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    Clinical Trial Results:
    A Multi-Center, Open-Label, Single-Arm Trial to Evaluate Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency

    Summary
    EudraCT number
    2015-003290-15
    Trial protocol
    GB   CZ   ES   DE   PL   HU   FR  
    Global end of trial date
    15 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Mar 2020
    First version publication date
    13 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GTI1503
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02806986
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Grifols Therapeutics LLC
    Sponsor organisation address
    Research Triangle Park, North Carolina, United States, 27709
    Public contact
    Rhonda Griffin, Grifols Therapeutics LLC, rhonda.griffin@grifols.com
    Scientific contact
    Rhonda Griffin, Grifols Therapeutics LLC, rhonda.griffin@grifols.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001853-PIP01-15
    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
    15 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether weekly administered Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) over a one year period achieved less than 1 serious bacterial infection (SBI) per subject per year in primary immunodeficiency (PI) subjects.
    Protection of trial subjects
    Standards for Good Clinical Practice were adhered to for all procedures in this study. The investigators ensured the study was conducted in full conformance with appropriate local laws and regulations and the Declaration of Helsinki.
    Background therapy
    Subjects must have been on immunoglobulin G (IgG) replacement therapy prior to enrolling in the study and continued to receive the same therapy during the Screening/Previous Regimen Phase. The previous regimen could be either intravenous immune globulin (IVIG) or subcutaneous immune globulin (SCIG).
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Jun 2016
    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
    Spain: 25
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Poland: 3
    Worldwide total number of subjects
    61
    EEA total number of subjects
    55
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    18
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    27
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Eligible participants for this study included male or female subjects who were 2 to 75 years of age and had a diagnosis of PI requiring IgG replacement treatment. A total of 61 subjects entered Treatment Stage 1 and received treatment with IGSC 20%. The study was conducted in 8 countries from June 2016 to May 2019.

    Pre-assignment
    Screening details
    Subjects had no SBI within last 3 months prior to Screening and were on IgG replacement therapy (stable regimen via intravenous [IV] or subcutaneous [SC] infusion) for ≥3 consecutive months prior to Screening. Subjects receiving IVIG prior to study entry must have received a dosage of ≥200 milligram/kilogram (mg/kg) per infusion.

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

    Arms
    Arm title
    IGSC 20%
    Arm description
    Treatment Stage 1: Subjects received 13 IGSC 20% infusions at weekly intervals from Baseline (Week 1) up to Week 13. Subjects were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower). Dose adjustments were permitted in this phase per the study protocol and the Investigator’s discretion. Treatment Stage 2: Subjects received 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52. The IGSC 20% dose (mg/kg) remained constant with no dose adjustment permitted in this phase, unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor Medical Monitor. A final follow-up visit occurred at Week 53.
    Arm type
    Experimental

    Investigational medicinal product name
    IGSC 20%
    Investigational medicinal product code
    GRF6017
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IGSC 20% is a sterile liquid formulation of immunoglobulin purified from human plasma. IGSC 20% was supplied in a 20 or 50 milliliter (mL) vial size containing a 20% solution of immunoglobulin (i.e. a concentration of 20 grams/100 mL, with a nominal 4 or 10 grams immunoglobulin per vial). Subjects received a total of 52 weekly SC infusions of IGSC 20% (13 weekly SC infusions in Treatment Stage 1 and 39 weekly SC infusions in Treatment Stage 2).

    Number of subjects in period 1
    IGSC 20%
    Started
    61
    Entered Treatment Stage 1
    61
    Entered Treatment Stage 2
    60
    Completed
    55
    Not completed
    6
         Adverse event, non-fatal
    4
         Consent withdrawn by subject
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IGSC 20%
    Reporting group description
    Treatment Stage 1: Subjects received 13 IGSC 20% infusions at weekly intervals from Baseline (Week 1) up to Week 13. Subjects were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower). Dose adjustments were permitted in this phase per the study protocol and the Investigator’s discretion. Treatment Stage 2: Subjects received 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52. The IGSC 20% dose (mg/kg) remained constant with no dose adjustment permitted in this phase, unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor Medical Monitor. A final follow-up visit occurred at Week 53.

    Reporting group values
    IGSC 20% Total
    Number of subjects
    61
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    27.3 ± 19.97 -
    Gender categorical
    Units: Subjects
        Female
    19 19
        Male
    42 42
    Race
    Units: Subjects
        White
    57 57
        American Indian or Alaska Native
    2 2
        Unknown
    2 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    10 10
        Not Hispanic or Latino
    49 49
        Unknown or Not Reported
    2 2
    Subject Entry Status
    Units: Subjects
        Subject entered on IVIG
    40 40
        Subject entered on SCIG
    21 21

    End points

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    End points reporting groups
    Reporting group title
    IGSC 20%
    Reporting group description
    Treatment Stage 1: Subjects received 13 IGSC 20% infusions at weekly intervals from Baseline (Week 1) up to Week 13. Subjects were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower). Dose adjustments were permitted in this phase per the study protocol and the Investigator’s discretion. Treatment Stage 2: Subjects received 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52. The IGSC 20% dose (mg/kg) remained constant with no dose adjustment permitted in this phase, unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor Medical Monitor. A final follow-up visit occurred at Week 53.

    Subject analysis set title
    IGSC 20% Treatment Stage 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received 13 IGSC 20% infusions at weekly intervals from Baseline (Week 1) up to Week 13.

    Subject analysis set title
    IGSC 20% Treatment Stage 2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52.

    Subject analysis set title
    IGSC 20% Overall
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received a total of 52 IGSC 20% infusions at weekly intervals from Baseline (Week 1) up to Week 52.

    Subject analysis set title
    Previous Regimen
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects were required to attend the clinic for infusion with their previous ongoing (“previous regimen”) IVIG/SCIG regimen (pIV/pSC) to obtain 2 trough IgG levels (obtained prior to each pIV/pSC infusion) on each subject’s "previous regimen". Trough levels for total IgG determined during the Previous Regimen Phase were used to confirm final eligibility for subjects entering the study to receive treatment with IGSC 20% (must be ≥500 milligrams per deciliter [mg/dL]).

    Subject analysis set title
    Recommended Standard Historical Control Rate
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subject analysis included to represent the recommended standard historical control rate of 1 SBI per person per year. This was used as part of the statistical analysis for comparison with rate of SBI events per subject per year during IGSC 20% treatment.

    Primary: Rate of SBIs Per Subject Per Year

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    End point title
    Rate of SBIs Per Subject Per Year
    End point description
    The rate of SBI events per subject per year during IGSC 20% treatment was calculated as the total number of SBI events divided by the total duration of exposure in years across all subjects. The 2-sided 98% confidence interval (CI) was determined from a generalized linear model for Poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable. Analysis was performed on the Efficacy Evaluable population which included all subjects who received at least 1 dose of IGSC 20%. Note: 999999 (or any variant thereof) indicates that a value could not be calculated.
    End point type
    Primary
    End point timeframe
    Baseline (Week 1) up to Final Visit (Week 53)
    End point values
    IGSC 20% Treatment Stage 1 IGSC 20% Treatment Stage 2 IGSC 20% Overall Recommended Standard Historical Control Rate
    Number of subjects analysed
    61
    60
    61
    1 [1]
    Units: Rate of events per subject per year
        number (confidence interval 98%)
    0.000 (-999999 to 999999)
    0.023 (0.008 to 0.049)
    0.017 (0.006 to 0.036)
    999999 (999999 to 999999)
    Notes
    [1] - Subject analysis set included only to permit selection as a comparison arm for statistical analysis.
    Statistical analysis title
    IGSC 20% Overall vs Recommended Standard SBI Rate
    Statistical analysis description
    The generalized linear model for Poisson regression with log link was used to estimate SBI rate and its 1-sided 99% upper confidence limit (CL), then compared with the recommended standard control rate of 1 SBI per person per year. Person-year during IGSC 20% treatment was calculated for each subject as (duration of exposure in days/365.25), and natural log-transformed person-year was used in the model as an offset variable. No covariates but the intercept term were included in the model.
    Comparison groups
    IGSC 20% Overall v Recommended Standard Historical Control Rate
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    Generalized linear model
    Point estimate
    0.017
    Confidence interval
         level
    99%
         sides
    1-sided
         lower limit
    -
         upper limit
    0.036
    Notes
    [2] - If the 1-sided 99% upper CL was <1, the null hypothesis that the SBI rate per person per year was ≥1 would be rejected at the 1-sided alpha = 0.01 level. The given number for 'Number of subjects included in analysis' is automatically calculated and states 62. This is incorrect and the number included in the analysis = 61 subjects.

    Secondary: Mean Trough Total IgG Concentration

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    End point title
    Mean Trough Total IgG Concentration
    End point description
    Mean trough total IgG concentration during the Previous Regimen Phase was calculated as the average of the trough concentrations at the pIV#1 and pIV#2 visits for subjects entering the study on a previous IVIG regimen, or at the pSC#1 and Baseline/SC#1 visits for subjects entering the study on a previous SCIG regimen. Mean trough total IgG concentration during the IGSC 20% phase was calculated as the average of all steady state trough concentrations measured during the IGSC 20% Treatment Stage 2 at the visits corresponding to Weeks 17, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 53. Analysis was performed on the IgG population which consisted of all subjects who received any amount of IGSC 20% and had total IgG concentration data to facilitate the comparison of mean trough IgG concentration during the IGSC 20% phase versus the pre-treatment phase.
    End point type
    Secondary
    End point timeframe
    Previous Regimen Phase: 2 timepoints pre-dose of pIV or pSC between Screening and Baseline (up to 8 weeks). IGSC 20% Phase: Pre-dose of IGSC 20% at Baseline (Week 1), Weeks 2, 5, 9, 13, 17, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Week 53.
    End point values
    IGSC 20% Overall Previous Regimen
    Number of subjects analysed
    59
    59
    Units: mg/dL
        arithmetic mean (standard deviation)
    947.64 ± 150.262
    891.37 ± 165.943
    No statistical analyses for this end point

    Secondary: Rate of Infection of Any Kind Per Subject Per Year

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    End point title
    Rate of Infection of Any Kind Per Subject Per Year
    End point description
    The total number of infections of any kind (serious/non-serious including acute sinusitis, exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea, etc.) as determined by the investigator were evaluated. The rate of infection events per subject per year during IGSC 20% treatment was calculated as the total number of infection events divided by the total duration of exposure in years across all subjects. The 2-sided 95% CI was determined from a generalized linear model for Poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable. Analysis was performed on the Efficacy Evaluable population which included all subjects who received at least 1 dose of IGSC 20%.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 1) up to Final Visit (Week 53)
    End point values
    IGSC 20% Treatment Stage 1 IGSC 20% Treatment Stage 2 IGSC 20% Overall
    Number of subjects analysed
    Units: Rate of events per subject per year
        number (confidence interval 95%)
    2.524 (1.720 to 3.547)
    2.353 (1.736 to 3.102)
    2.397 (1.824 to 3.079)
    No statistical analyses for this end point

    Secondary: Rate of Days on Antibiotics Per Subject Per Year

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    End point title
    Rate of Days on Antibiotics Per Subject Per Year
    End point description
    The rate of days on antibiotics per subject per year during IGSC 20% treatment was calculated as the total number of days on antibiotic divided by the total duration of exposure in years across all subjects. The 2-sided 95% CI was determined from a generalized linear model for Poisson regression for the log-transformed number of days with log-transformed duration of exposure in years as an offset variable. Analysis was performed on the Efficacy Evaluable population which included all subjects who received at least 1 dose of IGSC 20%.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 1) up to Final Visit (Week 53)
    End point values
    IGSC 20% Treatment Stage 1 IGSC 20% Treatment Stage 2 IGSC 20% Overall
    Number of subjects analysed
    61
    60
    61
    Units: Rate of days per subject per year
    number (confidence interval 95%)
        Prophylactic Antibiotics
    43.240 (24.786 to 69.152)
    44.846 (26.197 to 70.755)
    44.432 (26.351 to 69.339)
        Therapeutic Antibiotics
    13.085 (7.777 to 20.387)
    7.451 (4.843 to 10.861)
    8.904 (5.949 to 12.705)
    No statistical analyses for this end point

    Secondary: Rate of Hospitalization Due to Infection Per Subject Per Year

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    End point title
    Rate of Hospitalization Due to Infection Per Subject Per Year
    End point description
    The rate of hospitalization due to infection events per subject per year during IGSC 20% treatment was calculated as the total number of hospitalization due to infection events divided by the total duration of exposure in years across all subjects. The 2-sided 95% CI was determined from a generalized linear model for Poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable. Analysis was performed on the Efficacy Evaluable population which included all subjects who received at least 1 dose of IGSC 20%. Note: 999999 (or any variant thereof) indicates that a value could not be calculated.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 1) up to Final Visit (Week 53)
    End point values
    IGSC 20% Treatment Stage 1 IGSC 20% Treatment Stage 2 IGSC 20% Overall
    Number of subjects analysed
    61
    60
    61
    Units: Rate of events per subject per year
        number (confidence interval 95%)
    0.000 (-999999 to 999999)
    0.023 (0.010 to 0.044)
    0.017 (0.008 to 0.033)
    No statistical analyses for this end point

    Secondary: Rate of Days of Work/School/Daily Activities Missed Per Subject Year Due to Infections and Related Treatment

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    End point title
    Rate of Days of Work/School/Daily Activities Missed Per Subject Year Due to Infections and Related Treatment
    End point description
    The rate of days of work, school or daily activities missed per subject per year during IGSC 20% treatment was calculated as the total number of days of work/school/daily activities missed divided by the total duration of exposure in years across all subjects. The 2-sided 95% CI was determined from a generalized linear model for Poisson regression for the log-transformed number of days with log-transformed duration of exposure in years as an offset variable. Analysis was performed on the Efficacy Evaluable population which included all subjects who received at least 1 dose of IGSC 20%.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 1) up to Final Visit (Week 53)
    End point values
    IGSC 20% Treatment Stage 1 IGSC 20% Treatment Stage 2 IGSC 20% Overall
    Number of subjects analysed
    61
    60
    61
    Units: Rate of days missed per person per year
        number (confidence interval 95%)
    4.118 (2.270 to 6.769)
    5.283 (3.192 to 8.132)
    4.983 (3.064 to 7.572)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) were collected from the beginning of treatment administration with IGSC 20% (Baseline/Week 1) until the Final Visit (Week 53). Up to 1 year overall.
    Adverse event reporting additional description
    TEAEs are presented for the Safety population which included all subjects who received any amount of IGSC 20%.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    IGSC 20% Treatment Stage 1
    Reporting group description
    Subjects received 13 IGSC 20% infusions at weekly intervals from Baseline (Week 1) up to Week 13.

    Reporting group title
    IGSC 20% Treatment Stage 2
    Reporting group description
    Subjects received 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52.

    Reporting group title
    IGSC 20% Overall
    Reporting group description
    Subjects received a total of 52 IGSC 20% infusions at weekly intervals from Baseline (Week 1) up to Week 52.

    Serious adverse events
    IGSC 20% Treatment Stage 1 IGSC 20% Treatment Stage 2 IGSC 20% Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 61 (3.28%)
    5 / 60 (8.33%)
    7 / 61 (11.48%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Medical device site joint pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrotic syndrome
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    IGSC 20% Treatment Stage 1 IGSC 20% Treatment Stage 2 IGSC 20% Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 61 (54.10%)
    44 / 60 (73.33%)
    49 / 61 (80.33%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 61 (6.56%)
    5 / 60 (8.33%)
    9 / 61 (14.75%)
         occurrences all number
    4
    6
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 61 (6.56%)
    5 / 60 (8.33%)
    7 / 61 (11.48%)
         occurrences all number
    6
    15
    21
    General disorders and administration site conditions
    Infusion site erythema
         subjects affected / exposed
    8 / 61 (13.11%)
    4 / 60 (6.67%)
    10 / 61 (16.39%)
         occurrences all number
    16
    10
    26
    Infusion site pruritus
         subjects affected / exposed
    7 / 61 (11.48%)
    2 / 60 (3.33%)
    8 / 61 (13.11%)
         occurrences all number
    17
    2
    19
    Pyrexia
         subjects affected / exposed
    2 / 61 (3.28%)
    5 / 60 (8.33%)
    7 / 61 (11.48%)
         occurrences all number
    2
    5
    7
    Infusion site pain
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 60 (3.33%)
    5 / 61 (8.20%)
         occurrences all number
    3
    2
    5
    Infusion site swelling
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 60 (3.33%)
    4 / 61 (6.56%)
         occurrences all number
    3
    8
    11
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 60 (3.33%)
    6 / 61 (9.84%)
         occurrences all number
    5
    2
    7
    Vomiting
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 60 (6.67%)
    5 / 61 (8.20%)
         occurrences all number
    1
    6
    7
    Nausea
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 60 (3.33%)
    4 / 61 (6.56%)
         occurrences all number
    3
    3
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 61 (4.92%)
    3 / 60 (5.00%)
    5 / 61 (8.20%)
         occurrences all number
    3
    3
    6
    Back pain
         subjects affected / exposed
    0 / 61 (0.00%)
    4 / 60 (6.67%)
    4 / 61 (6.56%)
         occurrences all number
    0
    5
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 61 (11.48%)
    7 / 60 (11.67%)
    12 / 61 (19.67%)
         occurrences all number
    8
    15
    23
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 61 (6.56%)
    7 / 60 (11.67%)
    9 / 61 (14.75%)
         occurrences all number
    6
    11
    17
    Bronchitis
         subjects affected / exposed
    1 / 61 (1.64%)
    8 / 60 (13.33%)
    8 / 61 (13.11%)
         occurrences all number
    1
    8
    9
    Rhinitis
         subjects affected / exposed
    3 / 61 (4.92%)
    6 / 60 (10.00%)
    7 / 61 (11.48%)
         occurrences all number
    3
    7
    10
    Sinusitis
         subjects affected / exposed
    3 / 61 (4.92%)
    6 / 60 (10.00%)
    7 / 61 (11.48%)
         occurrences all number
    3
    7
    10
    Gastroenteritis
         subjects affected / exposed
    0 / 61 (0.00%)
    6 / 60 (10.00%)
    6 / 61 (9.84%)
         occurrences all number
    0
    6
    6
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 60 (1.67%)
    5 / 61 (8.20%)
         occurrences all number
    4
    2
    6
    Influenza
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
    4 / 61 (6.56%)
         occurrences all number
    1
    3
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 60 (1.67%)
    3 / 61 (4.92%)
         occurrences all number
    2
    1
    3
    Viral infection
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
    4 / 61 (6.56%)
         occurrences all number
    1
    3
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2015
    Amendment 1 provided a number of clarifications to the original protocol: • Re-designation of other efficacy variables to secondary efficacy variables. • Proteinuria eligibility range was changed to a single value. • Clarification on handling study drug added, recording concomitant medications, to collect only relevant medication history. • Corrections made to subject numbering and administrative updates. • Updates added to clarify urine pregnancy test will be performed at the investigative sites. • Provided procedures for pregnancy reporting and follow-up.
    22 Jul 2016
    Amendment 2 provided a number of clarifications to the original protocol: • Edited text to keep text consistent with European Medicines Agency guideline wording. • Increased criterion window to allow for varying institutional standards. • Revised visit day when recording of diary data begins. • Clarification of blood draw occurring at the Baseline visit does not apply to the pSC#2 trough as results are reported after first investigational product dose. • Added explanation of intent of criterion “The subject has known Selective Immunoglobulin A (IgA) Deficiency (with or without antibodies to IgA).” • Revised to exclude other IgG products as it is unnecessary to wait 3 months prior to screening a subject if they have received another investigational IgG product. • Revision to define a minimum time frame and human immunodeficiency virus screening results based on updated information from the Central Lab results timing. • Clarification of delegated medical monitor role. • “SC” added as it was intended only to be applicable to the investigational product Treatment Phase. • Expansion of visit window added for subject scheduling accommodation. • Expanded adverse event reporting criterion to include potential systemic infusion reactions. • Removed X-ray requirement during Screening for pediatric subjects to limit radiation exposure and comply with local requirements for adult subjects. • Moved initial use of the SC infusion diary from Screening to Baseline visit. • Removed requirement to repeat Screening safety labs as Screening/Previous Regimen Phase window is limited to 8 weeks and such lab parameters are not anticipated to significantly change in this timeframe for the targeted study population. • Revised for clarification on timing of withdrawal due to pregnancy. • Revisions made for internal consistency. • Removed IgG row to avoid an additional blood draw for certain subjects.
    21 Mar 2017
    Amendment 3 provided a number of clarifications to the original protocol: • Added requirement of assent as both consent and assent are required for inclusion. • Removed weight measurement at every clinic visit as it was not accurate. • The restriction to local infusion site reaction (ISRs) was removed to allow for the collection of all ISRs. • Added additional vial size of 20 mL that contains 4 grams of immune globulin. • Infusion rates were revised to reflect recently published data supporting the safety of higher infusion rates. • Clarification that the delegated medical monitor role may be consulted for such cases. • Deleted beginning time period of 4 weeks for clarity due to variable dosing intervals. • Added timing for consistency within the protocol. • Heading was revised as Visit #2 only applies to pIV dosing. • Expanded IgG trough sample collection window to accommodate subject visit logistics across sites • Added criterion for removal of subjects who develop an SBI prior to first dose of IGSC 20%.

    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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