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    Clinical Trial Results:
    A PROSPECTIVE MULTICENTER COHORT STUDY EVALUATING THE LONG TERM RETENTION OF GADOLINIUM IN HUMAN BONE AND SKIN AFTER THE RETROSPECTIVE ADMINISTRATION OF MULTIHANCE® OR PROHANCE® IN COMPARISON WITH A CONTROL GROUP RECEIVING NO EXPOSURE TO GADOLINIUM

    Summary
    EudraCT number
    		 2012-000941-11
    Trial protocol
    		 CZ  
    Global end of trial date
    31 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Mar 2021
    First version publication date
    25 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GMRA-102,Am.No.1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03108378
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bracco Imaging S.p.A
    Sponsor organisation address
    Via Folli 50, Milan, Italy, 20134
    Public contact
    Paola Pianezzola, Bracco Imaging S.p.A., 0039 0321772324, paola.pianezzola@bracco.com
    Scientific contact
    Paola Pianezzola, Bracco Imaging S.p.A., 0039 0321772324, paola.pianezzola@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
    19 Feb 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this study is to determine the long term Gadolinium (Gd) deposition in human bone and skin tissue (nmol Gd/g bone/skin) in subjects undergoing hip, shoulder or knee replacement surgery, limb amputations or other orthopedic surgical procedures following administration of MULTIHANCE or PROHANCE at least 1 month before their scheduled surgery in comparison with a control group receiving no exposure to Gd contrast agents (GBCA) across different sub groups.
    Protection of trial subjects
    Investigators agreed to make no informal changes to the protocol, except when necessary to protect the safety, the rights or the welfare of subjects. In addition, the Sponsor ensures insurance coverage for damages concerning the subject during the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Oct 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
    Czechia: 1
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    United States: 10
    Worldwide total number of subjects
    29
    EEA total number of subjects
    19
    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)
    8
    From 65 to 84 years
    20
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Informed consent was collected from 30 October 2014 to 19 April 2018.

    Pre-assignment
    Screening details
    		 Subjects >=18 years of age enrolled in the study if they were scheduled to undergo hip, shoulder or knee replacement surgery, limb amputations or other orthopedic surgical AND received at least 1 MultiHance or ProHance dose at least 1 month (3 months in Italy) before the surgery OR had no history of GBCA exposure.

    Pre-assignment period milestones
    Number of subjects started
    		 29
    Number of subjects completed
    		 28

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 did not undergo surgery: 1
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 Subjects with no history of GBCA exposure.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 MultiHance, Single Dose
    Arm description
    		 Subjects with previous exposure to a single dose of MultiHance
    Arm type
    		 No agent administered

    Investigational medicinal product name
    MultiHance
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No agent was administered during this study.

    Arm title
    		 MultiHance, Multiple Doses
    Arm description
    		 Subjects with previous exposure to multiple doses (2 or 3) of MultiHance
    Arm type
    		 No agent administered

    Investigational medicinal product name
    MultiHance
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No agent was administered during this study.

    Arm title
    		 ProHance, Single Dose
    Arm description
    		 Subjects with previous exposure to a single dose of ProHance
    Arm type
    		 No agent administered

    Investigational medicinal product name
    ProHance
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    No agent was administered during this study.

    Number of subjects in period 1 [1]
    		Control MultiHance, Single Dose MultiHance, Multiple Doses ProHance, Single Dose
    Started
    10
    7
    5
    6
    Completed
    10
    7
    5
    6
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One subject, who signed informed consent, did not undergo the bone surgery; therefore, bone and skin tissue samples were not collected, excluding the enrolled subject from study participation.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 28 28
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 8 8
        From 65-84 years
    		 19 19
        85 years and over
    		 1 1
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 20 20
    Type of Surgery
    Subjects were enrolled in this study if they were scheduled to undergo hip, shoulder or knee replacement surgery, and limb amputations or other orthopedic surgical procedures in countries other than Italy where the subject enrollment was limited to hip and knee replacement.
    Units: Subjects
        Knee
    		 2 2
        Hip
    		 22 22
        Shoulder
    		 0 0
        Limb amputation
    		 2 2
        Other
    		 2 2

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    		 Subjects with no history of GBCA exposure.

    Reporting group title
    MultiHance, Single Dose
    Reporting group description
    		 Subjects with previous exposure to a single dose of MultiHance

    Reporting group title
    MultiHance, Multiple Doses
    Reporting group description
    		 Subjects with previous exposure to multiple doses (2 or 3) of MultiHance

    Reporting group title
    ProHance, Single Dose
    Reporting group description
    		 Subjects with previous exposure to a single dose of ProHance

    Primary: Gadolinium Deposition in Bone Tissue, Trabecular

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    End point title
    		 Gadolinium Deposition in Bone Tissue, Trabecular [1]
    End point description
    End point type
    Primary
    End point timeframe
    At least 1 month (3 months for Italian sites) prior to planned surgery
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The descriptive statistics of mean, standard deviation, median, and range for the Gadolinium depositions were estimated for each study arm.
    End point values
    		 Control MultiHance, Single Dose MultiHance, Multiple Doses ProHance, Single Dose
    Number of subjects analysed
    10
    7
    5
    6
    Units: microgram(s)/gram
    arithmetic mean (standard deviation)
        Total Gd, trabecular
    0.0400 ± 0.00000
    0.8501 ± 0.56026
    1.7180 ± 1.13306
    0.1007 ± 0.08226
    No statistical analyses for this end point

    Primary: Gadolinium Deposition in Bone Tissue, Cortical

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    End point title
    		 Gadolinium Deposition in Bone Tissue, Cortical [2]
    End point description
    End point type
    Primary
    End point timeframe
    At least 1 month (3 months for Italian sites) prior to planned surgery
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The descriptive statistics of mean, standard deviation, median, and range for the Gadolinium depositions were estimated for each study arm.
    End point values
    		 Control MultiHance, Single Dose MultiHance, Multiple Doses ProHance, Single Dose
    Number of subjects analysed
    9
    6
    4
    6
    Units: microgram(s)/gram
    arithmetic mean (standard deviation)
        Total Gd, cortical
    0.0400 ± 0.00000
    0.8930 ± 0.62254
    1.0160 ± 0.69823
    0.0688 ± 0.02774
    No statistical analyses for this end point

    Primary: Gadolinium Deposition in Skin Tissue

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    End point title
    		 Gadolinium Deposition in Skin Tissue [3]
    End point description
    End point type
    Primary
    End point timeframe
    At least 1 month (3 months for Italian sites) prior to planned surgery
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The descriptive statistics of mean, standard deviation, median, and range for the Gadolinium depositions were estimated for each study arm.
    End point values
    		 Control MultiHance, Single Dose MultiHance, Multiple Doses ProHance, Single Dose
    Number of subjects analysed
    10
    7
    5
    6
    Units: microgram(s)/gram
    arithmetic mean (standard deviation)
        Total Gd
    0.0400 ± 0.00000
    0.0424 ± 0.00643
    0.0400 ± 0.00000
    0.0400 ± 0.00000
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    This was a prospective study of retrospective data. No investigational product was administered, therefore, adverse events were not collected.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    NA
    Frequency threshold for reporting non-serious adverse events: 0%
    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: This was a prospective study of retrospective data. No investigational product was administered during this study, therefore, adverse events were not collected.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2016
    To increase patient recruitment rates, the following changes were made to the original protocol: - Expansion of the patient population for including subjects undergoing additional procedures (i.e., shoulder replacement, limb amputations, or other orthopedic surgical procedures. However, it was agreed that patients with bone resection due to septic, infectious, or ischemic disease that had caused the bone to become diseased should not have been included in the study. This should not have prevented enrolment of patients with a diabetic limb amputation, as long as the complications of diabetes had not resulted in the bone becoming diseased. - Reduction of the minimum time between GBCA exposure and knee or hip surgery from 3 months to 1 month - Removal of the requirement to complete subgroup with multiple doses of the same GBCA and renal impairment - Collection of data for combined renal impairment subgroup with at least moderate renal impairment (eGFR≤60 ml/min) with a target size of at least 5 patients.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No robust conclusions could be drawn from the results of this study due to the small sample size.
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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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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