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    Clinical Trial Results:
    PHASE IV, DOUBLE-BLIND, MULTI-CENTER, RANDOMIZED, TWO-ARM CROSSOVER STUDY TO COMPARE 0.1 mmol/kg OF MULTIHANCE® WITH 0.1 mmol/kg OF DOTAREM® AND 0.05 mmol/kg OF MULTIHANCE® WITH 0.1 mmol/kg OF DOTAREM® IN MAGNETIC RESONANCE IMAGING (MRI) OF THE BRAIN (BENEFIT)

    Summary
    EudraCT number
    		 2013-003886-33
    Trial protocol
    		 CZ  
    Global end of trial date
    17 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Dec 2016
    First version publication date
    31 Dec 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MH-148
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02070380
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bracco Diagnostics, Inc.
    Sponsor organisation address
    259 Prospect Plains Rd, Cranbury, United States, 08512
    Public contact
    Gianpaolo Pirovano, Bracco Diagnostics, Inc., 609 514-2200, Gianpaolo.Pirovano@diag.bracco.com
    Scientific contact
    Gianpaolo Pirovano, Bracco Diagnostics, Inc., 609 514-2200, 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
    17 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives for this study are: 1) To show superiority of a 0.1 mmol/kg dose of MULTIHANCE as compared to 0.1 mmol/kg dose of DOTAREM, in terms of the by-subject global diagnostic preference between exams (i.e., based on pre-dose plus post-dose image sets). 2) To show superiority of a 0.05 mmol/kg dose of MULTIHANCE as compared to 0.1 mmol/kg dose of DOTAREM, in terms of the by-subject global diagnostic preference between exams (i.e., based on pre-dose plus post-dose image sets).
    Protection of trial subjects
    This study was conducted in compliance with Title 21, CFR Part 50, CFR Part 56, and CFR Part 312, with the ethical principles that have their origin in the Declaration of Helsinki (adopted by the 18th World Medical Association [WMA] General Assembly in Helsinki, Finland [June 1964] and amended by the 29th WMA in Tokyo, Japan [October 1975], by the 35th WMA in Venice, Italy [October 1983], by the 41st WMA in Hong Kong [September 1989], by the 48th WMA in Somerset West, Republic of South Africa [October 1996], by the 52nd WMA in Edinburgh, Scotland [October 2000], with note of clarification by the 53rd WMA in Washington DC, United States [2002] and the 55th WMA in Tokyo, Japan [2004], and by the 59th WMA in Seoul, Korea [October 2008]). In addition, this study was conducted in compliance with Good Clinical Practices (GCP) as outlined in ICH E6 (Good Clinical Practice: Consolidated Guideline).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Feb 2014
    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
    Germany: 3
    Country: Number of subjects enrolled
    Czech Republic: 103
    Country: Number of subjects enrolled
    United States: 71
    Worldwide total number of subjects
    177
    EEA total number of subjects
    106
    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)
    120
    From 65 to 84 years
    55
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 179 patients were recruited from February 2014 through February 2015 at 14 clinical trial sites. Off-site assessment of the images was performed between 19 February - 17 March 2015 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
    		 179 patients were enrolled and signed informed consent. Each enrolled patient was randomized and 177 were dosed with at least one contrast agent.

    Period 1
    Period 1 title
    First Injection
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    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.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg
    Arm description
    		 Patients randomized to receive MultiHance 0.1 mmol/kg first
    Arm type
    		 Experimental

    Investigational medicinal product name
    MultiHance 0.1 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MultiHance 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.1 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Arm title
    		 Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg
    Arm description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dotarem 0.1 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dotarem 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.1 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Arm title
    		 MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg
    Arm description
    		 Patients randomized to receive MultiHance 0.05 mmol/kg first
    Arm type
    		 Experimental

    Investigational medicinal product name
    MultiHance 0.05 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MultiHance 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.05 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Arm title
    		 Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg
    Arm description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dotarem 0.1 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dotarem 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.1 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Number of subjects in period 1
    		MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg
    Started
    31
    39
    53
    54
    Completed
    31
    39
    53
    54
    Period 2
    Period 2 title
    Washout (no Second Injection/MRI)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg
    Arm description
    		 Patients randomized to receive MultiHance 0.1 mmol/kg first
    Arm type
    		 Experimental

    Investigational medicinal product name
    MultiHance 0.1 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MultiHance 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.1 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Arm title
    		 Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg
    Arm description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dotarem 0.1 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dotarem 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.1 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Arm title
    		 MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg
    Arm description
    		 Patients randomized to receive MultiHance 0.05 mmol/kg first
    Arm type
    		 Experimental

    Investigational medicinal product name
    MultiHance 0.05 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MultiHance 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.05 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Arm title
    		 Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg
    Arm description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dotarem 0.1 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dotarem 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.1 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Number of subjects in period 2
    		MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg
    Started
    31
    39
    53
    54
    Completed
    31
    34
    51
    51
    Not completed
    0
    5
    2
    3
         Consent withdrawn by subject
    -
    5
    2
    3
    Period 3
    Period 3 title
    Second Injection
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg
    Arm description
    		 Patients randomized to receive MultiHance 0.1 mmol/kg first
    Arm type
    		 Experimental

    Investigational medicinal product name
    MultiHance 0.1 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MultiHance 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.1 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Arm title
    		 Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg
    Arm description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dotarem 0.1 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dotarem 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.1 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Arm title
    		 MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg
    Arm description
    		 Patients randomized to receive MultiHance 0.05 mmol/kg first
    Arm type
    		 Experimental

    Investigational medicinal product name
    MultiHance 0.05 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MultiHance 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.05 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Arm title
    		 Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg
    Arm description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dotarem 0.1 mmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dotarem 0.5 M solution for injection was manually or automatically (power injector) administered at a dose of 0.1 mmol/kg by venous injection as a rapid bolus using sterile syringes and aseptic techniques; power injections were followed by a 20-30 mL bolus injection of saline.

    Number of subjects in period 3
    		MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg
    Started
    31
    34
    51
    51
    Completed
    31
    32
    50
    46
    Not completed
    0
    2
    1
    5
         Image sets missing or technically inadeq
    -
    1
    -
    -
         Protocol deviation
    -
    1
    1
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive MultiHance 0.1 mmol/kg first

    Reporting group title
    Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first

    Reporting group title
    MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive MultiHance 0.05 mmol/kg first

    Reporting group title
    Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg
    Reporting group description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first

    Reporting group values
    		 MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg Total
    Number of subjects
    		 31 39 53 54 159
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 24 25 38 33 108
        Adults (>=65 years)
    		 7 14 15 21 51
    Gender categorical
    Units: Subjects
        Female
    		 20 21 26 26 93
        Male
    		 11 18 27 28 84
    Subject analysis sets

    Subject analysis set title
    MultiHance 0.1 mmol/kg Arm (Reader 1)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.1 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    MultiHance 0.1 mmol/kg Arm (Reader 2)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.1 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    MultiHance 0.1 mmol/kg Arm (Reader 3)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.1 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    MultiHance 0.05 mmol/kg Arm (Reader 1)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.05 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    MultiHance 0.05 mmol/kg Arm (Reader 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.05 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    MultiHance 0.05 mmol/kg Arm (Reader 3)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.05 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    Dummy Set
    Subject analysis set type
    		 Intention-to-treat
    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/group statistical analysis. This is dummy set is a workaround to that limitation. No subjects in this set.

    Subject analysis sets values
    		 MultiHance 0.1 mmol/kg Arm (Reader 1) MultiHance 0.1 mmol/kg Arm (Reader 2) MultiHance 0.1 mmol/kg Arm (Reader 3) MultiHance 0.05 mmol/kg Arm (Reader 1) MultiHance 0.05 mmol/kg Arm (Reader 2 MultiHance 0.05 mmol/kg Arm (Reader 3) Dummy Set
    Number of subjects
    63
    62
    62
    96
    94
    95
    1
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    44
    44
    44
    64
    64
    64
    0
        Adults (>=65 years)
    19
    19
    19
    32
    32
    32
    0
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    41
    41
    41
    52
    52
    52
        Male
    29
    29
    29
    55
    55
    55

    End points

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    End points reporting groups
    Reporting group title
    MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive MultiHance 0.1 mmol/kg first

    Reporting group title
    Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first

    Reporting group title
    MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive MultiHance 0.05 mmol/kg first

    Reporting group title
    Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg
    Reporting group description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first
    Reporting group title
    MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive MultiHance 0.1 mmol/kg first

    Reporting group title
    Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first

    Reporting group title
    MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive MultiHance 0.05 mmol/kg first

    Reporting group title
    Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg
    Reporting group description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first
    Reporting group title
    MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive MultiHance 0.1 mmol/kg first

    Reporting group title
    Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first

    Reporting group title
    MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg
    Reporting group description
    		 Patients randomized to receive MultiHance 0.05 mmol/kg first

    Reporting group title
    Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg
    Reporting group description
    		 Patients randomized to receive Dotarem 0.1 mmol/kg first

    Subject analysis set title
    MultiHance 0.1 mmol/kg Arm (Reader 1)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.1 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    MultiHance 0.1 mmol/kg Arm (Reader 2)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.1 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    MultiHance 0.1 mmol/kg Arm (Reader 3)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.1 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    MultiHance 0.05 mmol/kg Arm (Reader 1)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.05 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    MultiHance 0.05 mmol/kg Arm (Reader 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.05 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    MultiHance 0.05 mmol/kg Arm (Reader 3)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MRI with MultiHance 0.05 mmol/kg versus MRI with Dotarem 0.1 mmol/kg

    Subject analysis set title
    Dummy Set
    Subject analysis set type
    		 Intention-to-treat
    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/group statistical analysis. This is dummy set is a workaround to 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 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem 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 and endpoints. The 3 blinded readers assessed the available image sets as technically adequate in 84.3-90.7% of cases, depending on reader and study arm.
    End point type
    Primary
    End point timeframe
    Comparison of image sets obtained within 2 to 14 days
    End point values
    		 MultiHance 0.1 mmol/kg Arm (Reader 1) MultiHance 0.1 mmol/kg Arm (Reader 2) MultiHance 0.1 mmol/kg Arm (Reader 3) MultiHance 0.05 mmol/kg Arm (Reader 1) MultiHance 0.05 mmol/kg Arm (Reader 2 MultiHance 0.05 mmol/kg Arm (Reader 3) Dummy Set
    Number of subjects analysed
    63
    62
    62
    96
    94
    95
    1 [1]
    Units: participant exams
    number (not applicable)
        MultiHance Preferred
    31
    51
    43
    14
    18
    15
    0
        Contrast Agents Equal
    31
    9
    17
    75
    56
    63
    0
        Dotarem Preferred
    1
    2
    2
    7
    20
    17
    0
    Notes
    [1] - This is a dummy set.
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 1)
    Statistical analysis description
    63 Subjects in this analysis. Difference in percentage MultiHance better minus percentage Dotarem better (%), 2-sided 95% confidence interval was estimated using Altman's general approximate normal method.
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001 [3]
    Method
    		 Wilcoxon signed-rank test
    Parameter type
    		 ∆Percentage MH better minus DM better
    Point estimate
    47.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 34.5
         upper limit
    		 60.7
    Notes
    [2] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus postdose paired global assessment.
    [3] - Only 1 primary endpoint, no adjustment for multiple comparisons and the a priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 1)
    Statistical analysis description
    96 Subjects in this analysis. Difference in percentage MultiHance better minus percentage Dotarem better (%) , 2-sided 95% confidence interval was estimated using Altman's general approximate normal method.
    Comparison groups
    Dummy Set v MultiHance 0.05 mmol/kg Arm (Reader 1)
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.1295 [5]
    Method
    		 Wilcoxon signed-rank test
    Parameter type
    		 ∆Percentage MH better minus DM better
    Point estimate
    7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 16.5
    Notes
    [4] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus post-dose paired global assessment.
    [5] - Only 1 primary endpoint, no adjustment for multiple comparisons and the a priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 2)
    Statistical analysis description
    62 Subjects in this analysis. Difference in percentage MultiHance better minus percentage Dotarem better (%) , 2-sided 95% confidence interval was estimated using Altman's general approximate normal method.
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 2) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.0001 [7]
    Method
    		 Wilcoxon signed rank test
    Parameter type
    		 ∆Percentage MH better minus DM better
    Point estimate
    79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 67.1
         upper limit
    		 91
    Notes
    [6] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus postdose paired global assessment
    [7] - Only 1 primary endpoint, no adjustment for multiple comparisons and the a priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 2)
    Statistical analysis description
    94 Subjects in this analysis. Difference in percentage MultiHance better minus percentage Dotarem better (%) , 2-sided 95% confidence interval was estimated using Altman's general approximate normal method.
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 2 v Dummy Set
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.7503 [9]
    Method
    		 Wilcoxon signed rank test
    Parameter type
    		 ∆Percentage MH better minus DM better
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15
         upper limit
    		 10.7
    Notes
    [8] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus post-dose paired global assessment.
    [9] - Only 1 primary endpoint, no adjustment for multiple comparisons and the a priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 3)
    Statistical analysis description
    62 Subjects in this analysis. Difference in percentage MultiHance better minus percentage Dotarem better (%) , 2-sided 95% confidence interval was estimated using Altman's general approximate normal method
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 < 0.0001 [11]
    Method
    		 Wilcoxon signed rank test
    Parameter type
    		 ∆Percentage MH better minus DM better
    Point estimate
    66.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 52.8
         upper limit
    		 79.5
    Notes
    [10] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus post-dose paired global assessment
    [11] - Only 1 primary endpoint, no adjustment for multiple comparisons and the a priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 3)
    Statistical analysis description
    95 Subjects in this analysis. Difference in percentage MultiHance better minus percentage Dotarem better (%) , 2-sided 95% confidence interval was estimated using Altman's general approximate normal method.
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.7297 [13]
    Method
    		 Wilcoxon signed rank test
    Parameter type
    		 ∆Percentage MH better minus DM better
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.8
         upper limit
    		 9.6
    Notes
    [12] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus post-dose paired global assessment.
    [13] - Only 1 primary endpoint, no adjustment for multiple comparisons and the a priori threshold for statistical significance was 0.05.

    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 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem 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 and endpoints. The 3 blinded readers assessed the available image sets as technically adequate in 84.3-90.7% of cases, depending on reader and study arm.
    End point type
    Secondary
    End point timeframe
    Comparison of image sets obtained within 2 to 14 days
    End point values
    		 MultiHance 0.1 mmol/kg Arm (Reader 1) MultiHance 0.1 mmol/kg Arm (Reader 2) MultiHance 0.1 mmol/kg Arm (Reader 3) MultiHance 0.05 mmol/kg Arm (Reader 1) MultiHance 0.05 mmol/kg Arm (Reader 2 MultiHance 0.05 mmol/kg Arm (Reader 3) Dummy Set
    Number of subjects analysed
    63
    62
    62
    96
    94
    95
    1
    Units: participant exams
    number (not applicable)
        MultiHance Preferred
    29
    34
    25
    11
    12
    8
    0
        Contrast Agents Equal
    33
    27
    35
    76
    66
    77
    0
        Dotarem Preferred
    1
    1
    2
    9
    16
    10
    0
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 1)
    Statistical analysis description
    63 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 < 0.0001 [15]
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [14] - This is a secondary analysis. Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus post-dose paired global assessment.ent.
    [15] - The priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 1)
    Statistical analysis description
    96 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.8238 [17]
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [16] - This is a secondary analysis. Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus post-dose paired global assessment.
    [17] - The priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 2)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    Dummy Set v MultiHance 0.1 mmol/kg Arm (Reader 2)
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 2)
    Statistical analysis description
    94 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 2 v Dummy Set
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.4597 [19]
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [18] - This is a secondary analysis. Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus postdose paired global assessment.
    [19] - The priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 3)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 < 0.0001 [21]
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [20] - This is a secondary analysis. Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus postdose paired global assessment.
    [21] - The priori threshold for statistical significance was 0.05.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 3)
    Statistical analysis description
    95 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.8145 [23]
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [22] - This is a secondary analysis. Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus postdose paired global assessment.
    [23] - The priori threshold for statistical significance was 0.05.

    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 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem 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 and endpoints. The 3 blinded readers assessed the available image sets as technically adequate in 84.3-90.7% of cases, depending on reader and study arm.
    End point type
    Secondary
    End point timeframe
    Comparison of image sets obtained within 2 to 14 days
    End point values
    		 MultiHance 0.1 mmol/kg Arm (Reader 1) MultiHance 0.1 mmol/kg Arm (Reader 2) MultiHance 0.1 mmol/kg Arm (Reader 3) MultiHance 0.05 mmol/kg Arm (Reader 1) MultiHance 0.05 mmol/kg Arm (Reader 2 MultiHance 0.05 mmol/kg Arm (Reader 3) Dummy Set
    Number of subjects analysed
    63
    62
    62
    96
    94
    95
    1
    Units: participant exams
    number (not applicable)
        MultiHance better
    10
    14
    23
    4
    3
    5
    0
        No Difference Between MultiHance and Dotarem
    53
    48
    38
    88
    87
    82
    0
        Dotarem better
    0
    0
    1
    4
    4
    8
    0
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 1)
    Statistical analysis description
    Subjects in this analysis 63
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.002
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [24] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 1)
    Statistical analysis description
    96 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 1
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [25] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus post-dose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 2)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 2) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.0001
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [26] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 2)
    Statistical analysis description
    94 Subjects in this analysis
    Comparison groups
    Dummy Set v MultiHance 0.05 mmol/kg Arm (Reader 2
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 1
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [27] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 3)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [28] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 3)
    Statistical analysis description
    95 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.5811
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [29] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus postdose paired global assessment.

    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 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem 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 and endpoints. The 3 blinded readers assessed the available image sets as technically adequate in 84.3-90.7% of cases, depending on reader and study arm.
    End point type
    Secondary
    End point timeframe
    Comparison of image sets obtained within 2 to 14 days
    End point values
    		 MultiHance 0.1 mmol/kg Arm (Reader 1) MultiHance 0.1 mmol/kg Arm (Reader 2) MultiHance 0.1 mmol/kg Arm (Reader 3) MultiHance 0.05 mmol/kg Arm (Reader 1) MultiHance 0.05 mmol/kg Arm (Reader 2 MultiHance 0.05 mmol/kg Arm (Reader 3) Dummy Set
    Number of subjects analysed
    63
    62
    62
    96
    94
    95
    1
    Units: participant exams
    number (not applicable)
        MultiHance Better
    15
    18
    15
    6
    5
    7
    0
        No Difference between MultiHance and Dotarem
    48
    43
    45
    84
    83
    80
    0
        Dotarem Better
    0
    1
    2
    6
    6
    8
    0
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 1)
    Statistical analysis description
    63 Subjects in this analysis
    Comparison groups
    Dummy Set v MultiHance 0.1 mmol/kg Arm (Reader 1)
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [30] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 1)
    Statistical analysis description
    96 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 2)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 2) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [31] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 2)
    Statistical analysis description
    94 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 2 v Dummy Set
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 1
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [32] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 3)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.0023
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [33] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 3)
    Statistical analysis description
    95 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 = 1
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [34] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus postdose paired global assessment.

    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 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem 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 and endpoints. The 3 blinded readers assessed the available image sets as technically adequate in 84.3-90.7% of cases, depending on reader and study arm.
    End point type
    Secondary
    End point timeframe
    Comparison of image sets obtained within 2 to 14 days
    End point values
    		 MultiHance 0.1 mmol/kg Arm (Reader 1) MultiHance 0.1 mmol/kg Arm (Reader 2) MultiHance 0.1 mmol/kg Arm (Reader 3) MultiHance 0.05 mmol/kg Arm (Reader 1) MultiHance 0.05 mmol/kg Arm (Reader 2 MultiHance 0.05 mmol/kg Arm (Reader 3) Dummy Set
    Number of subjects analysed
    63
    62
    62
    96
    94
    95
    1
    Units: Participant Exams
    number (not applicable)
        MultiHance Better
    31
    51
    43
    10
    18
    14
    0
        No Difference between MultiHance and Dotarem
    31
    9
    17
    77
    56
    64
    0
        Dotarem Better
    1
    2
    2
    9
    20
    17
    0
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 1)
    Statistical analysis description
    63 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [35] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 1)
    Statistical analysis description
    96 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 = 1
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [36] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus post-dose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 2)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 2) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [37] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 2)
    Statistical analysis description
    94 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 2 v Dummy Set
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.7503
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [38] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 3)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [39] - Null hypotheses: A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus postdose paired global assessment.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 3)
    Statistical analysis description
    95 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [40]
    P-value
    		 = 0.5983
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [40] - Null hypotheses: A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.05 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus postdose paired global assessment.

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

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    End point title
    		 Lesion to Background Ratio on Post T1-weighed 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 MultiHance and Dotarem was calculated. The number presented in the result table below is "the mean difference in LBR postdose (MultiHance - Dotarem)"
    End point type
    Secondary
    End point timeframe
    5-10 minutes Postdose
    End point values
    		 MultiHance 0.1 mmol/kg Arm (Reader 1) MultiHance 0.1 mmol/kg Arm (Reader 2) MultiHance 0.1 mmol/kg Arm (Reader 3) MultiHance 0.05 mmol/kg Arm (Reader 1) MultiHance 0.05 mmol/kg Arm (Reader 2 MultiHance 0.05 mmol/kg Arm (Reader 3) Dummy Set
    Number of subjects analysed
    63
    62
    62
    96
    94
    95
    1
    Units: Lesions
    number (not applicable)
        Lesions
    64
    66
    54
    85
    89
    78
    0
        Mean
    0.22
    0.24
    0.21
    -0.01
    0.03
    0.01
    0
        Standard Deviation
    0.24
    0.2
    0.23
    0.21
    0.15
    0.15
    0
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 1)
    Statistical analysis description
    63 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 1)
    Statistical analysis description
    96 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6898 [41]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [41] - Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 2)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [42]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [42] - Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect.
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 2)
    Statistical analysis description
    94 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 2 v Dummy Set
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1156 [43]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [43] - Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 3)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [44]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [44] - Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect
    Statistical analysis title
    		 MultiHance 0.05 mmol/kg Arm (Reader 3)
    Statistical analysis description
    95 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7726 [45]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [45] - Mixed effect model with period, sequence, and IP and fixed effect and subject nested within sequence as random effect

    Secondary: Lesion-brain Contrast-to-noise Ratio

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    End point title
    		 Lesion-brain Contrast-to-noise Ratio
    End point description
    The Unit of Measure is "Lesion". For each lesion, Lesion-brain Contrast-to-noise Ratio (CNR) = [(SI of lesion - SI of brain)/SD for SI of noise] on Postdose Images of each lesion was calculated for each contrast agent image separately, then the difference in CNR between MultiHance and Dotarem was calculated. The number presented in the result table below is "the mean difference in CNR (MultiHance - Dotarem)"
    End point type
    Secondary
    End point timeframe
    5-10 minutes Postdose
    End point values
    		 MultiHance 0.1 mmol/kg Arm (Reader 1) MultiHance 0.1 mmol/kg Arm (Reader 2) MultiHance 0.1 mmol/kg Arm (Reader 3) MultiHance 0.05 mmol/kg Arm (Reader 1) MultiHance 0.05 mmol/kg Arm (Reader 2 MultiHance 0.05 mmol/kg Arm (Reader 3) Dummy Set
    Number of subjects analysed
    63
    62
    62
    96
    94
    95
    1
    Units: Lesions
    number (not applicable)
        Lesions
    64
    66
    54
    85
    89
    78
    0
        Mean
    17.4
    31.82
    39.73
    15.72
    19.06
    23.03
    0
        Standard Deviation
    36.14
    45.28
    65.26
    36.05
    29.37
    49.53
    0
    Statistical analysis title
    		 MultiHance 0.1 mmol/kg Arm (Reader 1)
    Statistical analysis description
    63 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [46]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [46] - 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
    		 MultiHance 0.05 mmol/kg Arm (Reader 1)
    Statistical analysis description
    96 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 1) v Dummy Set
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [47]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [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
    		 MultiHance 0.1 mmol/kg Arm (Reader 2)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 2) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [48]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [48] - 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
    		 MultiHance 0.05 mmol/kg Arm (Reader 2)
    Statistical analysis description
    94 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 2 v Dummy Set
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [49]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [49] - 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
    		 MultiHance 0.1 mmol/kg Arm (Reader 3)
    Statistical analysis description
    62 Subjects in this analysis
    Comparison groups
    MultiHance 0.1 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [50]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [50] - 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
    		 MultiHance 0.05 mmol/kg Arm (Reader 3)
    Statistical analysis description
    95 Subjects in this analysis
    Comparison groups
    MultiHance 0.05 mmol/kg Arm (Reader 3) v Dummy Set
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [51]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [51] - Investigation product (IP) effect from mixed model with period, sequence, and IP as fixed effects and subject nested within sequence as random effect.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 24 hours after contrast media injection
    Adverse event reporting additional description
    All adverse events collected were categorized using MedDRA 17.1 and tabulated
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Arm 1: MultiHance 0.1 mmol/kg
    Reporting group description
    		 -

    Reporting group title
    Arm 1: Dotarem 0.1 mmol/kg
    Reporting group description
    		 -

    Reporting group title
    Arm 2: MultiHance 0.05 mmol/kg
    Reporting group description
    		 -

    Reporting group title
    Arm 2: Dotarem 0.1 mmol/kg
    Reporting group description
    		 -

    Serious adverse events
    		 Arm 1: MultiHance 0.1 mmol/kg Arm 1: Dotarem 0.1 mmol/kg Arm 2: MultiHance 0.05 mmol/kg Arm 2: Dotarem 0.1 mmol/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 70 (0.00%)
    0 / 104 (0.00%)
    0 / 105 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm 1: MultiHance 0.1 mmol/kg Arm 1: Dotarem 0.1 mmol/kg Arm 2: MultiHance 0.05 mmol/kg Arm 2: Dotarem 0.1 mmol/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 70 (2.86%)
    3 / 104 (2.88%)
    5 / 105 (4.76%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 70 (0.00%)
    0 / 104 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 70 (0.00%)
    1 / 104 (0.96%)
    0 / 105 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 70 (0.00%)
    1 / 104 (0.96%)
    0 / 105 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 70 (0.00%)
    0 / 104 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 70 (2.86%)
    0 / 104 (0.00%)
    2 / 105 (1.90%)
         occurrences all number
    0
    2
    0
    2
    General disorders and administration site conditions
    Injection site pruritus
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 70 (0.00%)
    0 / 104 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    0
    1
    Injection site swelling
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 70 (0.00%)
    0 / 104 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 70 (0.00%)
    1 / 104 (0.96%)
    0 / 105 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 70 (0.00%)
    0 / 104 (0.00%)
    1 / 105 (0.95%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Skin infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 70 (0.00%)
    0 / 104 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2014
    The final protocol (dated 10 September 2013) was amended on 25 June 2014 (Protocol Amendment 1). There were seven changes to the protocol as described in Amendment 1: RATIONALE 1. The Sponsor physical address had changed. Cover pages in Protocol and Synopsis and Appendix G in the protocol were updated to reflect this change. 2. In addition to centers in North America and Europe, the Protocol was revised to allow centers also in Latin America. 3. The reference documents for the storage of the contrast agents for Latin America were added to the Storage Section (Sect. 6.2) of the Protocol 4. Table D was corrected to state that Parallel Image acquisitions are not permitted for T1 pre and post IP injection sequences, but for the T2 pre and post IP injections sequences, Parallel Imaging acquisitions could be used. 5. The Bracco personnel in Serious Adverse Event Sponsor Contact Personnel were changed. The ‘Serious Adverse Event Contact Personnel Table’ was changed in the Protocol to reflect these changes. 6. The following was added to Appendix B for Latin America: MultiHance ‘Sample Vial Label,’ ‘Dotarem Sample Vial Label,’ and ‘Sample Medication Box Label.’ 7. CRO Contact information was added to the Administrative Structure for Europe (Appendix H in the Protocol) for Ecron Acunova, the designated monitoring CRO for European sites in this study. Contact information for Clinical Research Personnel in Latin America was also added to the Administrative Structure.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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