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    Clinical Trial Results:
    Post-Authorization Safety, Tolerability and Immunogenicity Evaluation of HyQvia in Pediatric Subjects With Primary Immunodeficiency Diseases

    Summary
    EudraCT number
    		 2016-003438-26
    Trial protocol
    		 GB   SE   DK   CZ   SK   FR   GR   HU  
    Global end of trial date
    15 Jan 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Apr 2022
    First version publication date
    04 Aug 2021
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Study results data have been updated based on final CSR.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    161504
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03116347
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Baxalta Innovations GmbH
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, 1220
    Public contact
    Study Director, Baxalta Innovations GmbH, ClinicalTransparency@takeda.com
    Scientific contact
    Study Director, Baxalta Innovations GmbH, ClinicalTransparency@takeda.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the safety of HyQvia treatment in pediatric subjects with Primary Immunodeficiency Diseases (PIDD) who received immunoglobulin therapy prior to study enrollment.
    Protection of trial subjects
    This study was conducted in accordance with the principles and guidelines described in the study protocol, the International Council for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP R2, November 2016), Title 21 of the United States (US) Code of Federal Regulations, the European Union (EU) Directives 2001/20/EC and 2005/28/EC, the Declaration of Helsinki, and applicable national and local regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 May 2017
    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
    Czechia: 7
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Slovakia: 9
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Hungary: 3
    Worldwide total number of subjects
    42
    EEA total number of subjects
    33
    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)
    21
    Adolescents (12-17 years)
    21
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 42 subjects were enrolled and treated. This study consisted of 3 treatment periods: Epoch 1 (E1), Epoch 2 (E2) and Epoch 3 (E3). Subject with anti-rHuPH20 antibody titer >= 160 during E1 or E2 and who experienced either a related serious or severe adverse event (AE) was followed to E3.

    Pre-assignment
    Screening details
    		 Subjects treated with HyQvia in E1 followed by E2 were referred as “HyQvia new starters” and who started directly in E2 were referred as “HyQvia pre-treated”. 1 subject from “HyQvia new starters” discontinued E2, entered E3 due to a severe related AE and didn’t receive HyQvia treatment in E3.No further safety and efficacy data were collected in E3

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HyQvia New Starters
    Arm description
    		 Subjects who were treated with non-HyQvia treatment by time of enrollment were enrolled in Epoch 1 (ramp-up) and treated with HyQvia subcutaneously (SC) with a dose or interval ramp-up period of up to 6 weeks. HyQvia dose was planned to be equivalent to 100% (±5%) of pre-study treatment. Dosage frequency was one treatment interval of one week, then one treatment interval of two weeks, then one treatment interval of three weeks (for subjects in whom treatment was expected to be every four weeks). The ramp-up period was followed by Epoch 2 with HyQvia SC treatment at every 3 or 4 weeks, depending on the subject's previous dosing schedule and the discretion of the investigator and subject, for up to 20 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    10% (Human) with Recombinant Human Hyaluronidase (IGI, 10% with rHuPH20)
    Investigational medicinal product code
    Other name
    HyQvia
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects treated with HyQvia subcutaneously with a dose or interval ramp-up period of up to 6 weeks in Epoch 1.

    Arm title
    		 HyQvia Pre-treated
    Arm description
    		 Subjects already treated with HYQVIA by the time of enrollment were directly enrolled in Epoch 2 and treated with HyQvia SC at every 3 or 4 weeks for up to 20 months. HyQvia dose was planned to be equivalent to 100% (±5%) of pre-study treatment with a dosage frequency of once every three or four weeks, based on the subject's previous dosing schedule and the discretion of the investigator and subject.
    Arm type
    		 Experimental

    Investigational medicinal product name
    10% (Human) with Recombinant Human Hyaluronidase (IGI, 10% with rHuPH20)
    Investigational medicinal product code
    Other name
    HyQvia
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects already treated with HYQVIA by the time of enrollment were directly enrolled in Epoch 2 and treated with HyQvia SC at every 3 or 4 weeks for up to 20 months.

    Number of subjects in period 1
    		HyQvia New Starters HyQvia Pre-treated
    Started
    23
    19
    Completed
    22
    17
    Not completed
    1
    2
         Consent withdrawn by subject
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HyQvia New Starters
    Reporting group description
    		 Subjects who were treated with non-HyQvia treatment by time of enrollment were enrolled in Epoch 1 (ramp-up) and treated with HyQvia subcutaneously (SC) with a dose or interval ramp-up period of up to 6 weeks. HyQvia dose was planned to be equivalent to 100% (±5%) of pre-study treatment. Dosage frequency was one treatment interval of one week, then one treatment interval of two weeks, then one treatment interval of three weeks (for subjects in whom treatment was expected to be every four weeks). The ramp-up period was followed by Epoch 2 with HyQvia SC treatment at every 3 or 4 weeks, depending on the subject's previous dosing schedule and the discretion of the investigator and subject, for up to 20 months.

    Reporting group title
    HyQvia Pre-treated
    Reporting group description
    		 Subjects already treated with HYQVIA by the time of enrollment were directly enrolled in Epoch 2 and treated with HyQvia SC at every 3 or 4 weeks for up to 20 months. HyQvia dose was planned to be equivalent to 100% (±5%) of pre-study treatment with a dosage frequency of once every three or four weeks, based on the subject's previous dosing schedule and the discretion of the investigator and subject.

    Reporting group values
    		 HyQvia New Starters HyQvia Pre-treated Total
    Number of subjects
    		 23 19 42
    Age Categorical
    Units:
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.3 ( 3.82 ) 11.7 ( 4.33 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 5 3 8
        Male
    		 18 16 34
    Race
    Units: Subjects
        American Indian Or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Black Or African American
    		 0 0 0
        Native Hawaiian Or Other Pacific Islander
    		 0 0 0
        White
    		 22 19 41
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic Or Latino
    		 0 0 0
        Not Hispanic Or Latino
    		 23 19 42
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    HyQvia New Starters
    Reporting group description
    		 Subjects who were treated with non-HyQvia treatment by time of enrollment were enrolled in Epoch 1 (ramp-up) and treated with HyQvia subcutaneously (SC) with a dose or interval ramp-up period of up to 6 weeks. HyQvia dose was planned to be equivalent to 100% (±5%) of pre-study treatment. Dosage frequency was one treatment interval of one week, then one treatment interval of two weeks, then one treatment interval of three weeks (for subjects in whom treatment was expected to be every four weeks). The ramp-up period was followed by Epoch 2 with HyQvia SC treatment at every 3 or 4 weeks, depending on the subject's previous dosing schedule and the discretion of the investigator and subject, for up to 20 months.

    Reporting group title
    HyQvia Pre-treated
    Reporting group description
    		 Subjects already treated with HYQVIA by the time of enrollment were directly enrolled in Epoch 2 and treated with HyQvia SC at every 3 or 4 weeks for up to 20 months. HyQvia dose was planned to be equivalent to 100% (±5%) of pre-study treatment with a dosage frequency of once every three or four weeks, based on the subject's previous dosing schedule and the discretion of the investigator and subject.

    Primary: Safety: Number of Subjects With Any Severe Related Treatment-emergent Adverse Events (TEAEs) per Infusion (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Any Severe Related Treatment-emergent Adverse Events (TEAEs) per Infusion (Excluding Infections) [1]
    End point description
    An Adverse Event (AE) was defined as any untoward medical occurrence in a subject administered an investigational product (IP) that does not necessarily have a causal relationship with the treatment. TEAEs are AEs with onset after date-time of first dose of IP, or any medical condition present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. TEAEs recorded as “possibly related” or “probably related” to HYQVIA are considered HYQVIA-related. The number of subjects with any severe related TEAEs was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to 20 months
    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: No statistical and comparison analysis were performed for this endpoint.
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    1
    0
    No statistical analyses for this end point

    Primary: Safety: Rate of Any Severe Related TEAEs per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of Any Severe Related TEAEs per Infusion (Excluding Infections) [2]
    End point description
    An AE was defined as any untoward medical occurrence in a subject administered an IP that does not necessarily have a causal relationship with the treatment. TEAE was defined as AEs with onset after date-time of first dose of IP, or any medical conditions present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. Severe related TEAEs rate per infusion was calculated as number of severe related TEAEs/total number of infusions administered to subjects in the analysis set. Rate of any severe related TEAEs per infusion (excluding infections) was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to 20 months
    Notes
    [2] - 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: No statistical and comparison analysis were performed for this endpoint.
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Number of Severe Related TEAEs/Infusion
        number (not applicable)
    0.004
    0
    No statistical analyses for this end point

    Primary: Safety: Number of Subjects With Any Related Serious TEAEs per Infusion (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Any Related Serious TEAEs per Infusion (Excluding Infections) [3]
    End point description
    TEAE was defined as AEs with onset after date-time of first dose of IP, or any medical conditions present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in-patient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Related TEAE was defined as AEs recorded in the study database as “possibly related” or “probably related” to IP. Number of subjects with any related serious TEAEs per infusion (excluding infections) were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to 20 months
    Notes
    [3] - 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: No statistical and comparison analysis were performed for this endpoint.
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Primary: Safety: Rate of Any Related Serious TEAEs per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of Any Related Serious TEAEs per Infusion (Excluding Infections) [4]
    End point description
    TEAE was defined as AEs with onset after date-time of first dose of IP, or any medical conditions present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in-patient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Related TEAE was defined as AEs recorded in the study database as “possibly related” or “probably related” to IP. Rate of related serious TEAEs per infusion was calculated as number of related serious TEAEs/total number of infusions administered to subjects in the analysis set. Rate of any related serious TEAEs per Infusion (excluding infections) were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to 20 months
    Notes
    [4] - 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: No statistical and comparison analysis were performed for this endpoint.
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Number of Related Serious TEAEs/Infusion
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Efficacy: Change From Baseline in Total Serum Trough Levels of Immunoglobulin G (IgG) at Month 12

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    End point title
    		 Efficacy: Change From Baseline in Total Serum Trough Levels of Immunoglobulin G (IgG) at Month 12
    End point description
    Change from baseline in total serum trough levels of IgG in Epoch 1 and 2 was reported. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. Full analysis set included all subjects who provided informed consent and met enrollment eligibility. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    20
    17
    Units: Gram per liter (g/L)
        arithmetic mean (standard deviation)
    0.035 ( 1.6983 )
    -0.709 ( 2.6576 )
    No statistical analyses for this end point

    Secondary: Safety: Percentage of Subjects who Achieved a Treatment Interval of Three or Four Weeks in Epoch 2

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    End point title
    		 Safety: Percentage of Subjects who Achieved a Treatment Interval of Three or Four Weeks in Epoch 2
    End point description
    Percentage of subjects who achieved a treatment interval of three or four weeks in Epoch 2 were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Percentage of subjects
    number (not applicable)
        Every 3 weeks treatment interval
    39.1
    15.8
        Every 4 weeks treatment interval
    60.9
    84.2
    No statistical analyses for this end point

    Secondary: Safety: Percentage of Subjects who Maintained a Treatment Interval of Three or Four Weeks in Epoch 2 up to 12 Months

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    End point title
    		 Safety: Percentage of Subjects who Maintained a Treatment Interval of Three or Four Weeks in Epoch 2 up to 12 Months
    End point description
    Percentage of subjects who maintained a treatment interval of three or four weeks in Epoch 2 up to 12 months was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    Up to 12 Months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Percentage of subjects
        number (not applicable)
    87.0
    78.9
    No statistical analyses for this end point

    Secondary: Safety: Number of Subjects With Local TEAEs (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Local TEAEs (Excluding Infections)
    End point description
    TEAE was defined as AEs with onset after date-time of first dose of IP, or any medical conditions present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. Number of subjects with local TEAEs (excluding infections) were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    11
    3
    No statistical analyses for this end point

    Secondary: Safety: Rate of Local TEAEs per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of Local TEAEs per Infusion (Excluding Infections)
    End point description
    Rate of local TEAEs per infusion was calculated as number of local adverse events/total number of infusions administered to subjects in the analysis set. Only events are included which start prior to subjects start date of non-response. Rate of local TEAEs per infusion (excluding infections) was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Number of local TEAEs/Infusion
        number (not applicable)
    0.082
    0.009
    No statistical analyses for this end point

    Secondary: Safety: Number of Subjects With Local Adverse Reactions (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Local Adverse Reactions (Excluding Infections)
    End point description
    Adverse reactions was defined as any TEAE that meets any of the following criteria: 1) A TEAE considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration, or; 2) A TEAE that begins during infusion of IP or within 72 hours following the end of IP infusion, or; 3) A TEAE for which causality assessment is missing or indeterminate. Number of subjects with local adverse reactions (excluding infections) were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    11
    3
    No statistical analyses for this end point

    Secondary: Safety: Rate of Local Adverse Reaction per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of Local Adverse Reaction per Infusion (Excluding Infections)
    End point description
    Rate of local adverse reaction per infusion was calculated as number of local adverse reaction events/total number of infusions administered to subjects in the analysis set. Rate of local adverse reactions per infusion (excluding infections) was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Number of Local AR events/Infusion
        number (not applicable)
    0.080
    0.009
    No statistical analyses for this end point

    Secondary: Safety: Number of Subjects With Systemic TEAEs (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Systemic TEAEs (Excluding Infections)
    End point description
    TEAE was defined as AEs with onset after date-time of first dose of IP, or any medical conditions present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. Number of subjects with systemic TEAEs (excluding infections) were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    15
    10
    No statistical analyses for this end point

    Secondary: Safety: Rate of Systemic TEAEs per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of Systemic TEAEs per Infusion (Excluding Infections)
    End point description
    Rate of systemic TEAEs per infusion was calculated as number of systemic adverse events/total number of infusions administered to subjects in the analysis set. Rate of systemic TEAEs per infusion was assessed based on events per infusion. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Number of systemic TEAEs/Infusion
        number (not applicable)
    0.138
    0.142
    No statistical analyses for this end point

    Secondary: Safety: Number of Subjects With Systemic Adverse Reactions (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Systemic Adverse Reactions (Excluding Infections)
    End point description
    Adverse reaction was defined as any TEAE that meets any of the following criteria: 1) A TEAE considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration, or; 2) A TEAE that begins during infusion of IP or within 72 hours following the end of IP infusion, or; 3) A TEAE for which causality assessment is missing or indeterminate. Number of subjects with systemic adverse reactions (excluding infections) were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    3
    1
    No statistical analyses for this end point

    Secondary: Safety: Rate of Systemic Adverse Reactions per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of Systemic Adverse Reactions per Infusion (Excluding Infections)
    End point description
    Rate of Systemic adverse reactions per infusion was calculated as number of systemic adverse reaction events/total number of infusions administered to subjects in the analysis set. Rate of systemic adverse reactions per infusion (excluding infections) was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Number of Systemic AR events/Infusion
        number (not applicable)
    0.011
    0.012
    No statistical analyses for this end point

    Secondary: Safety: Number of Subjects With Any TEAEs (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Any TEAEs (Excluding Infections)
    End point description
    TEAE was defined as AEs with onset after date-time of first dose of IP, or any medical conditions present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. Number of subjects with any TEAEs (excluding infections) were reported. Safety analysis set included all subjects in the full analysis set (Enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    18
    11
    No statistical analyses for this end point

    Secondary: Safety: Rate of TEAEs per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of TEAEs per Infusion (Excluding Infections)
    End point description
    Rate of TEAEs per infusion was calculated as number of adverse events/total number of infusions administered to subjects in the analysis set. Rate of TEAEs per infusion (excluding infections) was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Number of TEAEs/Infusion
        number (not applicable)
    0.220
    0.151
    No statistical analyses for this end point

    Secondary: Safety: Number of Subjects With Any Adverse Reactions (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Any Adverse Reactions (Excluding Infections)
    End point description
    Adverse reaction was defined as any TEAE that meets any of the following criteria: 1) A TEAE considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration, or; 2) A TEAE that begins during infusion of IP or within 72 hours following the end of IP infusion, or; 3) A TEAE for which causality assessment is missing or indeterminate. Number of subjects with any adverse reactions (excluding infections) were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    12
    3
    No statistical analyses for this end point

    Secondary: Safety: Rate of Any Adverse Reaction per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of Any Adverse Reaction per Infusion (Excluding Infections)
    End point description
    Rate of all adverse reaction per infusion was calculated as number of adverse reaction events/total number of infusions administered to subjects in the analysis set. Rate of any adverse reactions per infusion (excluding infections) was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Adverse reaction event/Infusion
        number (not applicable)
    0.091
    0.021
    No statistical analyses for this end point

    Secondary: Safety: Number of Subjects With Any Temporally Associated TEAEs (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Any Temporally Associated TEAEs (Excluding Infections)
    End point description
    Temporally-associated TEAEs were defined as TEAEs which begin during infusion of IP or within 72 hours following the end of IP infusion. Number of subjects with any temporally associated TEAEs (excluding infections) were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    13
    6
    No statistical analyses for this end point

    Secondary: Safety: Rate of Any Temporally Associated TEAEs per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of Any Temporally Associated TEAEs per Infusion (Excluding Infections)
    End point description
    Rate of any temporally associated TEAEs per infusion was calculated as number of temporally associated adverse events/total number of infusions administered to subjects in the analysis set. Temporally-associated TEAEs were defined as TEAEs which begin during infusion of IP or within 72 hours following the end of IP infusion. Rate of any temporally associated TEAEs per infusion (excluding infections) was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Temporally associated TEAEs/Infusion
        number (not applicable)
    0.106
    0.027
    No statistical analyses for this end point

    Secondary: Safety: Number of Subjects With Any Related (Causally) and/or Temporally Associated TEAEs (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Any Related (Causally) and/or Temporally Associated TEAEs (Excluding Infections)
    End point description
    Number of subjects with any related (causally) and/or temporally associated TEAEs (excluding infections) were reported. Temporally-associated TEAEs were defined as TEAEs which begin during infusion of IP or within 72 hours following the end of IP infusion. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    13
    6
    No statistical analyses for this end point

    Secondary: Safety: Rate of Any Related (Causally) and/or Temporally Associated TEAEs per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of Any Related (Causally) and/or Temporally Associated TEAEs per Infusion (Excluding Infections)
    End point description
    Rate of any related (causally) and/or temporally associated TEAEs per infusion was calculated as number of related and/or temporally associated adverse events/ total number of infusions administered to subjects in the analysis set. TEAEs recorded in the study database as “possibly related” or “probably related” to HYQVIA are considered HYQVIA related adverse events. Temporally-associated TEAEs were defined as TEAEs which begin during infusion of IP or within 72 hours following the end of IP infusion. Rate of any related (causally) and/or temporally associated TEAEs per infusion (excluding infections) was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Related Temporally TEAEs/Infusion
        number (not applicable)
    0.112
    0.033
    No statistical analyses for this end point

    Secondary: Safety: Number of Subjects With Any Serious TEAEs (Excluding Infections)

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    End point title
    		 Safety: Number of Subjects With Any Serious TEAEs (Excluding Infections)
    End point description
    Serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in-patient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Number of subjects with any serious TEAEs (excluding infections) were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
    0
    3
    No statistical analyses for this end point

    Secondary: Safety: Rate of Serious TEAEs per Infusion (Excluding Infections)

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    End point title
    		 Safety: Rate of Serious TEAEs per Infusion (Excluding Infections)
    End point description
    Rate of serious TEAEs per infusion was calculated as number of serious adverse events/total number of infusions administered to subjects in the analysis set. Rate of serious TEAEs per infusion (excluding infections) was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Number of serious TEAEs/Infusion
        number (not applicable)
    0
    0.012
    No statistical analyses for this end point

    Secondary: Safety: Number of Subjects who Developed Positive Titer (>=160) of Binding or Neutralizing Antibodies to rHuPH20

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    End point title
    		 Safety: Number of Subjects who Developed Positive Titer (>=160) of Binding or Neutralizing Antibodies to rHuPH20
    End point description
    Number of subjects who developed positive titer (>=160) of binding or neutralizing antibodies to rHuPH20 were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Subjects
        Positive titer (>=160) of binding antibodies
    0
    0
        Neutralizing antibodies
    0
    0
    No statistical analyses for this end point

    Secondary: Other Analysis: Number of Infusions per Month

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    End point title
    		 Other Analysis: Number of Infusions per Month
    End point description
    Number of infusions per month was calculated as total number of infusions per duration of treatment (days) * 30.4 days per month. Number of infusions per month was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Infusions per month
        median (full range (min-max))
    1.30 (1.1 to 1.7)
    1.20 (1.0 to 1.6)
    No statistical analyses for this end point

    Secondary: Other Analysis: Number of Infusion Sites (Needle-Sticks) per Infusion

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    End point title
    		 Other Analysis: Number of Infusion Sites (Needle-Sticks) per Infusion
    End point description
    Number of infusion sites (needle-sticks) per infusion was calculated as total number of infusion sites / total number of infusions. Only infusions with complete data available was included. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Infusion sites (needle sticks)/Infusion
        arithmetic mean (standard deviation)
    1.65 ( 0.442 )
    1.25 ( 0.403 )
    No statistical analyses for this end point

    Secondary: Other Analysis: Duration of Infusion

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    End point title
    		 Other Analysis: Duration of Infusion
    End point description
    The duration of infusion was defined as the difference between the end time and the start time of the HyQvia infusion. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Minutes
        median (full range (min-max))
    75.0 (10 to 215)
    101.0 (15 to 257)
    No statistical analyses for this end point

    Secondary: Other Analysis: Maximum Infusion Rate per Site

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    End point title
    		 Other Analysis: Maximum Infusion Rate per Site
    End point description
    Maximum infusion rate per site was reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Milliliter per hour per site (mL/h/site)
        arithmetic mean (standard deviation)
    181.54 ( 77.772 )
    171.73 ( 90.203 )
    No statistical analyses for this end point

    Secondary: Other Analysis: Infusion Volume per Site

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    End point title
    		 Other Analysis: Infusion Volume per Site
    End point description
    Infusion volume per site was calculated as actual IgG volume (milliliter [mL]) per total number of infusion sites (hour) used. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: milliliter per hour
        arithmetic mean (standard deviation)
    112.39 ( 71.427 )
    178.23 ( 98.523 )
    No statistical analyses for this end point

    Secondary: Other Analysis: Number of Infusions That Were Interrupted or Stopped due to an AE

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    End point title
    		 Other Analysis: Number of Infusions That Were Interrupted or Stopped due to an AE
    End point description
    Number of infusions that were interrupted or stopped due to an AE were reported. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Infusions
    number (not applicable)
        Number of infusions interrupted
    4
    0
        Number of infusions Stopped
    1
    0
    No statistical analyses for this end point

    Secondary: Other Analysis: Number of Weeks to Reach Final 3 or 4-week Dose Interval in Epoch 1

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    End point title
    		 Other Analysis: Number of Weeks to Reach Final 3 or 4-week Dose Interval in Epoch 1 [5]
    End point description
    Final dose interval was defined as three or four weeks infusion interval in Epoch 1 of treatment period was reported. Safety analysis set included all subjects in the full analysis set (enrolled Set) who received at least one dose of HyQvia. Here, "number analysed" signifies subjects who are evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As pre-specified in protocol, Data collection and analysis was not planned for HyQvia pre-treated.
    End point values
    		 HyQvia New Starters
    Number of subjects analysed
    22
    Units: Weeks
        median (full range (min-max))
    6.10 (3.0 to 7.0)
    No statistical analyses for this end point

    Secondary: Health Related Quality of Life (HR QoL): Change from Baseline in Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9)

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    End point title
    		 Health Related Quality of Life (HR QoL): Change from Baseline in Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9)
    End point description
    TSQM-9 is a 9-item, validated, self-administered instrument to assess subjects satisfaction with medication. It consists of 3 sub-scales: effectiveness, convenience and global satisfaction. The scores were computed by adding items for each domain, i.e. 1 to 3 for effectiveness, 4 - 6 for convenience and 7 to 9 for global satisfaction. The lowest possible score (1 for each item and 3 for all 3 sub-scales) was subtracted from the composite score and divided by the greatest possible score range. The greatest range was (7-1)*3 items = 18 for the effectiveness and convenience, and (5-1)*3 items = 12 for global satisfaction. The item scores of each of the 3 domains are summed and transformed to create a score of 0 (extremely dissatisfied) to 100 (extremely satisfied). Higher score=greater satisfaction in that domain. A negative change from baseline indicates less satisfaction in that domain. Safety analysis set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    3
    6
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Effectiveness: Change at 20 months
    12.96 ( 32.552 )
    -0.92 ( 10.783 )
        Convenience: Change at 20 months
    14.81 ( 27.398 )
    4.63 ( 15.873 )
        Global satisfaction: Change 20 months
    11.90 ( 10.911 )
    -2.38 ( 19.518 )
    No statistical analyses for this end point

    Secondary: HRQoL: Change from Baseline in Pediatric Quality of Life Questionnaire (PedsQL)

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    End point title
    		 HRQoL: Change from Baseline in Pediatric Quality of Life Questionnaire (PedsQL)
    End point description
    PedsQL Generic Core Scale (GCS) used for QOL assessment. It encompasses 4 dimensions (physical functioning [PF], emotional functioning [EF], social functioning [SF], school functioning [ScF]). Age groups: Toddler (2-4 years), Young child (5-7 years), Child (8-12 years) and Teens (13-<18 years). Depending on the subjects age, the questionnaire may be completed by either the subject or the parent/caregiver. For Toddler, PedsQL GCS as 21 items, using 5-point Likert scale (0 to 4); for all other, PedsQL as 23 items, with 3-point Likert scale (0, 2, 4) for young child, and 5-point Likert scale for child and teens. All scores were transformed on a scale from 0-100 where 0=100, 1=75, 2=50, 3=25 and 4=0. Higher scores= better quality of life. A negative change from baseline=worse quality of life. Safety analysis set. Here, “number of subjects analysed”= subjects evaluable for this endpoint and “n=number analysed” evaluable at specific timepoint. Here, '99999' = mean and SD was not estimated.
    End point type
    Secondary
    End point timeframe
    Baseline up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    5
    8
    Units: Score on a scale
    arithmetic mean (standard deviation)
        PF in Toddler: Change up to 20 months (n=0,1)
    99999 ( 99999 )
    -3.12 ( 99999 )
        PF in Young child: Change up to 20 months (n=0,1)
    99999 ( 99999 )
    -31.25 ( 99999 )
        PF in Child: Change up to 20 months (n=2,1)
    7.81 ( 6.626 )
    -71.88 ( 99999 )
        PF in Teens: Change up to 20 months (n=3,5)
    -12.65 ( 12.726 )
    13.75 ( 24.664 )
        EF in Toddler: Change up to 20 months (n=0,1)
    99999 ( 99999 )
    0.00 ( 99999 )
        EF in Young child: Change up to 20 months (n=0,1)
    99999 ( 99999 )
    -25.00 ( 99999 )
        EF in Child: Change up to 20 months (n=2,1)
    5.00 ( 14.142 )
    -20.00 ( 99999 )
        EF in Teens: Change up to 20 months (n=3,5)
    -13.33 ( 7.638 )
    1.25 ( 14.307 )
        SF in Toddler: Change up to 20 months (n=0,1)
    99999 ( 99999 )
    0.00 ( 99999 )
        SF in Young child: Change up to 20 months (n=0,1)
    99999 ( 99999 )
    -35.00 ( 99999 )
        SF in Child: Change up to 20 months (n=2,1)
    -20.00 ( 0.000 )
    -40.00 ( 99999 )
        SF in Teens: Change up to 20 months (n=3,5)
    1.67 ( 7.638 )
    8.00 ( 11.511 )
        ScF in Toddler: Change up to 20 months (n=0,1)
    99999 ( 99999 )
    25.00 ( 99999 )
        ScF in Young child: Change up to 20 months (n=0,1)
    99999 ( 99999 )
    -45.00 ( 99999 )
        ScF in Child: Change up to 20 months (n=2,1)
    -12.50 ( 10.607 )
    -65.00 ( 99999 )
        ScF in Teens: Change up to 20 months (n=3,5)
    1.67 ( 7.638 )
    -17.00 ( 24.135 )
    No statistical analyses for this end point

    Secondary: HRQoL: Change from Baseline in EuroQoL (Quality of Life)-5 Dimensions (EQ-5D)

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    End point title
    		 HRQoL: Change from Baseline in EuroQoL (Quality of Life)-5 Dimensions (EQ-5D)
    End point description
    EQ-5D considered five attributes of QOL evaluation, that is, mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Each dimension had five possible levels: 1 (no problems); 2 (slight problems); 3 (moderate problems); 4 (severe problems), and; 5 (extreme problems). The subjects rating of their current HRQoL state was recorded using a standard vertical 20-cm visual analog scale (EQ-VAS), which ranged from 0 to 100, where 0 indicated worst imaginable health state and 100 was best imaginable health state. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. A negative change from baseline indicates worse health state. Safety analysis set. Here, “number of subjects analysed”= subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    5
    7
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -8.60 ( 11.149 )
    -4.43 ( 15.447 )
    No statistical analyses for this end point

    Secondary: Efficacy: Change From Baseline in Serum Trough Levels of IgG Subclasses at Month 12

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    End point title
    		 Efficacy: Change From Baseline in Serum Trough Levels of IgG Subclasses at Month 12
    End point description
    Change from baseline in serum trough levels of IgG subclasses 1, 2, 3, and 4 in Epoch 1 and 2 was reported. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. All subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia. Here, "number of subjects analysed" signifies subjects who were evaluable for endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    16
    15
    Units: g/L
    arithmetic mean (standard deviation)
        IgG Subclass 1 : Changed at Month 12
    -0.813 ( 1.1087 )
    -0.467 ( 1.5976 )
        IgG Subclass 2 : Changed at Month 12
    0.000 ( 0.8944 )
    -0.667 ( 1.3452 )
        IgG Subclass 3 : Changed at Month 12
    0.000 ( 0.3651 )
    0.133 ( 0.3519 )
        IgG Subclass 4 : Changed at Month 12
    0.094 ( 0.0854 )
    -0.027 ( 0.0799 )
    No statistical analyses for this end point

    Secondary: Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Clostridium Tetani Toxoid IgG at Month 12

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    End point title
    		 Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Clostridium Tetani Toxoid IgG at Month 12 [6]
    End point description
    Change from baseline in trough levels of specific antibodies in clostridium tetani toxoid IgG at Month 12 was reported. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. Here, IU/ml was defined as "International units per milliliter". All subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia. Here, "number of subjects analysed" signifies subjects who were evaluable for endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Specific antibody data were not scheduled to be collected at Epoch 2 Month 0, so for most subjects baseline could not be defined and change from baseline was not reported in HYQVIA Pre-treated arm.
    End point values
    		 HyQvia New Starters
    Number of subjects analysed
    21
    Units: IU/ml
        arithmetic mean (standard deviation)
    -0.218 ( 0.9345 )
    No statistical analyses for this end point

    Secondary: Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Hepatitis B Virus (HBV) at Month 12

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    End point title
    		 Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Hepatitis B Virus (HBV) at Month 12 [7]
    End point description
    Change from baseline in trough levels of specific antibodies in HBV at Month 12 was reported. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. All subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia. Here, "number of subjects analysed" signifies subjects who were evaluable for endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Specific antibody data were not scheduled to be collected at Epoch 2 Month 0, so for most subjects baseline could not be defined and change from baseline was not reported in HYQVIA Pre-treated arm.
    End point values
    		 HyQvia New Starters
    Number of subjects analysed
    16
    Units: International units per liter (IU/L)
        arithmetic mean (standard deviation)
    167.875 ( 147.4887 )
    No statistical analyses for this end point

    Secondary: Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Haemophilus influenzae B IgG at Month 12

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    End point title
    		 Efficacy: Change From Baseline in Trough Levels of Specific Antibodies to Haemophilus influenzae B IgG at Month 12 [8]
    End point description
    Change from baseline in trough levels of specific antibodies in Haemophilus influenzae B IgG at Month 12 was reported. Baseline was defined as the last non-missing value before the initial dose of HYQVIA. All subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia. Here, "number of subjects analysed" signifies subjects who were evaluable for endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Specific antibody data were not scheduled to be collected at Epoch 2 Month 0, so for most subjects baseline could not be defined and change from baseline was not reported in HYQVIA Pre-treated arm.
    End point values
    		 HyQvia New Starters
    Number of subjects analysed
    20
    Units: Milligram per liter (mg/L)
        arithmetic mean (standard deviation)
    -0.017 ( 0.9503 )
    No statistical analyses for this end point

    Secondary: Other Analysis: Number of Infusion Sites (Needle-Sticks) per Month

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    End point title
    		 Other Analysis: Number of Infusion Sites (Needle-Sticks) per Month
    End point description
    Number of infusion sites per month was calculated as total number of infusion sites / duration of treatment (days) * 30.4 days. Only infusions with complete data available was included. Safety analysis set included all subjects in the full analysis set (enrolled set) who received at least one dose of HyQvia.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    End point values
    		 HyQvia New Starters HyQvia Pre-treated
    Number of subjects analysed
    23
    19
    Units: Infusion sites (needle sticks)/Month
        arithmetic mean (standard deviation)
    1.96 ( 0.780 )
    1.33 ( 0.634 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to end of the study (up to 43 months)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    HyQvia New Starters
    Reporting group description
    		 Subjects who were treated with non-HyQvia treatment by time of enrollment were enrolled in Epoch 1 (ramp-up) and treated with HyQvia SC with a dose or interval ramp-up period of up to 6 weeks. HyQvia dose was planned to be equivalent to 100% (±5%) of pre-study treatment. Dosage Frequency was one treatment interval of one week, then one treatment interval of two weeks, then one treatment interval of three weeks (for subjects in whom treatment was expected to be every four weeks). The ramp-up period was followed by Epoch 2 (no ramp-up) with HyQvia SC treatment at every 3 or 4 weeks, depending on the subjects previous dosing schedule and the discretion of the investigator and subject, for up to 20 months.

    Reporting group title
    HyQvia Pre-treated
    Reporting group description
    		 Subjects already treated with HYQVIA by the time of enrollment were directly enrolled in Epoch 2 and treated with HyQvia SC at every 3 or 4 weeks for up to 20 months. HyQvia dose was planned to be equivalent to 100% (±5%) of pre-study treatment with a dosage frequency of once every three or four weeks, based on the subjects previous dosing schedule and the discretion of the investigator and subject.

    Serious adverse events
    		 HyQvia New Starters HyQvia Pre-treated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 23 (8.70%)
    5 / 19 (26.32%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Idiopathic orbital inflammation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dental caries
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammatory bowel disease
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 HyQvia New Starters HyQvia Pre-treated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 23 (95.65%)
    14 / 19 (73.68%)
    Investigations
    Blood immunoglobulin G decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Radius fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    Blood and lymphatic system disorders
    Neutropenia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Application site pruritus
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 19 (5.26%)
         occurrences all number
    3
    2
    Infusion site erythema
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Infusion site pain
         subjects affected / exposed
    6 / 23 (26.09%)
    1 / 19 (5.26%)
         occurrences all number
    11
    1
    Infusion site pruritus
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 19 (0.00%)
         occurrences all number
    6
    0
    Pyrexia
         subjects affected / exposed
    3 / 23 (13.04%)
    3 / 19 (15.79%)
         occurrences all number
    5
    7
    Eye disorders
    Conjunctival haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Eye pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 19 (5.26%)
         occurrences all number
    1
    5
    Inflammatory bowel disease
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 19 (5.26%)
         occurrences all number
    4
    2
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    8 / 23 (34.78%)
    6 / 19 (31.58%)
         occurrences all number
    13
    12
    Epistaxis
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 19 (10.53%)
         occurrences all number
    2
    6
    Oropharyngeal pain
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 19 (10.53%)
         occurrences all number
    4
    2
    Rhinorrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Solar urticaria
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Bacterial infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis
         subjects affected / exposed
    5 / 23 (21.74%)
    0 / 19 (0.00%)
         occurrences all number
    7
    0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Impetigo
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 23 (21.74%)
    1 / 19 (5.26%)
         occurrences all number
    6
    1
    Otitis media
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Rhinitis
         subjects affected / exposed
    3 / 23 (13.04%)
    6 / 19 (31.58%)
         occurrences all number
    4
    12
    Sinusitis
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    3
    Viral infection
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 19 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2016
    Amendment 1: - To update the study termination/completion criteria for subjects entering Epoch 3. - To change the reference information for KIOVIG from IB to SmPC. - To match the dosing frequency suggestions of the SmPC for Cuvitru. - To update the study inclusion criteria. - To provide information on Cuvitru instead of SUBCUVIA. - To specify timelines for screening, to provide an option to treat the subject in the time period between signing the informed consent and first IP infusion, and to limit the number of re-screenings. - To define the timepoint for blood drawing for all trough level measurements. - To remove ‘HRQoL assessments’ from the Epoch 3 data under Table 6. - To define the timepoint for blood drawing for all trough level measurements.
    04 Dec 2019
    Amendment 2: - To revise duration of study periods and subject participation till 2023 scenario in case ‘last subject in’ went until Epoch 2 Year 3 and then 1 year in Epoch 3. - To clarify that safety follow-up and the antibody testing were to continue for one year, not less, for all subjects who switched to Epoch 3. - To add ‘planned interim analysis’ for the study into the study protocol. - To update the HyQvia indication for the European region. - To add reference for the Cuvitru IB for countries where sites were open but Cuvitru was not registered. - To provide update on the study status during the protocol amendment 2. - To updated to the latest version of GCP E6 guideline (Nov 2016) and to add ‘Declaration of Helsinki’ in the ‘compliance statement’ section. - To add a description to allow shorter infusion intervals (2 weeks, instead of 3 or 4 weeks) if preferable due to tolerability, at the discretion of the investigator. - To clarify in Table 8 that for some subjects Month 0 of Epoch 2 was to be considered as baseline for those subjects who did not have to participate in Epoch 2; therefore specific antibody tests also had to be performed.

    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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