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    Clinical Trial Results:
    A Randomized, Single-blinded, Cross-over Study investigating the Non-inferiority of Efficacy and Safety of HyQvia in comparison with Conventional Subcutaneous Ig Therapy in Multifocal Motor Neuropathy

    Summary
    EudraCT number
    		 2015-003453-18
    Trial protocol
    		 DK  
    Global end of trial date
    03 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2020
    First version publication date
    18 Dec 2020
    Other versions
    Summary report(s)
    		 Abstract

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RH-2015-200
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02556437
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet - Department of Neurology
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark,
    Public contact
    Ali Al-Zuhairy, Rigshospitalet - Department of Neurology, 0045 22981147, al_zuhairy@hotmail.com
    Scientific contact
    Ali Al-Zuhairy, Rigshospitalet - Department of Neurology, 0045 22981147, al_zuhairy@hotmail.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
    03 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of immunoglobulin administered together with hyaluronidase (HyQvia) in large doses subcutaneously compared to conventional treatment with subcutaneous immunoglobulin (Subcuvia) in patients with MMN
    Protection of trial subjects
    This study was conducted in accordance with the recommendations of the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice and was monitored by the the local GCP units throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2015
    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
    Denmark: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    16
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was conducted at all three departments in Denmark responsible for the treatment of multifocal motor neuropathy, the Department of Neurology, Aarhus University Hospital, the Department of Neurology, Odense University Hospital and Department of Neurology, Rigshospitalet, Copenhagen University Hospital.

    Pre-assignment
    Screening details
    		 Thirty-eight patients with MMN were screened. Eleven did not meet inclusion criteria and 7 declined to participate. Twenty were included.

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [1]
    Roles blinded
    		 Data analyst, Assessor [2]

    Arms
    Arm title
    		 Baseline
    Arm description
    		 -
    Arm type
    		 Pre-study conventional SCIG

    Investigational medicinal product name
    Pre-study conventional subcutaneous immune globuline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients receiving their regular conventional subcutaneous immune globuline at a stable dose for at least three months prior to inclusion.

    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 same blinded person assessed the patients during study and upon study completion was unblinded and analyzed data.
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The same blinded person assessed the patients during study and upon study completion was unblinded and analyzed data.
    Number of subjects in period 1
    		Baseline
    Started
    20
    Completed
    20
    Period 2
    Period 2 title
    First period of treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [3]
    Roles blinded
    		 Data analyst, Assessor [4]
    Blinding implementation details
    All patients throughout the study were examined by the same assessor, who was blinded during the entire study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 fSCIG --> cSCIG
    Arm description
    		 Patients receiving facilitated subcutaneous immune globulin during the first 24 weeks of the study before crossing over
    Arm type
    		 Experimental

    Investigational medicinal product name
    facilitated subcutaneous immune globuline
    Investigational medicinal product code
    Other name
    HyQvia
    Pharmaceutical forms
    Infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Recombinant human hyaluronidase was manually injected at a dose of 80 U/g IgG followed by infusion of a 10% solution of human normal immunoglobulin (HyQvia, Shire, Lexington, MA, USA) [3] using an electronic peristaltic pump (Mini Rythmic PN+ R, Micrel Medical Devices, Athens, Greece). The maximum volume infused at one site was 600 ml at a rate of 300 ml/h.

    Arm title
    		 cSCIG --> fSCIG
    Arm description
    		 Patients receiving conventional subcutaneous immune globulin for the first 24 weeks before crossing over
    Arm type
    		 Experimental

    Investigational medicinal product name
    conventional subcutaneous immune globuline
    Investigational medicinal product code
    Other name
    Subcuvia
    Pharmaceutical forms
    Infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Conventional SCIG was infused at a concentration of 16% human normal immunoglobulin (Subcuvia, Shire) [5] at the abdomen or the thighs using one or two mechanical pumps (Freedom Pump, RMS Medical Products, Chester, NY, USA), one or two 60 ml syringes and a maximum of four subcutaneous lines per pump. The average infusion speed was 20 ml/h with a maximum infusion volume of 20 ml at each site.

    Notes
    [3] - 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 same blinded person assessed the patients during study and upon study completion was unblinded and analyzed data.
    [4] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The same blinded person assessed the patients during study and upon study completion was unblinded and analyzed data.
    Number of subjects in period 2
    		fSCIG --> cSCIG cSCIG --> fSCIG
    Started
    10
    10
    Completed
    9
    10
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -
    Period 3
    Period 3 title
    Second period of treatment, cross-over
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [5]
    Roles blinded
    		 Data analyst, Assessor [6]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 fSCIG --> cSCIG
    Arm description
    		 Patients treated with facilitated subcutaneous immune globulin for the first 24 weeks of study cross-over to 24 weeks of treatment with conventional subcutaneous immune globulin
    Arm type
    		 Experimental

    Investigational medicinal product name
    conventional subcutaneous immune globuline
    Investigational medicinal product code
    Other name
    Subcuvia
    Pharmaceutical forms
    Infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Please refer to previous description

    Arm title
    		 cSCIG --> fSCIG
    Arm description
    		 Patients treated with conventional subcutaneous immune globulin for the first 24 weeks of study cross-over to 24 weeks of treatment with facilitated subcutaneous immune globulin
    Arm type
    		 Experimental

    Investigational medicinal product name
    facilitated subcutaneous immune globuline
    Investigational medicinal product code
    Other name
    HyQvia
    Pharmaceutical forms
    Infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Please refer to previous description

    Notes
    [5] - 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 same blinded person assessed the patients during study and upon study completion was unblinded and analyzed data.
    [6] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The same blinded person assessed the patients during study and upon study completion was unblinded and analyzed data.
    Number of subjects in period 3
    		fSCIG --> cSCIG cSCIG --> fSCIG
    Started
    9
    10
    Completed
    9
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    		 -

    Reporting group values
    		 Baseline period Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 54 (46.5 to 62.5) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 10 10

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -
    Reporting group title
    fSCIG --> cSCIG
    Reporting group description
    		 Patients receiving facilitated subcutaneous immune globulin during the first 24 weeks of the study before crossing over

    Reporting group title
    cSCIG --> fSCIG
    Reporting group description
    		 Patients receiving conventional subcutaneous immune globulin for the first 24 weeks before crossing over
    Reporting group title
    fSCIG --> cSCIG
    Reporting group description
    		 Patients treated with facilitated subcutaneous immune globulin for the first 24 weeks of study cross-over to 24 weeks of treatment with conventional subcutaneous immune globulin

    Reporting group title
    cSCIG --> fSCIG
    Reporting group description
    		 Patients treated with conventional subcutaneous immune globulin for the first 24 weeks of study cross-over to 24 weeks of treatment with facilitated subcutaneous immune globulin

    Subject analysis set title
    fSCIG
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients following 24 weeks of treatment with facilitated subcutaneous immune globuline

    Subject analysis set title
    cSCIG
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients following 24 weeks of treatment with conventional subcutaneous immune globuline

    Primary: Normalized isometric strength

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    End point title
    		 Normalized isometric strength
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    19
    19
    Units: Percentage
        arithmetic mean (confidence interval 95%)
    100.8 (94.5 to 107.1)
    105.9 (99.8 to 112.0)
    Statistical analysis title
    		 Non-inferiority test with a 15% margin
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.0014
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [1] - Since this is a paried design, the values of 19 patients following each therapy were compared.

    Secondary: Medical Research Council (MRC)

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    End point title
    		 Medical Research Council (MRC)
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    19
    19
    Units: au
        median (inter-quartile range (Q1-Q3))
    88.0 (86.0 to 89.0)
    87.0 (84.0 to 89.0)
    Statistical analysis title
    		 Non-inferiority test with a 15% margin
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.0001
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [2] - Since this is a paried design, the values of 19 patients following each therapy were compared.

    Secondary: Overall Disability Sum Score (ODSS)

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    End point title
    		 Overall Disability Sum Score (ODSS)
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    19
    19
    Units: au
        median (inter-quartile range (Q1-Q3))
    2.0 (2.0 to 4.0)
    2.0 (2.0 to 4.0)
    Statistical analysis title
    		 Non-inferiority test with a 15% margin
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.0007
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [3] - Since this is a paried design, the values of 19 patients following each therapy were compared.

    Secondary: 9-Hole Peg Test (9-HPT)

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    End point title
    		 9-Hole Peg Test (9-HPT)
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    19
    19
    Units: second
        median (inter-quartile range (Q1-Q3))
    25.4 (18.4 to 28.5)
    24.8 (18.1 to 28.4)
    Statistical analysis title
    		 Non-inferiority test with a 15% margin
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    P-value
    		 = 0.0085
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [4] - Since this is a paried design, the values of 19 patients following each therapy were compared.

    Secondary: Grip strength

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    End point title
    		 Grip strength
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    19
    19
    Units: kgf
        arithmetic mean (confidence interval 95%)
    23.7 (17.1 to 30.3)
    22.6 (16.8 to 28.5)
    Statistical analysis title
    		 Non-inferiority test with a 15% margin
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 < 0.0001
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [5] - Since this is a paried design, the values of 19 patients following each therapy were compared.

    Secondary: Sixt Spot Step Test

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    End point title
    		 Sixt Spot Step Test
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    19
    19
    Units: second
        arithmetic mean (confidence interval 95%)
    6.5 (5.4 to 7.6)
    6.7 (5.6 to 7.7)
    Statistical analysis title
    		 Non-inferiority test with a 15% margin
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    P-value
    		 < 0.0001
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [6] - Since this is a paried design, the values of 19 patients following each therapy were compared.

    Secondary: EQ-5D-5L Index value

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    End point title
    		 EQ-5D-5L Index value
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    19
    19
    Units: au
        arithmetic mean (confidence interval 95%)
    0.84 (0.78 to 0.91)
    0.81 (0.76 to 0.86)
    Statistical analysis title
    		 Non-inferiority test with a 15% margin
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 < 0.0001
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [7] - Since this is a paried design, the values of 19 patients following each therapy were compared.

    Secondary: EQ-5D-5L VAS

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    End point title
    		 EQ-5D-5L VAS
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    19
    19
    Units: percent
        median (inter-quartile range (Q1-Q3))
    82.0 (65.0 to 95.0)
    85.0 (80.0 to 95.0)
    Statistical analysis title
    		 Non-inferiority test with a 15% margin
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    P-value
    		 = 0.0001
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [8] - Since this is a paried design, the values of 19 patients following each therapy were compared.

    Secondary: Headache or nausea

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    End point title
    		 Headache or nausea
    End point description
    Number of patients experiencing headache or nausea at least once during the 24 weeks of therapy
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    16
    16
    Units: At least once
    7
    7
    Statistical analysis title
    		 McNemar's test
    Statistical analysis description
    Only 16 subjects logged specifically every infusion and whether any systemic adverse event occured or not. Since this is a paired design, only 16 subjects were compared.
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 Mcnemar
    Confidence interval

    Secondary: Percentage of infusions causing local side-effects

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    End point title
    		 Percentage of infusions causing local side-effects
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    14
    14
    Units: percent
        median (inter-quartile range (Q1-Q3))
    62.6 (23.1 to 100.0)
    9.4 (0.0 to 21.7)
    Statistical analysis title
    		 Wilcoxon Signed Rank Test
    Statistical analysis description
    Only 14 patients had systematically logged all their infusions during both treatment periods with respect to any side-effects. Since this is a paried design, the values of the 14 patients following each therapy were compared.
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Wilcoxon Signed Rank Test
    Confidence interval

    Secondary: Total infusions associated with local side-effects during the 24 weeks of each treatment

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    End point title
    		 Total infusions associated with local side-effects during the 24 weeks of each treatment
    End point description
    Total infusions associated with local side-effects during the 24 weeks period of each treatment
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 fSCIG cSCIG
    Number of subjects analysed
    14
    14
    Units: Infusions
        median (inter-quartile range (Q1-Q3))
    6.0 (3.0 to 13.0)
    2.5 (0.0 to 6.0)
    Statistical analysis title
    		 Wilcoxon Signed Rank Test
    Statistical analysis description
    Only 14 patients had systematically logged all their infusions during both treatment periods with respect to any side-effects. Since this is a paried design, the values of the 14 patients following each therapy were compared.
    Comparison groups
    fSCIG v cSCIG
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon Signed Rank Test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 weeks
    Adverse event reporting additional description
    Interviews every 6 weeks + patient logs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    20200930
    Reporting groups
    Reporting group title
    fSCIG
    Reporting group description
    		 -

    Reporting group title
    cSCIG
    Reporting group description
    		 -

    Serious adverse events
    		 fSCIG cSCIG
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 fSCIG cSCIG
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 20 (80.00%)
    10 / 19 (52.63%)
    General disorders and administration site conditions
    Systemic and local side-effects
         subjects affected / exposed
    16 / 20 (80.00%)
    10 / 19 (52.63%)
         occurrences all number
    16
    10

    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
    For support, Contact us.
    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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