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    Clinical Trial Results:
    Multicenter, open-label extension study to investigate the long-term safety and efficacy of IgPro20 in maintenance treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in subjects completing study IgPro20_3003

    Summary
    EudraCT number
    2013-004157-24
    Trial protocol
    GB   IT   DE   ES   FI   NL   CZ  
    Global end of trial date
    10 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Jul 2018
    First version publication date
    25 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IgPro20_3004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02027701
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CSL Behring GmbH
    Sponsor organisation address
    Emil-von-Behring-Strasse 76, Marburg, Germany,
    Public contact
    Clin Trial Registration Coordinator, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Scientific contact
    Clin Trial Registration Coordinator, CSL Behring GmbH, clinicaltrials@cslbehring.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 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate long-term safety and efficacy of IgPro20.
    Protection of trial subjects
    This study was carried out in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and standard operating procedures for clinical research and development at CSL Behring, LLC (CSLB).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Jul 2014
    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
    Japan: 10
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Australia: 1
    Worldwide total number of subjects
    82
    EEA total number of subjects
    55
    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)
    55
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subject had completed Study 3003 (SC Week 25) or was successfully rescued from a relapse during the SC Treatment Period of Study 3003, and if treatment for CIDP was required it had to include IgGs.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    IgPro20
    Arm description
    20% liquid formulation (200 mg/mL) of human normal immunoglobulin administered SC weekly at 0.2 g/kg, and subjects who experience CIDP relapse on 0.2 g/kg IgPro20 will have an increase to 0.4 g/kg IgPro20.
    Arm type
    Experimental

    Investigational medicinal product name
    IgPro20
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    20% liquid formulation (200 mg/mL) of human normal immunoglobulin for SC use administered SC weekly: 0.2 g/kg bw (low-dose IgPro20) for up to 48 weeks. Subjects who experience CIDP relapse on 0.2 g/kg IgPro20 will have an increase to 0.4 g/kg IgPro20 immediately and will continue on high-dose until they have completed a total of 48 weeks of IgPro20 treatment.

    Number of subjects in period 1
    IgPro20
    Started
    82
    Completed
    66
    Not completed
    16
         Physician decision
    2
         Lack of efficacy
    8
         Adverse event, non-fatal
    3
         Consent withdrawn by subject
    3

    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
    82 82
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    55 55
        From 65-84 years
    27 27
    Gender categorical
    Units: Subjects
        Male
    50 50
        Female
    32 32

    End points

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    End points reporting groups
    Reporting group title
    IgPro20
    Reporting group description
    20% liquid formulation (200 mg/mL) of human normal immunoglobulin administered SC weekly at 0.2 g/kg, and subjects who experience CIDP relapse on 0.2 g/kg IgPro20 will have an increase to 0.4 g/kg IgPro20.

    Subject analysis set title
    Safety Data Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety Data Set (SDS): all subjects who received at least 1 dose of IgPro20 in this study.

    Subject analysis set title
    Total Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Total Set: all subjects enrolled in the study, ie, the subject's informed consent was obtained. In the study protocol, this analysis set was referred to as the Intention-to-Treat Data Set.

    Primary: Overall rate of Adverse Events (AEs) per infusion (SDS)

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    End point title
    Overall rate of Adverse Events (AEs) per infusion (SDS) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 49 weeks
    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: Only descriptive statistics were given for this outcome measure.
    End point values
    IgPro20
    Number of subjects analysed
    82
    Units: Adverse events per infusion
        number (not applicable)
    0.032
    No statistical analyses for this end point

    Secondary: Change From Baseline in CIDP Total Adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) Score (Total Set)

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    End point title
    Change From Baseline in CIDP Total Adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) Score (Total Set)
    End point description
    The INCAT score is a 10-point scale that covers the functionality of legs and arms, and has been successfully used to measure treatment effects in various CIDP studies. Scores for arm disability range from 0 ("No upper limb problems") to 5 ("Inability to use either arm for any purposeful movement"), and scores for leg disability range from 0 ("Walking not affected") to 5 ("Restricted to wheelchair, unable to stand and walk a few steps with help"). The INCAT (total) score is the sum of these 2 scores and ranges from 0 to 10. For the "adjusted" INCAT score, changes in the function of the upper limbs from 0 (normal) to 1 (minor symptoms) or from 1 to 0 were not recorded as deterioration or improvement because these changes are not considered clinically significant.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    80
    Units: Units on a scale
        median (full range (min-max))
    0.0 (-3 to 6)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Medical Research Council (MRC) Score (Total Set)

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    End point title
    Change From Baseline in Medical Research Council (MRC) Score (Total Set)
    End point description
    An adapted version of the MRC sum score as published by Kleyweg and the RMC trial group was used. With the MRC sum score, the following 8 bilateral muscle pairs were assessed, and individual muscle scores as well as the sum score documented: Shoulder abduction; Elbow flexion; Wrist extension; Index finger abduction; Hip flexion; Knee extension; Foot dorsiflexion; Great toe dorsiflexion. The MRC sum score ranges from 0 (paralysis) to 80 (normal strength) points.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    78
    Units: Units on a scale
        median (full range (min-max))
    0.0 (-23 to 18)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Rasch-built Overall Disability Scale (R-ODS) (Total Set)

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    End point title
    Change From Baseline in Rasch-built Overall Disability Scale (R-ODS) (Total Set)
    End point description
    The R-ODS is a recently published outcome measure that captures activity and social participation in subjects with Guillain-Barré Syndrome, CIDP, and monoclonal gammopathy of uncertain significance. The 24-item questionnaire covers a wide range of tasks of daily life that are each to be rated as “impossible to perform”, “able to perform with difficulty”, or “easy to perform” (scale of 0 - 2 points respectively). Items are sorted in order of increasing difficulty to perform, based on data from subjects with peripheral neuropathies (chronic inflammatory demyelinating polyneuropathy, Guillain-Barré Syndrome, or monoclonal gammopathy of uncertain significance) and subjects recruited at the university outpatient clinics of Rotterdam and Maastricht.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    71
    Units: Units on a scale
        median (full range (min-max))
    0.0 (-76 to 33)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Grip Strength (Total Set)

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    End point title
    Change From Baseline in Mean Grip Strength (Total Set)
    End point description
    The hand-held Vigorimeter from Martin (Tuttlingen, Germany) is a device that measures the strength of small muscles in the hand, ie, grip strength. The subject squeezes a rubber bulb lying between the palm of the hand and the thumb and index fingers. The pressure is recorded via a rubber tube on a nanometer and expressed in kilopascal (kPa). At each assessment, the subject squeezes 3 times with each hand.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    79
    Units: Units on a scale
        median (full range (min-max))
    -0.7 (-80 to 27)
    No statistical analyses for this end point

    Secondary: Rate of AEs by Severity Per Infusion (SDS)

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    End point title
    Rate of AEs by Severity Per Infusion (SDS)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    82
    Units: Adverse events per infusion
    number (not applicable)
        Mild
    0.024
        Moderate
    0.006
        Severe
    0.002
    No statistical analyses for this end point

    Secondary: Rate of Causally Related AEs Per Infusion (SDS)

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    End point title
    Rate of Causally Related AEs Per Infusion (SDS)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    82
    Units: Adverse Events per infusion
        number (not applicable)
    0.011
    No statistical analyses for this end point

    Secondary: Rate of Serious AEs Per Infusion (SDS)

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    End point title
    Rate of Serious AEs Per Infusion (SDS)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    82
    Units: Adverse events per infusion
        number (not applicable)
    0.001
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Adverse Events (AEs) (SDS)

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    End point title
    Percentage of Subjects with Adverse Events (AEs) (SDS)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    82
    Units: percentage of subjects
        number (not applicable)
    75.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with AEs by Severity (SDS)

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    End point title
    Percentage of Subjects with AEs by Severity (SDS)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    82
    Units: Percentage of subjects
    number (not applicable)
        Mild
    62.2
        Moderate
    29.3
        Severe
    9.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Causally Related AEs (SDS)

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    End point title
    Percentage of Subjects with Causally Related AEs (SDS)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    82
    Units: Percentage of subjects
        number (not applicable)
    25.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with AEs by Seriousness (SDS)

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    End point title
    Percentage of Subjects with AEs by Seriousness (SDS)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 49 weeks
    End point values
    IgPro20
    Number of subjects analysed
    82
    Units: Percentage of subjects
        number (not applicable)
    8.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 49 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    IgPro20
    Reporting group description
    -

    Serious adverse events
    IgPro20
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 82 (4.88%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Sepsis
         subjects affected / exposed
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Chronic inflammatory demyelinating polyradiculoneuropathy
         subjects affected / exposed
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Nerve compression
         subjects affected / exposed
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Faecaloma
         subjects affected / exposed
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Gallbladder perforation
         subjects affected / exposed
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 82 (1.22%)
         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
    IgPro20
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 82 (30.49%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 82 (4.88%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Infusion site erythema (local)
         subjects affected / exposed
    7 / 82 (8.54%)
         occurrences all number
    9
    Infusion site erythema (general)
         subjects affected / exposed
    7 / 82 (8.54%)
         occurrences all number
    9
    Infusion site swelling (local)
         subjects affected / exposed
    9 / 82 (10.98%)
         occurrences all number
    11
    Infusion site swelling (general)
         subjects affected / exposed
    9 / 82 (10.98%)
         occurrences all number
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 82 (13.41%)
         occurrences all number
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2014
    •Study design modified to require direct transition from the completion visit of study IgPro20_3003 to the Week 1 (baseline) visit of this study. •Inclusion criteria modified to define the study population (subjects who completed the SC Period or successfully recovered from CIDP relapse during the SC Period of the IgPro20_3003 study). •Exclusion criteria modified because of study design change, ie, direct transition from study IgPro20_3003. •IgPro20 dose reduced to 0.2 g/kg bw; if CIDP relapse occurs, subject will have the dose adjusted up to 0.4 g/kg bw; subject must successfully recover within 4 weeks (±2 days) in order to continue in the study. Dose justification and maximum volume per infusion site increased to 50 mL, as tolerated. •Subjects enrolled under the original protocol will be re-consented for Amendment 1 and started on Amendment 1 dose requirements and procedures at Week 25. If a subject enrolled under the original protocol, relapses and successfully recovers from the relapse prior to Week 25, the subject will remain on 0.4 g/kg bw for the remainder of the study. If the subject relapses again, they will be discontinued. •Week 17 and Week 41 visits converted to dispensing and inventory only visits. •Viral safety testing deleted, only retention sample collected for possible future testing if a suspected treatment-emergent viral infection occurs. •Biomarker text modified to delete anonymization of samples. This should not have been required in the original protocol, because no genetics will be tested. Biomarker results will need to be correlated with the subject’s treatment in both studies and other test results in order to benefit understanding of CIDP disease progression and how to treat it. Biomarker sample collection is optional for Japan. •Missing efficacy (R-ODS) and HRQL (EQ-5D) instruments added to Section 8 and the Appendix, respectively. •Statement added that IgG levels will not be disclosed to the site or CSLB until the IgP
    22 Jun 2015
    •Number of subjects increased to approximately 80 subjects. •IVRS language updated to more closely align with the IgPro20_3003 protocol. •Biomarker language modified to confirm that a biomarker sample is required to be collected upon a CIDP relapse, either at a scheduled visit, or an unscheduled visit whichever is more timely. An unscheduled laboratory kit should be used for biomarker sample collection for both scheduled and unscheduled visits.
    08 Dec 2015
    •Adverse reactions were updated per current safety information. •IVRS language updated to clarify volume needed for each infusion session.

    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.
    For the "Endpoint Time to First CIDP Relapse (Total Set)", the subjects analyzed is 82, subjects started is 82, median is 266.0, 95%CI is 225.0 to NA (not evaluable).
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