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    Clinical Trial Results:
    Intra-individual, comparison of the MRI contrast agents gadoxetic acid (Primovist®) versus gadoterate meglumine (Dotarem®) in liver MRI of patients with HCC and underlying cirrhosis

    Summary
    EudraCT number
    		 2013-002409-75
    Trial protocol
    		 DE  
    Global end of trial date
    13 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 May 2022
    First version publication date
    26 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Dota-PrimoLIV
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité Universitätsmedizin Campus Mitte
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    PD Dr. med. Timm Denecke, Diagnostische Radiologie Institut für Radiologie, +49 30450527082, timm.denecke@charite.de
    Scientific contact
    PD Dr. med. Timm Denecke, Diagnostische Radiologie Institut für Radiologie, +49 30450527082, timm.denecke@charite.de
    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
    13 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the peak maximum enhancement between both contrast agents in the lesion with reference to normal tissue (peak enhancement = SI post-contrast (lesion) - SI pre-contrast (lesion)).
    Protection of trial subjects
    This prospective intra-individual comparative study was performed in accordance with the Declaration of Helsinki and was approved by the local ethics committee and the Federal Institute for Drugs and Medical Devices. Further all inclusion/exclusion criteria are intended to protect the patients. At each visit, an IV line will be established, a blood sample obtained for determination of the creatinine value (calculation of the GFR), and the patients positioned within the 3.0 T MRI device (Siemens MAGNETOM Skyra). The second visit will include the recording of any changes to the patient’s condition.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2013
    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: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    0
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients potentially meeting the in- and exclusion criteria will be informed about the study and invited to participate. Patients will be identified in the HCC out/in-patient departments. Informed and written consent will be obtained directly before the first MRI examination. Patients will have at least 24 hours to consider their participation.

    Pre-assignment
    Screening details
    		 Adult patients (> 18 years of age) with liver cirrhosis and diagnosis of HCC based on histology or noninvasive HCC diagnostic criteria were evaluated for study inclusion if they had a clinical indication for liver MRI.

    Period 1
    Period 1 title
    Visitation 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The quantitative and qualitative evaluation of the acquired MRI datasets will be performed by a radiologist experienced in liver MRI who will be blinded to the patient-related information and the type of contrast medium used in each series . The reader will be informed about the suspected lesion and the suspected location of the lesion in order to allow a reliable placement of the ROIs. Both datasets will be evaluated in the same reading session to ensure comparability of ROI placement.

    Arms
    Arm title
    		 Extracellular contrast agent (ECA)
    Arm description
    		 Dotarem: each 1 mL of Dotarem solution contains 279.32 mg of gadoterate meglumine (representing 0.5 mmol/mL) The first visit consists of one MRI examination with gadoterate meglumine Injection of gadoterate meglumine , followed by post-contrast MRI
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dotarem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Dotarem: Single IV bolus injection of an equivalent of 0,5 mmol Gd/kg body weight at an injection speed of 2 mL/sec, followed by a saline flush of 20 mL at an injection speed of 2 mL/sec.

    Number of subjects in period 1
    		Extracellular contrast agent (ECA)
    Started
    23
    Completed
    23
    Period 2
    Period 2 title
    Visitation 2
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The quantitative and qualitative evaluation of the acquired MRI datasets will be performed by a radiologist experienced in liver MRI who will be blinded to the patient-related information and the type of contrast medium used in each series . The reader will be informed about the suspected lesion and the suspected location of the lesion in order to allow a reliable placement of the ROIs. Both datasets will be evaluated in the same reading session to ensure comparability of ROI placement.

    Arms
    Arm title
    		 Hepatocyte-specific contrast agent (HSCA)
    Arm description
    		 Primovist: each 1 mL of Primovist contains 0.25 mmol gadoxetic acid (Gd-EOP-DTPA disodium) Injection of gadoxetic acid and followed by post-contrast MRI
    Arm type
    		 Experimental

    Investigational medicinal product name
    Primovist
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Single IV bolus injection of an equivalent of 1 mmol Gd/kg body weight at an injection speed of 1 mL/sec, followed by a saline flush of 20 mL at an injection speed of 1 mL/sec.

    Number of subjects in period 2
    		Hepatocyte-specific contrast agent (HSCA)
    Started
    23
    Completed
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Visitation 1
    Reporting group description
    		 -

    Reporting group values
    		 Visitation 1 Total
    Number of subjects
    		 23 23
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 69 (53 to 87) -
    Gender categorical
    Units: Subjects
        Female
    		 19 19
        Male
    		 4 4
    causes for liver cirrhosis
    Units: Subjects
        hepatitis B
    		 3 3
        hepatitis C
    		 4 4
        alcohol abuse
    		 6 6
        cryptogenic
    		 10 10
    HCCs confirmation through histopathology
    Units: Subjects
        surgical resection
    		 12 12
        image guided biopsy
    		 11 11

    End points

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    End points reporting groups
    Reporting group title
    Extracellular contrast agent (ECA)
    Reporting group description
    		 Dotarem: each 1 mL of Dotarem solution contains 279.32 mg of gadoterate meglumine (representing 0.5 mmol/mL) The first visit consists of one MRI examination with gadoterate meglumine Injection of gadoterate meglumine , followed by post-contrast MRI
    Reporting group title
    Hepatocyte-specific contrast agent (HSCA)
    Reporting group description
    		 Primovist: each 1 mL of Primovist contains 0.25 mmol gadoxetic acid (Gd-EOP-DTPA disodium) Injection of gadoxetic acid and followed by post-contrast MRI

    Primary: Image quality between ECA and HSCA

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    End point title
    		 Image quality between ECA and HSCA
    End point description
    The results of qualitative analysis for overall image quality, artifacts and lesion conspicuity for both contrast agents and throughout the different perfusion phases are reported LAP: late arterial phase, PVP: portal venous phase and DP: delayed phase
    End point type
    Primary
    End point timeframe
    Visitation 1 and Visitation 2
    End point values
    		 Extracellular contrast agent (ECA) Hepatocyte-specific contrast agent (HSCA)
    Number of subjects analysed
    23
    23
    Units: Score
    median (inter-quartile range (Q1-Q3))
        LAP
    5 (4 to 5)
    5 (4 to 5)
        PVP
    5 (4 to 5)
    4 (4 to 5)
        DP
    4 (4 to 5)
    4 (3 to 5)
    Statistical analysis title
    		 qualitative analysis for overall image quality
    Statistical analysis description
    Due to small sample size, a non-parametric distribution of metric data was 167 assumed. In consequence metric data are given as median and interquartile range (25- 168 75th-percentiles) and the paired Wilcoxon signed-rank test was used. Categorical data 169 were analyzed using contingency tables and exact McNemar-test (2x2) as well as 170 McNemar-Bowker-test (>2 categories).
    Comparison groups
    Extracellular contrast agent (ECA) v Hepatocyte-specific contrast agent (HSCA)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [1] - All tests were two-sided and the level of signifi- 171 cance was set to 0.05

    Primary: Artefacts between ECA and HSCA

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    End point title
    		 Artefacts between ECA and HSCA
    End point description
    End point type
    Primary
    End point timeframe
    V1-V2
    End point values
    		 Extracellular contrast agent (ECA) Hepatocyte-specific contrast agent (HSCA)
    Number of subjects analysed
    23
    23
    Units: Score
    median (inter-quartile range (Q1-Q3))
        LAP
    4 (4 to 5)
    4 (3 to 4)
        PVP
    5 (4 to 5)
    4 (4 to 5)
        DP
    4 (4 to 5)
    4 (4 to 5)
    Statistical analysis title
    		 qualitative analysis for overall artifacts
    Comparison groups
    Extracellular contrast agent (ECA) v Hepatocyte-specific contrast agent (HSCA)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Primary: Lesion conspicuity between ECA and HSCA

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    End point title
    		 Lesion conspicuity between ECA and HSCA
    End point description
    End point type
    Primary
    End point timeframe
    V1-V2
    End point values
    		 Extracellular contrast agent (ECA) Hepatocyte-specific contrast agent (HSCA)
    Number of subjects analysed
    23
    23
    Units: Score
    median (inter-quartile range (Q1-Q3))
        LAP
    5 (4 to 5)
    4 (3 to 4.5)
        PVP
    5 (4 to 5)
    5 (4 to 5)
        DP
    5 (4 to 5)
    5 (4 to 5)
    Statistical analysis title
    		 qualitative analysis: overall lesion conspicuit
    Comparison groups
    Hepatocyte-specific contrast agent (HSCA) v Extracellular contrast agent (ECA)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Quantitative Analysis comperison SNR and CNR values

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    End point title
    		 Quantitative Analysis comperison SNR and CNR values
    End point description
    SNR= Signal-to-noise ratio; CNR=Contrast-to-noise ratio
    End point type
    Secondary
    End point timeframe
    After Visitation 1 and 2.
    End point values
    		 Extracellular contrast agent (ECA) Hepatocyte-specific contrast agent (HSCA)
    Number of subjects analysed
    23
    23
    Units: SI
    median (inter-quartile range (Q1-Q3))
        Signal-to-noise ratio
    298.7 (183.3 to 482.9)
    264.1 (220.3 to 380.4)
        Contrast-to-noise ratio
    72.7 (50.8 to 165)
    49.4 (18.1 to 154.4)
    Statistical analysis title
    		 Comperison between V1 and V2
    Statistical analysis description
    Due to small sample size, a non-parametric distribution of metric data was 167 assumed. In consequence metric data are given as median and interquartile range (25- 168 75th-percentiles) and the paired Wilcoxon signed-rank test was used.Categorical data 169 were analyzed using contingency tables and exact McNemar-test (2x2) as well as 170 McNemar-Bowker-test (>2 categories).
    Comparison groups
    Extracellular contrast agent (ECA) v Hepatocyte-specific contrast agent (HSCA)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.05 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [2] - This study assesses the diagnostic value of Primovist® in patients with liver cirrhosis. If successful, the study will show superiority of Primovist® in lesion identification in these “difficult-to-diagnose” patients which would warrant additional clinical studies (aiming at an overall improvement of diagnostic accuracy).
    [3] - All tests were two-sided and the level of significance was set to 0.05.

    Secondary: Quantitative Analysis comperison Wash-in/-out

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    End point title
    		 Quantitative Analysis comperison Wash-in/-out
    End point description
    End point type
    Secondary
    End point timeframe
    After V1 and V2
    End point values
    		 Extracellular contrast agent (ECA) Hepatocyte-specific contrast agent (HSCA)
    Number of subjects analysed
    23
    23
    Units: [1/s]
    median (inter-quartile range (Q1-Q3))
        Wash-in
    0.9 (0.6 to 1.5)
    0.4 (0.1 to 0.7)
        Wash-out
    19.8 (7.3 to 35.6)
    9.3 (-6.5 to 21)
    Statistical analysis title
    		 Comperison the Wash-in and -out values
    Comparison groups
    Extracellular contrast agent (ECA) v Hepatocyte-specific contrast agent (HSCA)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Other pre-specified: The frequencies Arterial phase hyperenhancement

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    End point title
    		 The frequencies Arterial phase hyperenhancement
    End point description
    End point type
    Other pre-specified
    End point timeframe
    V1-V2
    End point values
    		 Extracellular contrast agent (ECA) Hepatocyte-specific contrast agent (HSCA)
    Number of subjects analysed
    23
    23
    Units: Subjects
        LAP
    21
    17
        PVP
    0
    0
        DP
    0
    0
    Statistical analysis title
    		 analyzed fields of major imaging features
    Comparison groups
    Hepatocyte-specific contrast agent (HSCA) v Extracellular contrast agent (ECA)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Other pre-specified: The frequencies Non-peripheral washout

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    End point title
    		 The frequencies Non-peripheral washout
    End point description
    End point type
    Other pre-specified
    End point timeframe
    V1-V2
    End point values
    		 Extracellular contrast agent (ECA) Hepatocyte-specific contrast agent (HSCA)
    Number of subjects analysed
    23
    23
    Units: Subjects
        LAP
    0
    0
        PVP
    19
    17
        DP
    21
    20
    Statistical analysis title
    		 analyzed fields: Non-peripheral washout
    Comparison groups
    Extracellular contrast agent (ECA) v Hepatocyte-specific contrast agent (HSCA)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Other pre-specified: The frequencies of Enhancing capsule

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    End point title
    		 The frequencies of Enhancing capsule
    End point description
    End point type
    Other pre-specified
    End point timeframe
    V1-V2
    End point values
    		 Extracellular contrast agent (ECA) Hepatocyte-specific contrast agent (HSCA)
    Number of subjects analysed
    23
    23
    Units: Subjects
        LAP
    0
    0
        PVP
    15
    10
        DP
    17
    12
    Statistical analysis title
    		 analyzed fields of Enhancing capsule
    Comparison groups
    Extracellular contrast agent (ECA) v Hepatocyte-specific contrast agent (HSCA)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From Visitation 1 to Visitation 2
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Frequency threshold for reporting non-serious adverse events: 0.5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No SAEs and no non-serious adverse events were reported

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Dec 2015
    update study protocol Version 3.0 (22/12/2015): change PI (LKP)

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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