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    Clinical Trial Results:
    A European, randomised, double-blind, active comparator-controlled, cross-over, efficacy and safety study of a new 10% ready-to-use liquid human intravenous immunoglobulin (I10E) versus Kiovig® in patients with Multifocal Motor Neuropathy .

    Summary
    EudraCT number
    2012-001995-12
    Trial protocol
    IT   GB   ES   FR  
    Global end of trial date
    01 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Jun 2017
    First version publication date
    03 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I10E-0901
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    LFB Biotechnologies
    Sponsor organisation address
    3, Avenue des Tropiques - BP 40305, COURTABOEUF, France, 91958
    Public contact
    Global Clinical Development Leader, LFB BIOTECHNOLOGIES, +33 169 82 56 56,
    Scientific contact
    Global Clinical Development Leader, LFB BIOTECHNOLOGIES, +33 169 82 56 56,
    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
    04 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy of I10E compared to Kiovig® for maintenance treatment of patients with MMN in a randomised, double-blind, active comparator-controlled, cross-over design.
    Protection of trial subjects
    No specific protection.
    Background therapy
    None
    Evidence for comparator
    The comparator was Kiovig, the only human normal immunoglobulin with an indication in Multifocal Motor Neuropathy when the study protocol was written
    Actual start date of recruitment
    04 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Italy: 9
    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)
    22
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The first patient signed a consent form on 4 September 2013 The last patient signed a consent form on 2 July 2015

    Pre-assignment
    Screening details
    A blood sample was drawn during the screening visit for laboratory tests, in order to rule out some exclusion criteria.

    Pre-assignment period milestones
    Number of subjects started
    30 [1]
    Number of subjects completed
    22

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    screening failure: 8
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 8 patients are on screening failure.
    Period 1
    Period 1 title
    Before 1st administration of study drug
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Before shipment to investigational sites, each vial of IMP was covered by a masking system and was packaged in an individual box. Each vial and box was labelled with a unique identification number and all other useful information for the study except information enabling the identification of IMP. Before each course, the hospital pharmacist logged in the IWRS and obtained the vial identification numbers for vials to be administered to the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence A arm
    Arm description
    The patients randomized in Sequence A received Kiovig in Period 1 and I10E in period 2.
    Arm type
    Active comparator

    Investigational medicinal product name
    Kiovig
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    No administration during this period.

    Arm title
    Sequence B arm
    Arm description
    The patients randomized in Sequence B received I10E in Period 1 and Kiovig in period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    I10E
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    No administration during this period.

    Number of subjects in period 1 [2]
    Sequence A arm Sequence B arm
    Started
    12
    10
    Completed
    12
    10
    Notes
    [2] - 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: 23 patients randomized (worldwide number) but one patient on screening failure after randomization.
    Period 2
    Period 2 title
    Treatment period 1
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Before shipment to investigational sites, each vial of IMP was covered by a masking system and was packaged in an individual box. Each vial and box was labelled with a unique identification number and all other useful information for the study except information enabling the identification of IMP. Before each course, the hospital pharmacist logged in the IWRS and obtained the vial identification numbers for vials to be administered to the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence A arm
    Arm description
    The patients randomized in Sequence A received Kiovig in Period 1 and I10E in period 2.
    Arm type
    Active comparator

    Investigational medicinal product name
    Kiovig
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage and treatment course frequency could vary from subject to subject. The treatment schedule was to be maintained stable at the same level as before inclusion into the study. The allowed range was between 1 g/kg over 1-3 days and 2 g/kg over 2-5 days every 4 to 8 weeks. I10E and Kiovig were administered in a double-blind manner by investigators. Duration of treatment: Randomized subjects were treated for between 42 and 50 weeks including two 21 to 25-week periods with Kiovig and I10E or vice versa. The exact duration of the treatment and follow-up depended on each subject’s own schedule.

    Arm title
    sequence B arm
    Arm description
    The patients randomized in Sequence B received I10E in Period 1 and Kiovig in period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    I10E
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage and treatment course frequency could vary from subject to subject. The treatment schedule was to be maintained stable at the same level as before inclusion into the study. The allowed range was between 1 g/kg over 1-3 days and 2 g/kg over 2-5 days every 4 to 8 weeks. I10E and Kiovig were administered in a double-blind manner by investigators. Duration of treatment: Randomized subjects were treated for between 42 and 50 weeks including two 21 to 25-week periods with Kiovig and I10E or vice versa. The exact duration of the treatment and follow-up depended on each subject’s own schedule.

    Number of subjects in period 2
    Sequence A arm sequence B arm
    Started
    12
    10
    Completed
    12
    9
    Not completed
    0
    1
         Patient dissatisfaction with IMP
    -
    1
    Period 3
    Period 3 title
    Treatment period 2
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Before shipment to investigational sites, each vial of IMP was covered by a masking system and was packaged in an individual box. Each vial and box was labelled with a unique identification number and all other useful information for the study except information enabling the identification of IMP. Before each course, the hospital pharmacist logged in the IWRS and obtained the vial identification numbers for vials to be administered to the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence A arm
    Arm description
    The patients randomized in Sequence A received I10E during Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    I10E
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage and treatment course frequency could vary from subject to subject. The treatment schedule was to be maintained stable at the same level as before inclusion into the study. The allowed range was between 1 g/kg over 1-3 days and 2 g/kg over 2-5 days every 4 to 8 weeks. I10E and Kiovig were administered in a double-blind manner by investigators. Duration of treatment: Randomized subjects were treated for between 42 and 50 weeks including two 21 to 25-week periods with Kiovig and I10E or vice versa. The exact duration of the treatment and follow-up depended on each subject’s own schedule.

    Arm title
    Sequence B arm
    Arm description
    The patients randomized in Sequence B received Kiovig during period 2.
    Arm type
    Active comparator

    Investigational medicinal product name
    Kiovig
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage and treatment course frequency could vary from subject to subject. The treatment schedule was to be maintained stable at the same level as before inclusion into the study. The allowed range was between 1 g/kg over 1-3 days and 2 g/kg over 2-5 days every 4 to 8 weeks. I10E and Kiovig were administered in a double-blind manner by investigators. Duration of treatment: Randomized subjects were treated for between 42 and 50 weeks including two 21 to 25-week periods with Kiovig and I10E or vice versa. The exact duration of the treatment and follow-up depended on each subject’s own schedule.

    Number of subjects in period 3
    Sequence A arm Sequence B arm
    Started
    12
    9
    Completed
    12
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence A arm
    Reporting group description
    The patients randomized in Sequence A received Kiovig in Period 1 and I10E in period 2.

    Reporting group title
    Sequence B arm
    Reporting group description
    The patients randomized in Sequence B received I10E in Period 1 and Kiovig in period 2.

    Reporting group values
    Sequence A arm Sequence B arm Total
    Number of subjects
    12 10 22
    Age categorical
    Units: Subjects
        Adults (18-79 years)
    12 10 22
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    49.8 (32 to 78) 48.3 (31 to 64) -
    Gender categorical
    Units: Subjects
        Female
    1 2 3
        Male
    11 8 19
    Subject analysis sets

    Subject analysis set title
    Modified Intent-To-Treat set Kiovig
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The modified intent-to-treat (mITT) population was defined as all randomized subjects who received at least one administration of IMP, with the baseline and at least one post treatment MMRC efficacy assessment available. The EOS visit assessment constituted a valid post treatment assessment for this definition.

    Subject analysis set title
    Modified Intent-To-Treat set I10E
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The modified intent-to-treat (mITT) population was defined as all randomized subjects who received at least one administration of IMP, with the baseline and at least one post treatment MMRC efficacy assessment available. The EOS visit assessment constituted a valid post treatment assessment for this definition.

    Subject analysis set title
    Total treated set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Total treated set is defined as all subjets who received at least one administration of IMP

    Subject analysis sets values
    Modified Intent-To-Treat set Kiovig Modified Intent-To-Treat set I10E Total treated set
    Number of subjects
    21
    22
    22
    Age categorical
    Units: Subjects
        Adults (18-79 years)
    21
    22
    22
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    48.9 (31 to 78)
    49.1 (31 to 78)
    49.1 (31 to 78)
    Gender categorical
    Units: Subjects
        Female
    3
    3
    3
        Male
    18
    19
    19

    End points

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    End points reporting groups
    Reporting group title
    Sequence A arm
    Reporting group description
    The patients randomized in Sequence A received Kiovig in Period 1 and I10E in period 2.

    Reporting group title
    Sequence B arm
    Reporting group description
    The patients randomized in Sequence B received I10E in Period 1 and Kiovig in period 2.
    Reporting group title
    Sequence A arm
    Reporting group description
    The patients randomized in Sequence A received Kiovig in Period 1 and I10E in period 2.

    Reporting group title
    sequence B arm
    Reporting group description
    The patients randomized in Sequence B received I10E in Period 1 and Kiovig in period 2.
    Reporting group title
    Sequence A arm
    Reporting group description
    The patients randomized in Sequence A received I10E during Period 2.

    Reporting group title
    Sequence B arm
    Reporting group description
    The patients randomized in Sequence B received Kiovig during period 2.

    Subject analysis set title
    Modified Intent-To-Treat set Kiovig
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The modified intent-to-treat (mITT) population was defined as all randomized subjects who received at least one administration of IMP, with the baseline and at least one post treatment MMRC efficacy assessment available. The EOS visit assessment constituted a valid post treatment assessment for this definition.

    Subject analysis set title
    Modified Intent-To-Treat set I10E
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The modified intent-to-treat (mITT) population was defined as all randomized subjects who received at least one administration of IMP, with the baseline and at least one post treatment MMRC efficacy assessment available. The EOS visit assessment constituted a valid post treatment assessment for this definition.

    Subject analysis set title
    Total treated set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Total treated set is defined as all subjets who received at least one administration of IMP

    Primary: Mean MMRC 10 sum score during the evaluation period

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    End point title
    Mean MMRC 10 sum score during the evaluation period [1]
    End point description
    The MMRC 10 sum score measure muscle strength in 10 muscle groups (5 in upper limbs and 5 in lower limbs) right and left. Each muscle group is scored from 0 (paralysis) to 5 (normal strength), resulting in a global score from 0 to 100.
    End point type
    Primary
    End point timeframe
    The evaluation period started 13 weeks after the initiation of each product and lasted until the end of the respective period.
    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 linear mixed model used in this study estimated the effects of the products, periods and sequence on the mean MMRC 10 sumscore. The estimates of the effect of each of these 3 factors were adjusted based on the 2 other factors and on the baseline values. The estimated 95% confidence interval was also calculated for these 3 factors. The non-inferiority of I10E compared to Kiovig was tested at 1-sided alfa risk of 2.5%. The non-inferiority margin was of 2 points.
    End point values
    Modified Intent-To-Treat set Kiovig Modified Intent-To-Treat set I10E
    Number of subjects analysed
    21
    22
    Units: score (from 0 to 100)
        arithmetic mean (standard deviation)
    94.8 ± 7.3
    94.6 ± 7.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first administration of the IMP to the end-of-study visit
    Adverse event reporting additional description
    All the adverse events that occured in at least 5% of patients (i.e. in at least 2 patients among 22)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    Kiovig group
    Reporting group description
    -

    Reporting group title
    I10E group
    Reporting group description
    -

    Serious adverse events
    Kiovig group I10E group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Kiovig group I10E group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 21 (71.43%)
    16 / 22 (72.73%)
    Vascular disorders
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    3
    Blood and lymphatic system disorders
    Leukopenia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    3
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 21 (47.62%)
    8 / 22 (36.36%)
         occurrences all number
    23
    22
    Sciatica
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    5 / 22 (22.73%)
         occurrences all number
    2
    6
    Gait disturbances
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 22 (9.09%)
         occurrences all number
    1
    4
    Musculoskeletal and connective tissue disorders
    Muscle spasms
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 22 (9.09%)
         occurrences all number
    3
    3
    Pain in extremity
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Arthralgia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Back pain
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Infections and infestations
    nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 22 (13.64%)
         occurrences all number
    3
    3
    Influenza
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 22 (9.09%)
         occurrences all number
    1
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Sep 2014
    - The inclusion of subjects who received Kiovig more than 6 months before enrolment was permitted. - The definition of the PPS population was modified to be more conservative. - The limitation to 4 subjects per site was withdrawn to help enrol one or two more subjects in a few sites. - The IMP dosage reduction in obese subjects was removed because it was not appropriate during the maintenance treatment phase with IVIg. - The enrolment period was extended until the end of 3rd quarter 2016.
    26 Aug 2015
    - For the replacement of non-evaluable subjects, the new subject was to undergo a new randomization rather than having the same sequence group as the replaced subject. - Modifications on some exclusion criteria. - The potential risks related to the IMP were aligned with the European Guideline EMA/CHMP/BPWP/94038/2007 rev. 4. - The follow-up of AEs was clarified. - This amendment also incorporated rephrasing for clarification and consistencies between different clinical protocols. - This amendment also specified various administrative changes.
    18 Sep 2015
    A urine protein reagent strip test was added before IMP administration at all follow-up visits in subjects who had an abnormal (one cross or more) urine protein reagent strip test at screening and/or had GFR in the range of 60-80 mL/min/1.73 m2 measured according to the MDRD formula.

    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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