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    The EU Clinical Trials Register currently displays   40977   clinical trials with a EudraCT protocol, of which   6698   are clinical trials conducted with subjects less than 18 years old.
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    Clinical Trial Results:
    A Multicenter, Prospective, Open-Label, Non-Controlled Clinical Trial to Assess the Efficacy and Safety of Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C) in Patients With Myasthenia Gravis Exacerbations

    Summary
    EudraCT number
    2013-005098-28
    Trial protocol
    CZ   HU   BE   RO   PL   EE   LV  
    Global end of trial date
    17 Apr 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Apr 2019
    First version publication date
    03 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GTI1305
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02413580
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Grifols Therapeutics LLC
    Sponsor organisation address
    79 TW Alexander Drive, Research Triangle Park, North Carolina, United States, NC 27709
    Public contact
    Rhonda Griffin, Grifols Therapeutics LLC, rhonda.griffin@grifols.com
    Scientific contact
    Rhonda Griffin, Grifols Therapeutics LLC, rhonda.griffin@grifols.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 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of an intravenous (IV) infusion of Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C) (total dose of 2 grams per kilogram [g/kg] administered over 2 consecutive days at a dose of 1 g/kg per day) in subjects with myasthenia gravis (MG) exacerbations (not attributable to an infection or change in medication) by assessing the change in score of MG symptoms as measured by the Quantitative Myasthenia Gravis (QMG) scale from Baseline to Day 14.
    Protection of trial subjects
    Standards for Good Clinical Practice were adhered to for all procedures in this clinical study. The investigators ensured that the clinical study was conducted in full conformance with appropriate local laws and regulations and the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jun 2015
    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
    Argentina: 3
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Latvia: 10
    Worldwide total number of subjects
    49
    EEA total number of subjects
    31
    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)
    42
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Forty-nine subjects with MG exacerbations falling in the class IVb-V of the disease severity staging proposed by the Myasthenia Gravis Foundation of America (MGFA) were enrolled. MG exacerbations were characterized by worsening muscle weakness causing swallowing difficulty, acute respiratory failure or major functional disability.

    Pre-assignment
    Screening details
    There was no separate screening visit; screening evaluations were performed at the Baseline Visit (Day 0).

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

    Arms
    Arm title
    All subjects
    Arm description
    Subjects with MG exacerbations not attributable to an infection or change in medication were planned to receive 2 g/kg of IGIV-C on Day 0 (Baseline) and on Day 1 (dosed as 1 g/kg per day), followed by 28 days of post-infusion assessments.
    Arm type
    Experimental

    Investigational medicinal product name
    Gamunex-C
    Investigational medicinal product code
    IGIV-C
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 g/kg of IGIV-C was administered as IV infusions over 2 consecutive days so that subjects received a total dose of 2 g/kg.

    Number of subjects in period 1
    All subjects
    Started
    49
    Received IGIV-C on Day 0
    49
    Received IGIV-C on Day 1
    46
    Completed
    46
    Not completed
    3
         Adverse event, non-fatal
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    Subjects with MG exacerbations not attributable to an infection or change in medication were planned to receive 2 g/kg of IGIV-C on Day 0 (Baseline) and on Day 1 (dosed as 1 g/kg per day), followed by 28 days of post-infusion assessments.

    Reporting group values
    Overall Study Total
    Number of subjects
    49 49
    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)
    42 42
        From 65-84 years
    7 7
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    47.3 ± 15.22 -
    Gender categorical
    Units: Subjects
        Female
    34 34
        Male
    15 15
    MGFA classification at enrollment
    MGFA class IVb includes symptoms predominantly affecting oropharyngeal, respiratory muscles, or both. There may also be a lesser or equal involvement of limb, axial muscles or both. MGFA class V is defined as intubation, with or without mechanical ventilation, except when employed during routine postoperative management.
    Units: Subjects
        Class IVb
    49 49
        Class V
    0 0

    End points

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    End points reporting groups
    Reporting group title
    All subjects
    Reporting group description
    Subjects with MG exacerbations not attributable to an infection or change in medication were planned to receive 2 g/kg of IGIV-C on Day 0 (Baseline) and on Day 1 (dosed as 1 g/kg per day), followed by 28 days of post-infusion assessments.

    Primary: Mean Change in QMG Scale Score from Baseline (Day 0) to Day 14

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    End point title
    Mean Change in QMG Scale Score from Baseline (Day 0) to Day 14 [1]
    End point description
    The mean change in the QMG score from Baseline to Day 14 in the Evaluable population is presented. The QMG scale consists of 13 test items, each of which was given a score of either 0 (no symptoms), 1 (mild symptoms), 2 (moderate symptoms) or 3 (severe symptoms). The Evaluable population was defined as all subjects who received the entire dose of investigational product (IP) (2 g/kg over 2 consecutive days) and had valid Baseline and Day 14 QMG score measurements. The change in QMG score from Baseline to Day 14 was analyzed using the paired t-test (p<0.001, 95% confidence interval [CI]: -7.957 to -4.787).
    End point type
    Primary
    End point timeframe
    From Baseline (Day 0) to Day 14.
    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: As data is presented for a single reporting arm, the analysis of the change from Baseline to Day 14 is reported within the end point description.
    End point values
    All subjects
    Number of subjects analysed
    43
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    -6.4 ± 5.15
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clinical Improvement as Assessed by at Least a 3-Point Decrease in the QMG Scale from Baseline (Day 0) to Day 14

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    End point title
    Percentage of Subjects with Clinical Improvement as Assessed by at Least a 3-Point Decrease in the QMG Scale from Baseline (Day 0) to Day 14
    End point description
    The percentage of subjects with clinical improvement at Day 14 as assessed by the QMG scale in the Evaluable population is presented. The QMG scale consists of 13 test items, each of which was given a score of either 0 (no symptoms), 1 (mild symptoms), 2 (moderate symptoms) or 3 (severe symptoms). Subjects with clinical improvement had at least a 3-point decrease from Baseline in QMG score. The Evaluable population was defined as all subjects who received the entire dose of IP (2 g/kg over 2 consecutive days) and had valid Baseline and Day 14 QMG score measurements.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) to Day 14.
    End point values
    All subjects
    Number of subjects analysed
    43
    Units: Percentage of subjects
        number (not applicable)
    76.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clinical Improvement as Assessed by at Least a 2-Point Decrease in the MG-Activities of Daily Living (MG-ADL) from Baseline (Day 0) to Day 14

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    End point title
    Percentage of Subjects with Clinical Improvement as Assessed by at Least a 2-Point Decrease in the MG-Activities of Daily Living (MG-ADL) from Baseline (Day 0) to Day 14
    End point description
    The percentage of subjects with clinical improvement at Day 14 as assessed by the MG-ADL in the Evaluable population is presented. The MG-ADL is an 8-item, patient-reported questionnaire that is completed to assess the symptoms and activities of MG. Each item is scored from 0 (normal/no symptoms) to 3 (severe symptoms). Clinical improvement was defined as at least a 2-point decrease in the MG-ADL score. The Evaluable population was defined as all subjects who received the entire dose of IP (2 g/kg over 2 consecutive days) and had valid Baseline and Day 14 QMG score measurements.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 0) to Day 14.
    End point values
    All subjects
    Number of subjects analysed
    43
    Units: Percentage of subjects
        number (not applicable)
    88.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clinical Improvement as Assessed by at Least a 3-Point Decrease in the MG Composite Scale from Baseline (Day 0) to Day 14

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    End point title
    Percentage of Subjects with Clinical Improvement as Assessed by at Least a 3-Point Decrease in the MG Composite Scale from Baseline (Day 0) to Day 14
    End point description
    The percentage of subjects with clinical improvement at Day 14 as assessed by the MG Composite scale in the Evaluable population is presented. The MG Composite scale is a quantitative measure for determining improvement and worsening for subjects with generalized MG. It consists of 3 ocular, 3 bulbar, 1 respiratory, 1 neck and 2 limb items. The total score ranges from 0 to 50, with a higher score indicating more severe symptoms. Clinical improvement was defined as at least a 3-point decrease in the MG-ADL score. The Evaluable population was defined as all subjects who received the entire dose of IP (2 g/kg over 2 consecutive days) and had valid Baseline and Day 14 QMG score measurements.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 0) to Day 14.
    End point values
    All subjects
    Number of subjects analysed
    43
    Units: Percentage of subjects
        number (not applicable)
    86.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline (Day 0) up to Day 28.
    Adverse event reporting additional description
    Adverse events are reported for the Safety population which consisted of all subjects who received any amount of IP.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    Subjects with MG exacerbations not attributable to an infection or change in medication were planned to receive 2 g/kg of IGIV-C on Day 0 (Baseline) and on Day 1 (dosed as 1 g/kg per day), followed by 28 days of post-infusion assessments.

    Serious adverse events
    All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 49 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 49 (61.22%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 49 (38.78%)
         occurrences all number
    21
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    8 / 49 (16.33%)
         occurrences all number
    9
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Rash
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jun 2014
    -The percentage of subjects with clinical improvement was included and was defined by 3-point decreases in QMG and MG Composite scores and by 2-point decreases in MG-ADL scores. -MGFA post-intervention status was removed from Days 7, 21 and 28. -The time frame for long-term corticosteroid (CS) treatment for MG was 8 weeks. -Inclusion and exclusion criteria were updated with respect to use of contraception to prevent pregnancy during the course of the clinical study. -CS treatment newly initiated within 8 weeks and any IPs received within 3 months prior to study participation were prohibited. -Instructions for restricted concomitant medications during the clinical study were updated to prohibit cholinesterase inhibitors within 12 hours prior to assessment, and within 24 hours prior to assessment for subjects receiving slow-release cholinesterase inhibitors. -Thromboembolic events and hemolysis were added as AEs of special interest, and assessments were added on Days 1, 7 and 21 for additional safety monitoring.
    03 Sep 2015
    - Biomarker testing for peripheral blood mononucleated cells was removed from the clinical study. - The central laboratory could have been used if the local laboratory was unable to perform hemolysis laboratory testing. - Blood testing included serum or plasma free hemoglobin. - Instructions were provided that MG assessments should be performed by the same clinical staff member, if possible. - The definition of ‘infection’ was updated to be defined as ‘evident infection’ which included, but was not limited to, the presence of at least one of the following diagnostic features: axillary temperature ≥38°C, positive blood culture of infective microorganism, white blood cell (WBC) count >12×10^9/L and differential WBC count of >10% band neutrophils (>1.2×10^9/L), and pulmonary infiltrate with consolidation on chest X-ray. Alternatively, other signs and symptoms could have been considered for the diagnosis of evident infection according to the investigator’s judgement. - Use of prophylactic anti-coagulant therapy would not be considered ‘exceptional’ when administered during hospitalization as prophylactic treatment as part of standard of care for deep vein thrombosis prevention. - Prohibited medications were updated to include systemic antibiotic therapy. - Physical examinations did not include breast and genitourinary areas. - The Baseline Visit was to occur after the subject was stabilized according to the investigator’s judgement.
    30 Mar 2016
    - There was no screening visit in this clinical study. - Subjects with hemoglobin levels <9 grams/deciliter were not eligible for clinical study participation.

    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.
    As subjects may have been intubated or otherwise compromised, and the assessments may have been performed in extenuating circumstances, it was necessary to standardize methodology to obtain consistent scoring across study centers.
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