostics Inc.
    Sponsor organisation address
    259 Prospect Plains Road, Building H, Monroe Township, United States, 08831
    Public contact
    Gianpaolo Pirovano, MD Executive Director, MRI, Bracco Diagnostics Inc. Global Medical and Regulatory Affairs (GM&RA), 1 609-514-2226, gianpaolo.pirovano@diag.bracco.com
    Scientific contact
    Gianpaolo Pirovano, MD Executive Director, MRI, Bracco Diagnostics Inc. Global Medical and Regulatory Affairs (GM&RA), 1 609-514-2226, gianpaolo.pirovano@diag.bracco.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
    02 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective for this study is to show non-inferiority of a 0.1 mmol/kg dose of ProHance as compared to 0.1 mmol/kg dose of Gadovist/Gadavist, in terms of the by-subject global diagnostic preference between exams (i.e., based on predose + postdose image sets).
    Protection of trial subjects
    none
    Background therapy
    		 none
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Aug 2012
    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: 23
    Country: Number of subjects enrolled
    Czech Republic: 71
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    United States: 102
    Country: Number of subjects enrolled
    Canada: 16
    Worldwide total number of subjects
    229
    EEA total number of subjects
    111
    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)
    162
    From 65 to 84 years
    66
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 229 patients were enrolled from August 2012 through December 2013 at 19 clinical trial sites. Offsite assessment of the images was performed between 21 January and 3 April 2014 by 3 board-certified neuroradiologists blinded as to which contrast agent was used, patient clinical information, and the results of other imaging studies.

    Pre-assignment
    Screening details
    		 229 patients were enrolled and signed informed consent. Each enrolled patient was randomized and dosed with at least one contrast agent.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ProHance then Gadovist/Gadavist/Gadobutrol
    Arm description
    		 In this double-blind, two-arm study, the Investigator and the patient were blinded to the investigational product administered for Exam 1 and for Exam 2. A computer generated randomization code list was provided by the Sponsor to each site for the assignment of study arm as well as for the assignment of investigational product. Patients from the 2 arms were mixed in one randomization list.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    Other name
    Gadovist/Gadavist
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.1 mmol/kg IV

    Arm title
    		 Gadovist/Gadavist then ProHance/Gadoteridol
    Arm description
    		 In this double-blind, two-arm study, the Investigator and the patient were blinded to the investigational product administered for Exam 1 and for Exam 2. A computer generated randomization code list was provided by the Sponsor to each site for the assignment of study arm as well as for the assignment of investigational product. Patients from the 2 arms were mixed in one randomization list.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gadoteridol
    Investigational medicinal product code
    Other name
    ProHance
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.1 mmol/kg IV

    Number of subjects in period 1
    		ProHance then Gadovist/Gadavist/Gadobutrol Gadovist/Gadavist then ProHance/Gadoteridol
    Started
    113
    116
    Completed
    113
    116
    Period 2
    Period 2 title
    Crossover Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ProHance then Gadovist/Gadavist
    Arm description
    		 Patients randomized to receive ProHance first then Gadovist/Gadavist
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    Other name
    Gadovist/Gadavist
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.1 mmol/kg IV

    Investigational medicinal product name
    Gadoteridol
    Investigational medicinal product code
    Other name
    ProHance
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.1 mmol/kg IV

    Arm title
    		 Gadovist/Gadavist then ProHance
    Arm description
    		 Patients randomized to receive Gadovist/Gadavist first then ProHance
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gadobutrol
    Investigational medicinal product code
    Other name
    Gadovist/Gadavist
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.1 mmol/kg IV

    Investigational medicinal product name
    Gadoteridol
    Investigational medicinal product code
    Other name
    ProHance
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.1 mmol/kg IV

    Number of subjects in period 2
    		ProHance then Gadovist/Gadavist Gadovist/Gadavist then ProHance
    Started
    113
    116
    Completed
    93
    105
    Not completed
    20
    11
         Consent withdrawn by subject
    6
    5
         Adverse event, non-fatal
    2
    -
         Protocol deviation
    12
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 In this double-blind, two-arm study, the Investigator and the patient were blinded to the investigational product administered for Exam 1 and for Exam 2. A computer generated randomization code list was provided by the Sponsor to each site for the assignment of the sequence of study agents (sequence of investigational products). Patients from the 2sequences were mixed in one randomization list.

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 229 229
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 162 162
        From 65-84 years
    		 67 67
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.3 ( 14.39 ) -
    Gender categorical
    Units: Subjects
        Female
    		 131 131
        Male
    		 98 98
    Race
    Units: Subjects
        White
    		 220 220
        Black
    		 3 3
        Asian
    		 4 4
        Other
    		 2 2
    Subject analysis sets

    Subject analysis set title
    Blinded Reader 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Paired Exams Reviewed by Reader 1

    Subject analysis set title
    Blinded Reader 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Paired exams reviewed by Reader 2

    Subject analysis set title
    Blinded Reader 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Paired exams reviewed by Reader 3

    Subject analysis set title
    Dummy Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Due to the system limitation with the EudraCT system, a Dummy set was created and used to as a comparison group. EudraCT does not allow single arm for paired statistical analysis. This dummy set is a workaround for that limitation. No subjects in this set.

    Subject analysis sets values
    		 Blinded Reader 1 Blinded Reader 2 Blinded Reader 3 Dummy Set
    Number of subjects
    198
    194
    196
    1
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    140
    138
    139
    1
        From 65-84 years
    58
    56
    57
    0
        85 years and over
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.2 ( 14.31 )
    55.2 ( 14.31 )
    55.2 ( 14.31 )
    55.2 ( 0 )
    Gender categorical
    Units: Subjects
        Female
    108
    106
    107
    1
        Male
    90
    88
    89
    0
    Race
    Units: Subjects
        White
    190
    186
    188
    1
        Black
    2
    2
    2
    0
        Asian
    4
    4
    4
    0
        Other
    2
    2
    2
    0

    End points

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    End points reporting groups
    Reporting group title
    ProHance then Gadovist/Gadavist/Gadobutrol
    Reporting group description
    		 In this double-blind, two-arm study, the Investigator and the patient were blinded to the investigational product administered for Exam 1 and for Exam 2. A computer generated randomization code list was provided by the Sponsor to each site for the assignment of study arm as well as for the assignment of investigational product. Patients from the 2 arms were mixed in one randomization list.

    Reporting group title
    Gadovist/Gadavist then ProHance/Gadoteridol
    Reporting group description
    		 In this double-blind, two-arm study, the Investigator and the patient were blinded to the investigational product administered for Exam 1 and for Exam 2. A computer generated randomization code list was provided by the Sponsor to each site for the assignment of study arm as well as for the assignment of investigational product. Patients from the 2 arms were mixed in one randomization list.
    Reporting group title
    ProHance then Gadovist/Gadavist
    Reporting group description
    		 Patients randomized to receive ProHance first then Gadovist/Gadavist

    Reporting group title
    Gadovist/Gadavist then ProHance
    Reporting group description
    		 Patients randomized to receive Gadovist/Gadavist first then ProHance

    Subject analysis set title
    Blinded Reader 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Paired Exams Reviewed by Reader 1

    Subject analysis set title
    Blinded Reader 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Paired exams reviewed by Reader 2

    Subject analysis set title
    Blinded Reader 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Paired exams reviewed by Reader 3

    Subject analysis set title
    Dummy Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Due to the system limitation with the EudraCT system, a Dummy set was created and used to as a comparison group. EudraCT does not allow single arm for paired statistical analysis. This dummy set is a workaround for that limitation. No subjects in this set.

    Primary: Global Diagnostic Preference Between the Two Exams

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    End point title
    		 Global Diagnostic Preference Between the Two Exams
    End point description
    Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance 0.1 mmol/kg and Gadovist 0.1 mmol/kg. Readers assessed whether images with ProHance were preferred or images with Gadovist were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers (194-198). Per Protocol = patients who completed both exams, had global paired image data available, and had no major protocol violations.
    End point type
    Primary
    End point timeframe
    Comparison of image sets obtained within 2 to 14 days
    End point values
    		 Blinded Reader 1 Blinded Reader 2 Blinded Reader 3 Dummy Set
    Number of subjects analysed
    198
    194
    196
    1 [1]
    Units: participant exams
        Number of Patient Exams Analyzed
    198
    194
    196
    1
        ProHance Preferred
    14
    7
    1
    0
        Contrast Agents Equal
    171
    180
    195
    1
        Gadovist/Gadavist Preferred
    13
    7
    0
    0
    Notes
    [1] - Due to the system limitation with the EudraCT system, a Dummy set was created.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Global Diagnostic Preference Between the Two Paired Exams. Difference in percentage of which image is better tested by Wilcoxon signed rank test , 2-sided 95% confidence interval was estimated using Altman's general approximate normal method.
    Comparison groups
    Blinded Reader 1 v Dummy Set
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.8516 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion PH better minus GV better
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 5.6
    Notes
    [2] - Power calculation was based on primary endpoint. 185 patients were deemed necessary for the lower limit of the observed 2-sided 95% confidence interval for the difference to exceed non-inferiority margin of -5% with 85% power.
    [3] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Global Diagnostic Preference Between the Two Paired Exams. Difference in percentage of which image is better tested by Wilcoxon signed rank test , 2-sided 95% confidence interval was estimated using Altman's general approximate normal method.
    Comparison groups
    Blinded Reader 2 v Dummy Set
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    P-value
    		 = 1 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion PH better minus GV better
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 3.8
    Notes
    [4] - Power calculation was based on primary endpoint. 185 patients were deemed necessary for the lower limit of the observed 2-sided 95% confidence interval for the difference to exceed non-inferiority margin of -5% with 85% power.
    [5] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Global Diagnostic Preference Between the Two Paired Exams. Difference in percentage of which image is better tested by Wilcoxon signed rank test , 2-sided 95% confidence interval was estimated using Altman's general approximate normal method.
    Comparison groups
    Blinded Reader 3 v Dummy Set
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    P-value
    		 = 1 [7]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion PH better minus GV better
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 1.5
    Notes
    [6] - Power calculation was based on primary endpoint. 185 patients were deemed necessary for the lower limit of the observed 2-sided 95% confidence interval for the difference to exceed non-inferiority margin of -5% with 85% power.
    [7] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.

    Secondary: Lesion Border Delineation

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    End point title
    		 Lesion Border Delineation
    End point description
    Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance 0.1 mmol/kg and Gadovist 0.1 mmol/kg. Readers assessed whether images with ProHance were preferred or images with Gadovist were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers (194-198).
    End point type
    Secondary
    End point timeframe
    Comparison of image sets obtained within 2 to 14 days
    End point values
    		 Blinded Reader 1 Blinded Reader 2 Blinded Reader 3 Dummy Set
    Number of subjects analysed
    198
    194
    196
    1 [8]
    Units: participant exams
        Number of Patient Exams Analyzed
    198
    194
    196
    1
        ProHance Better
    8
    2
    1
    0
        No Difference between Prohance and Gadovist/Gadavi
    181
    189
    195
    1
        Gadovist/Gadavist Better
    9
    3
    0
    0
    Notes
    [8] - Due to the system limitation with the EudraCT system, a Dummy set was created.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Lesion Border Delineation
    Comparison groups
    Blinded Reader 1 v Dummy Set
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 1 [10]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - analysis based on paired assessments.
    [10] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Lesion Border Delineation
    Comparison groups
    Blinded Reader 2 v Dummy Set
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 1 [12]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - analysis based on paired assessments.
    [12] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Lesion Border Delineation
    Comparison groups
    Blinded Reader 3 v Dummy Set
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 1 [14]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [13] - analysis based on paired assessments.
    [14] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.

    Secondary: Lesion Internal Morphology

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    End point title
    		 Lesion Internal Morphology
    End point description
    Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance 0.1 mmol/kg and Gadovist 0.1 mmol/kg. Readers assessed whether images with ProHance were preferred or images with Gadovist were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers (194-198).
    End point type
    Secondary
    End point timeframe
    Comparison of image sets obtained within 2 to 14 days
    End point values
    		 Blinded Reader 1 Blinded Reader 2 Blinded Reader 3 Dummy Set
    Number of subjects analysed
    198
    194
    196
    1 [15]
    Units: participant exams
        Number of Patient Exams Analyzed
    198
    194
    196
    1
        ProHance Better
    2
    2
    1
    0
        No Difference Between ProHance and Gadovist/Gadavi
    195
    188
    195
    1
        Gadovist/Gadavist Better
    1
    4
    0
    0
    Notes
    [15] - Due to the system limitation with the EudraCT system, a Dummy set was created
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Lesion Internal Morphology
    Comparison groups
    Blinded Reader 1 v Dummy Set
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 1 [17]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [16] - analysis based on paired assessments.
    [17] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Lesion Internal Morphology
    Comparison groups
    Blinded Reader 2 v Dummy Set
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.6875 [19]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [18] - analysis is based on paired assessments.
    [19] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Lesion Internal Morphology
    Comparison groups
    Blinded Reader 3 v Dummy Set
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 1 [21]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [20] - analysis is based on paired assessments.
    [21] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.

    Secondary: Extent of Disease

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    End point title
    		 Extent of Disease
    End point description
    Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance 0.1 mmol/kg and Gadovist 0.1 mmol/kg. Readers assessed whether images with ProHance were preferred or images with Gadovist were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers (194-198).
    End point type
    Secondary
    End point timeframe
    Comparison of image sets obtained within 2 to 14 days.
    End point values
    		 Blinded Reader 1 Blinded Reader 2 Blinded Reader 3 Dummy Set
    Number of subjects analysed
    198
    194
    196
    1 [22]
    Units: participant exams
        Number of Patient Exams Analyzed
    198
    194
    196
    1
        ProHance Better
    1
    2
    1
    0
        No Difference Between ProHance and Gadovist/Gadavi
    196
    190
    195
    1
        Gadovist/Gadavist Better
    1
    2
    0
    0
    Notes
    [22] - Due to the system limitation with the EudraCT system, a Dummy set was created.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Extent of Disease
    Comparison groups
    Blinded Reader 1 v Dummy Set
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 1 [24]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [23] - analysis is based on paired assessments.
    [24] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Extent of Disease
    Comparison groups
    Blinded Reader 2 v Dummy Set
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 1 [26]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [25] - analysis is based on paired assessments.
    [26] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Extent of Disease
    Comparison groups
    Blinded Reader 3 v Dummy Set
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 1 [28]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [27] - analysis is based on paired assessments.
    [28] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.

    Secondary: Lesion Contrast Enhancement

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    End point title
    		 Lesion Contrast Enhancement
    End point description
    Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance 0.1 mmol/kg and Gadovist 0.1 mmol/kg. Readers assessed whether images with ProHance were preferred or images with Gadovist were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers (194-198).
    End point type
    Secondary
    End point timeframe
    Comparison of image sets obtained within 2 to 14 days
    End point values
    		 Blinded Reader 1 Blinded Reader 2 Blinded Reader 3 Dummy Set
    Number of subjects analysed
    198
    194
    196
    1 [29]
    Units: participant exams
        Number of Patient Exams Analyzed
    198
    194
    196
    1
        ProHance Better
    14
    10
    2
    0
        No Difference Between ProHance and Gadovist/Gadavi
    170
    174
    193
    1
        Gadovist/Gadavist Better
    14
    10
    1
    0
    Notes
    [29] - Due to the system limitation with the EudraCT system, a Dummy set was created.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Lesion Contrast Enhancement
    Comparison groups
    Blinded Reader 1 v Dummy Set
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 = 1 [31]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [30] - analysis is based on paired assessments.
    [31] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Lesion Contrast Enhancement
    Comparison groups
    Blinded Reader 2 v Dummy Set
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 = 1 [33]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [32] - analysis is based on paired assessments.
    [33] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Lesion Contrast Enhancement
    Comparison groups
    Blinded Reader 3 v Dummy Set
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 = 1 [35]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [34] - analysis is based on paired assessments.
    [35] - Difference in percentage of which image is better tested by Wilcoxon signed rank test.

    Secondary: Lesion to Background Ratio on Post T1-weighted Spin Echo Images

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    End point title
    		 Lesion to Background Ratio on Post T1-weighted Spin Echo Images
    End point description
    The Unit of Measure is "Lesion". For each lesion, Lesion-to-background ratio (LBR) = SI of lesion/SI of brain. Firstly, LBR of each lesion was assessed for each contrast agent postdose image separately, then the difference in LBR between ProHance and Gadovist was calculated. The number presented in the result table below is "the mean difference in LBR postdose (ProHance - Gadovist ) Per protocol population
    End point type
    Secondary
    End point timeframe
    Postdose
    End point values
    		 Blinded Reader 1 Blinded Reader 2 Blinded Reader 3 Dummy Set
    Number of subjects analysed
    194
    137
    162
    1 [36]
    Units: signal intensity
        arithmetic mean (standard deviation)
    -0.02 ( 0.17 )
    -0.16 ( 1.12 )
    -0.01 ( 0.18 )
    0 ( 0 )
    Notes
    [36] - Due to the system limitation with the EudraCT system, a Dummy set was created.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Lesion to Background Ratio on Post T1-weighted Spin Echo Images
    Comparison groups
    Blinded Reader 1 v Dummy Set
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 = 0.2758 [38]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [37] - 2-sided paired comparison
    [38] - Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Lesion to Background Ratio on Post T1-weighted Spin Echo Images
    Comparison groups
    Blinded Reader 2 v Dummy Set
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 = 0.0676 [40]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [39] - 2-sided paired comparison
    [40] - Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Lesion to Background Ratio on Post T1-weighted Spin Echo Images
    Comparison groups
    Blinded Reader 3 v Dummy Set
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 other [41]
    P-value
    		 = 0.5267 [42]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [41] - 2-sided paired comparison
    [42] - Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect

    Secondary: Percentage Signal Intensity Enhhancement on Postdose Images

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    End point title
    		 Percentage Signal Intensity Enhhancement on Postdose Images
    End point description
    Difference in percentage signal intensity enhancement on postdose T1-weighted SE/FSE images (ProHance - Gadovist/Gadavist). Per protocol population
    End point type
    Secondary
    End point timeframe
    Postdose
    End point values
    		 Blinded Reader 1 Blinded Reader 2 Blinded Reader 3 Dummy Set
    Number of subjects analysed
    191
    133
    159
    1 [43]
    Units: signal intensity
        arithmetic mean (standard deviation)
    1.06 ( 28.61 )
    -2.09 ( 29.06 )
    -1.59 ( 29.16 )
    0 ( 0 )
    Notes
    [43] - Due to the system limitation with the EudraCT system, a Dummy set was created.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Percentage Signal Intensity Enhancement on Postdose Images
    Comparison groups
    Blinded Reader 1 v Dummy Set
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [44]
    P-value
    		 = 0.6201 [45]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [44] - 2-sided comparison
    [45] - Investigation product (IP) effect from mixed model with period, sequence, and IP as fixed effects and subject nested within sequence as random effect.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Percentage Signal Intensity Enhancement on Postdose Images
    Comparison groups
    Blinded Reader 2 v Dummy Set
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 other [46]
    P-value
    		 = 0.4514 [47]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [46] - 2-sided comparison
    [47] - Investigation product (IP) effect from mixed model with period, sequence, and IP as fixed effects and subject nested within sequence as random effect.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Percentage Signal Intensity Enhancement on Postdose Images
    Comparison groups
    Blinded Reader 3 v Dummy Set
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 other [48]
    P-value
    		 = 0.7722 [49]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [48] - 2-sided comparison
    [49] - Investigation product (IP) effect from mixed model with period, sequence, and IP as fixed effects and subject nested within sequence as random effect.

    Secondary: Lesion Detection Rate

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    End point title
    		 Lesion Detection Rate
    End point description
    Lesion detection rate by contrast agent and reader Per protocol patients with histologically confirmed lesions
    End point type
    Secondary
    End point timeframe
    Postdose
    End point values
    		 Blinded Reader 1 Blinded Reader 2 Blinded Reader 3 Dummy Set
    Number of subjects analysed
    139
    139
    139
    1 [50]
    Units: participant exams
        True Positive (Patients) ProHance
    133
    137
    136
    1
        True Postive (Patients) Gadovist/Gadavist
    135
    136
    132
    1
        False Negative (Patients) ProHance
    6
    2
    3
    0
        False Negative (Patients) Gadovist/Gadavist
    4
    3
    7
    0
    Notes
    [50] - Due to the system limitation with the EudraCT system, a Dummy set was created
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Lesion Detection Rate Reader 1 - ProHance, Reader 1 - Gadovist/Gadavist
    Comparison groups
    Blinded Reader 1 v Dummy Set
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 other [51]
    P-value
    		 = 0.3173
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [51] - 2-sided paired comparison
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Lesion Detection Rate Reader 2 - ProHance, Reader 2 - Gadovist/Gadavist
    Comparison groups
    Blinded Reader 2 v Dummy Set
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 other [52]
    P-value
    		 = 0.5637
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [52] - 2-sided paired comparison
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Lesion Detection Rate Reader 3 - ProHance, Reader 3 - Gadovist/Gadavist
    Comparison groups
    Blinded Reader 3 v Dummy Set
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 other [53]
    P-value
    		 = 0.0455
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [53] - 2-sided paired comparison

    Secondary: Accuracy for Tumor Characterization

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    End point title
    		 Accuracy for Tumor Characterization
    End point description
    Blinded Reader assessment of accuracy of tumor characterization (benign/malignant) - patient level assessment Subjects with histologically confirmed lesions
    End point type
    Secondary
    End point timeframe
    Postdose
    End point values
    		 Blinded Reader 1 Blinded Reader 2 Blinded Reader 3 Dummy Set
    Number of subjects analysed
    128
    128
    128
    1 [54]
    Units: participant exams
        Correctly Categorized (ProHance)
    94
    106
    93
    1
        Correctly Categorized (Gadovist/Gadavist)
    96
    101
    83
    1
        Incorrectly Categorized (ProHance)
    34
    22
    35
    0
        Incorrectly Categorized (Gadovist/Gadavist)
    32
    27
    45
    0
    Notes
    [54] - Due to the system limitation with the EudraCT system, a Dummy set was created.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Accuracy for Tumor Characterization Reader 1 - ProHance, Reader 1 - Gadovist/Gadavist
    Comparison groups
    Blinded Reader 1 v Dummy Set
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 other [55]
    P-value
    		 = 0.6949 [56]
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [55] - 2-sided paired comparison
    [56] - McNemar test of difference (ProHance minus Gadovist/Gadavist) in accuracy for tumor characterization
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Accuracy for Tumor Characterization Reader 2 - ProHance, Reader 2 - Gadovist/Gadavist
    Comparison groups
    Blinded Reader 2 v Dummy Set
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 other [57]
    P-value
    		 = 0.1317 [58]
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [57] - 2-sided comparison
    [58] - McNemar test of difference (ProHance minus Gadovist/Gadavist) in accuracy for tumor characterization
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Accuracy for Tumor Characterization Reader 3 - ProHance, Reader 3 - Gadovist/Gadavist
    Comparison groups
    Blinded Reader 3 v Dummy Set
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 other [59]
    P-value
    		 = 0.0124 [60]
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [59] - 2-sided paired comparison
    [60] - McNemar test of difference (ProHance minus Gadovist/Gadavist) in accuracy for tumor characterization

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signed Informed Consent, and within 24 h prior to admin. of 1st drug (Exam 1) to 24 h after admin. of 1st drug. Then 24 h prior to admin. of 2nd drug (Exam 2) to 24 h after admin. of 2nd drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Safety Population (ProHance)
    Reporting group description
    		 All enrolled patients who received a randomized injection of ProHance

    Reporting group title
    Safety Population (Gadovist/Gadavist)
    Reporting group description
    		 All enrolled patients who received a randomized injection of Gadovist/Gadavist

    Serious adverse events
    		 Safety Population (ProHance) Safety Population (Gadovist/Gadavist)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 222 (0.00%)
    0 / 216 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety Population (ProHance) Safety Population (Gadovist/Gadavist)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 222 (6.76%)
    8 / 216 (3.70%)
    Vascular disorders
    Vascular rupture
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 216 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 216 (0.46%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 216 (0.46%)
         occurrences all number
    1
    1
    Dysgeusia
         subjects affected / exposed
    4 / 222 (1.80%)
    1 / 216 (0.46%)
         occurrences all number
    4
    1
    Headache
         subjects affected / exposed
    2 / 222 (0.90%)
    1 / 216 (0.46%)
         occurrences all number
    2
    1
    Lethargy
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 216 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 216 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 216 (0.46%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 216 (0.46%)
         occurrences all number
    0
    1
    Feeling hot
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 216 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 216 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    4 / 222 (1.80%)
    1 / 216 (0.46%)
         occurrences all number
    4
    1
    Vomiting
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 216 (0.46%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 222 (0.90%)
    0 / 216 (0.00%)
         occurrences all number
    2
    0
    Dyspnoea
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 216 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 216 (0.46%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 216 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 216 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 216 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 216 (0.46%)
         occurrences all number
    0
    1
    Mood altered
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 216 (0.46%)
         occurrences all number
    0
    1

    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.
    Histologic confirmation of disease available for only 139/198 patients in PP analysis. Of these, 128 patients had confirmed brain tumors and were available for the analyses of diagnostic performance (tumor detection and tumor characterization).
    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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