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    Clinical Trial Results:
    Mycophenolate sodium in Graves’ orbitopathy

    Summary
    EudraCT number
    2008-002123-93
    Trial protocol
    DE  
    Global end of trial date
    10 May 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jan 2020
    First version publication date
    26 Jan 2020
    Other versions
    Summary report(s)
    Lancet Diabetes Endocrinol 2018

    Trial information

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    Trial identification
    Sponsor protocol code
    MINGO
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University Medical Center Mainz
    Sponsor organisation address
    Langenbeckstreet 1, Mainz, Germany,
    Public contact
    Professor George J. Kahaly, University Medical Center Mainz, george.kahaly@unimedizin-mainz.de
    Scientific contact
    Professor George J. Kahaly, University Medical Center Mainz, george.kahaly@unimedizin-mainz.de
    Sponsor organisation name
    University Medical Center Mainz
    Sponsor organisation address
    Langenbeckstreet 1, Mainz, Germany,
    Public contact
    George J. Kahaly University Medical Center Mainz Langenbeckstreet 1 55131 Mainz, George J. Kahaly University Medical Center Mainz Langenbeckstreet 1 55131 Mainz, george.kahaly@unimedizin-mainz.de
    Scientific contact
    George J. Kahaly University Medical Center Mainz Langenbeckstreet 1 55131 Mainz, George J. Kahaly University Medical Center Mainz Langenbeckstreet 1 55131 Mainz, george.kahaly@unimedizin-mainz.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
    07 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - Response rate at week 12: comparison of the combination treatment vs. steroid monotherapy - Relapse rate at weeks 24 and 36 in both groups
    Protection of trial subjects
    All patients underwent complete ophthalmic and endocrine assessment at baseline and 6, 12, 24, and 36 weeks after starting treatment. Secondary Endpoint was safety of the combination treatment Mycophenolate Sodium + Methylprednisolone i.v. Adverse events were documented and coded in accordance with the standardised medical dictionary for regulatory affairs (MedDRA),17–19 as recommended by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Nov 2009
    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: 137
    Country: Number of subjects enrolled
    Italy: 27
    Worldwide total number of subjects
    164
    EEA total number of subjects
    164
    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)
    153
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Baseline assessments (general medical history, laboratory tests, endocrine and ophthalmic investigations, physical examination, vital signs, subjective assessments) may also be performed up to 2 weeks before baseline (Screening period). Results must be available and negative prior to administration of medication.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind [1]
    Roles blinded
    Data analyst, Investigator [2]
    Blinding implementation details
    All ophthalmologists and the Johannes Gutenberg University expert statistician were masked to group assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Methylprednisolone Monotherapy
    Arm description
    During the first 12 weeks, intravenous methylprednisolone was administered to all patients at 500 mg once per week for 6 weeks, then 250 mg once per week for 6 weeks with a cumulative dose of 4·5 g.
    Arm type
    Active comparator

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the first 12 weeks, intravenous methylprednisolone was administered to all patients at 500 mg once per week for 6 weeks, then 250 mg once per week for 6 weeks with a cumulative dose of 4·5 g.

    Arm title
    Methylprednisolone and Mycophenolate Sodium
    Arm description
    During the first 12 weeks, intravenous methylprednisolone was administered to all patients at 500 mg once per week for 6 weeks, then 250 mg once per week for 6 weeks with a cumulative dose of 4·5 g. In addition to the methylprednisolone, patients in the combination methylprednisolone and mycophenolate group also received 360 mg of mycophenolate orally twice per day for 24 weeks with a cumulative mycophenolate dose of 120 g.
    Arm type
    Experimental

    Investigational medicinal product name
    Mycophenolate Sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the first 12 weeks, intravenous methylprednisolone was administered to all patients at 500 mg once per week for 6 weeks, then 250 mg once per week for 6 weeks with a cumulative dose of 4·5 g. In addition to the methylprednisolone, patients in the combination methylprednisolone and mycophenolate group also received 360 mg of mycophenolate orally twice per day for 24 weeks with a cumulative mycophenolate dose of 120 g.

    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: The trial was observer-masked. Only Opththalmologists and the statistician were blinded to treatment allocation.
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The trial was observer-masked. Only Opththalmologists and the statistician were blinded to treatment allocation.
    Number of subjects in period 1
    Methylprednisolone Monotherapy Methylprednisolone and Mycophenolate Sodium
    Started
    81
    83
    Completed
    81
    83

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Methylprednisolone Monotherapy
    Reporting group description
    During the first 12 weeks, intravenous methylprednisolone was administered to all patients at 500 mg once per week for 6 weeks, then 250 mg once per week for 6 weeks with a cumulative dose of 4·5 g.

    Reporting group title
    Methylprednisolone and Mycophenolate Sodium
    Reporting group description
    During the first 12 weeks, intravenous methylprednisolone was administered to all patients at 500 mg once per week for 6 weeks, then 250 mg once per week for 6 weeks with a cumulative dose of 4·5 g. In addition to the methylprednisolone, patients in the combination methylprednisolone and mycophenolate group also received 360 mg of mycophenolate orally twice per day for 24 weeks with a cumulative mycophenolate dose of 120 g.

    Primary: Response rate at week 12: comparison of the combination treatment vs. steroid

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    End point title
    Response rate at week 12: comparison of the combination treatment vs. steroid
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to week 12
    End point values
    Methylprednisolone Monotherapy Methylprednisolone and Mycophenolate Sodium
    Number of subjects analysed
    73
    76
    Units: patients
    36
    48
    Statistical analysis title
    Primary outcome
    Comparison groups
    Methylprednisolone Monotherapy v Methylprednisolone and Mycophenolate Sodium
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.05
    Method
    Fisher exact
    Confidence interval
    Notes
    [1] - Comparison

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From Baseline to visit 36 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Safety Analysis
    Reporting group description
    from baseline to visit 36 weeks

    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: Frequency threshold for reporting non-serious adverse Events was set at 5%. No AE occurred in more than 3 patients; a detailed safety analysis is given in the attached manuscript.
    Serious adverse events
    Safety Analysis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 164 (14.02%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituritary gland neoplasm
         subjects affected / exposed
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    trauma
         subjects affected / exposed
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Thyroidectomy
         subjects affected / exposed
    3 / 164 (1.83%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    appendectomy
         subjects affected / exposed
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Tachyarrhythmia
         subjects affected / exposed
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Optic neuropathy
         subjects affected / exposed
    12 / 164 (7.32%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    hallux rigidus
         subjects affected / exposed
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Safety Analysis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 164 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    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
    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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