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    Clinical Trial Results:
    A Phase III Open-Label, Prospective, Multicenter Study of the Efficacy, Tolerability, Safety, and Pharmacokinetics of Immune Globulin Subcutaneous (Human), IgPro20 in Subjects With Primary Immunodeficiency (PID)

    Summary
    EudraCT number
    2014-003607-30
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    27 Oct 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZLB04_009CR
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00419341
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CSL Behring, LLC
    Sponsor organisation address
    1020 First Avenue, King of Prussia, PA, United States, 19406-0901
    Public contact
    Trial Registration Co-ordinator, CSL Behring, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Registration Co-ordinator, CSL Behring, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Nov 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to assess the efficacy, tolerability, safety and pharmacokinetics of IgPro20 in patients with primary humoral immunodeficiency (PID).
    Protection of trial subjects
    This study was conducted in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki (version of 1996), and standard operating procedures for clinical research and development at CSL Behring and the Clinical Research Organizations involved. Compliance with these requirements also constitutes conformity with the ethical principles of the Declaration of Helsinki. The study was conducted under a protocol reviewed and approved by an IRB; the study was conducted by scientifically and medically qualified persons; the benefits of the study were in proportion to the risks; the rights and welfare of the subjects were respected; the physicians conducting the study did not find the hazards to outweigh the potential benefits; the results reported are accurate; and each subject or subject’s parent or legal guardian gave his or her written informed consent before any protocol-driven tests or evaluations were performed. A properly executed, written informed consent in compliance with the Declaration of Helsinki (version of 1996), ICH, GCP, and local regulations was obtained for each subject prior to entering the subject into the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Nov 2006
    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
    United States: 49
    Worldwide total number of subjects
    49
    EEA total number of subjects
    0
    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)
    3
    Adolescents (12-17 years)
    14
    Adults (18-64 years)
    26
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 12 centers in the United States enrolled subjects for this study.

    Pre-assignment
    Screening details
    A total of 52 subjects were screened, and 49 subjects were enrolled into the study and treated with IgPro20.

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

    Arms
    Arm title
    IgPro20
    Arm description
    IgPro20 is a liquid formulation of normal human IgG at a concentration of 20% administered as a subcutaneous (SC) infusion at weekly intervals.
    Arm type
    Experimental

    Investigational medicinal product name
    IgPro20
    Investigational medicinal product code
    Other name
    Human Normal Immunoglobulin for Subcutaneous Administration (IGSC), Hizentra
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IgPro20 is a liquid formulation of normal human IgG at a concentration of 20% administered as a SC infusion at weekly intervals. The initial weekly dose was determined based on subjects' previous treatment. Dose adjustments could be performed during the wash-in/wash-out period at the discretion of the investigator.

    Number of subjects in period 1
    IgPro20
    Started
    49
    Wash in/Wash Out Period
    49
    Efficacy Period
    38
    Completed
    28
    Not completed
    21
         Lost to follow-up (efficacy period)
    1
         Consent withdrawn by subject
    8
         Adverse event, non-fatal
    2
         Protocol deviation (efficacy period)
    1
         Termination of study site (efficacy period)
    1
         Disqualifying laboratory results
    1
         Consent withdrawn by subject (efficacy period)
    6
         Non-compliance (efficacy period)
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IgPro20
    Reporting group description
    IgPro20 is a liquid formulation of normal human IgG at a concentration of 20% administered as a subcutaneous (SC) infusion at weekly intervals.

    Reporting group values
    IgPro20 Total
    Number of subjects
    49 49
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    3 3
        Adolescents (12-17 years)
    14 14
        Adults (18-64 years)
    26 26
        From 65-84 years
    6 6
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    34.4 ( 20.09 ) -
    Gender categorical
    Units: Subjects
        Female
    27 27
        Male
    22 22
    Race
    Units: Subjects
        Black or African American
    3 3
        White
    46 46
    Type of Primary Immunodeficiency
    Units: Subjects
        Common variable immunodeficiency (CVID)
    46 46
        X-linked agammaglobulinemia (XLA)
    3 3

    End points

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    End points reporting groups
    Reporting group title
    IgPro20
    Reporting group description
    IgPro20 is a liquid formulation of normal human IgG at a concentration of 20% administered as a subcutaneous (SC) infusion at weekly intervals.

    Subject analysis set title
    IgPro20 (PK Substudy)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    IgPro20 is a liquid formulation of normal human IgG at a concentration of 20% administered as a SC infusion at weekly intervals. The Per Protocol Pharmacokinetic (PPK) population included all subjects with the disease under study who fulfilled the requirements of the PK substudy, including PK sampling in a preceding study with IVIG (Privigen, CSL Behring), and fulfilling IgPro20 dosing requirements and providing adequate PK blood samples in the current study.

    Subject analysis set title
    IVIG (Privigen; Previous Study)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Privigen is a liquid formulation of normal human IgG at a concentration of 10% administered as an intravenous infusion every 3 or 4 weeks. The Per Protocol Pharmacokinetic (PPK) population included all subjects with the disease under study who fulfilled the requirements of the PK substudy, including PK sampling in a preceding study with IVIG (Privigen, CSL Behring), and fulfilling IgPro20 dosing requirements and providing adequate PK blood samples in the current study.

    Subject analysis set title
    IgPro20 - ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intention To Treat (ITT) population included all subjects who were treated with IgPro20 during any study period.

    Primary: Annualized Rate of Clinically Documented Serious Bacterial Infections (SBIs) (MITT Population)

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    End point title
    Annualized Rate of Clinically Documented Serious Bacterial Infections (SBIs) (MITT Population) [1]
    End point description
    The annualized rate was based on the total number of SBIs and the total number of subject study days during the efficacy period for all subjects in the specified analysis population and adjusted to 365 days. Potential SBIs included pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. If an adverse event (AE) was identified as a potential SBI, the AE was adjudicated by a review committee to determine if the event fulfilled the predefined criteria for SBIs. The modified intention-to-treat (MITT) population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 13) who had the disease under study.
    End point type
    Primary
    End point timeframe
    Efficacy period: up to 12 months (week 13 to the completion visit)
    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: End point data analysis consisted of a comparison of the annualized rate 99% upper confidence interval limit to 1 (in accordance with the US Food and Drug Administration Guidance for Industry on “Safety, efficacy, and pharmacokinetic studies to support marketing of immune globulin intravenous (human) as replacement therapy for primary humoral immunodeficiency” [June 2008]).
    End point values
    IgPro20
    Number of subjects analysed
    38 [2]
    Units: SBIs per subject year
        number (not applicable)
    0
    Notes
    [2] - Number of Efficacy Period Subject Study Days Analyzed = 12697 MITT population
    No statistical analyses for this end point

    Primary: Area Under the Concentration-time Curve (AUC) of Total Serum Immunoglobulin G (IgG)

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    End point title
    Area Under the Concentration-time Curve (AUC) of Total Serum Immunoglobulin G (IgG)
    End point description
    Evaluate non-inferiority of steady-state IgG area under the concentration-time curves standardized to a 7-day period (sAUCs) for subcutaneous immunoglobulin (SCIG) (IgPro20) versus the sAUC under intravenous immunoglobulin (IVIG) (Privigen) treatment. The sAUC under IVIG was taken from the same subjects in a preceding study (either ZLB03_002CR [NCT00168025] or ZLB05_006CR [NCT00322556, 2014-003772-23]).
    End point type
    Primary
    End point timeframe
    Measured during a single dosing interval after at least 12 weeks of stable subcutaneous (SC) dosing with IgPro20 treatment
    End point values
    IgPro20 (PK Substudy) IVIG (Privigen; Previous Study)
    Number of subjects analysed
    18 [3]
    18 [4]
    Units: days*g/L
        arithmetic mean (standard deviation)
    105.6 ( 31.56 )
    103.2 ( 20 )
    Notes
    [3] - PPK population
    [4] - PPK population
    Statistical analysis title
    AUC of IgG: IgPro20 vs IVIG
    Statistical analysis description
    Individual sAUC values (standardized to a 7-day period) of the IV and adjusted SC sampling periods in each individual subject were log transformed and a parametric 2-sided 90% confidence interval (CI) for the mean of the individual differences was obtained. Back-transformation of the mean and its CI produced the geometric mean ratio (GMR) and its respective 90% CI.
    Comparison groups
    IgPro20 (PK Substudy) v IVIG (Privigen; Previous Study)
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    Method
    t-test, 2-sided
    Parameter type
    Geometric mean ratio (GMR)
    Point estimate
    1.002
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.951
         upper limit
    1.055
    Notes
    [5] - Non-inferiority of SCIG:IVIG treatment was concluded if the lower GMR confidence limit was 0.8 or more. With 18 evaluable subjects, the power to show this non-inferiority was calculated to be 85% based on the assumptions of an intra-individual variability with a coefficient of variation (CV) = 25% and a GMR equal to or greater than 1.

    Secondary: Annualized Rate of Clinically Documented SBIs (ITT Population)

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    End point title
    Annualized Rate of Clinically Documented SBIs (ITT Population)
    End point description
    The annualized rate was based on the total number of SBIs and the total number of subject study days during the study for all subjects in the specified analysis population and adjusted to 365 days. Potential SBIs included pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. If an AE was identified as a potential SBI, the AE was adjudicated by a review committee to determine if the event fulfilled the predefined criteria for SBIs.
    End point type
    Secondary
    End point timeframe
    For the duration of the study, up to 15 months
    End point values
    IgPro20 - ITT
    Number of subjects analysed
    49 [6]
    Units: SBIs per subject year
        number (not applicable)
    0
    Notes
    [6] - ITT population Number of Subject Study Days Analyzed: 16234
    No statistical analyses for this end point

    Secondary: Annualized Rate of Clinically Documented SBIs (PPE Population)

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    End point title
    Annualized Rate of Clinically Documented SBIs (PPE Population)
    End point description
    The annualized rate was based on the total number of SBIs and the total number of subject study days during the efficacy period for all subjects in the specified analysis population and adjusted to 365 days. Potential SBIs included pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. If an AE was identified as a potential SBI, the AE was adjudicated by a review committee to determine if the event fulfilled the predefined criteria for SBIs. The Per Protocol Efficacy (PPE) population included all subjects who completed the 12-month efficacy period according to the protocol-defined requirements.
    End point type
    Secondary
    End point timeframe
    Efficacy period: up to 12 months (week 13 to the completion visit)
    End point values
    IgPro20
    Number of subjects analysed
    25 [7]
    Units: SBIs per subject year
        number (not applicable)
    0
    Notes
    [7] - PPE population Number of Efficacy Period Subject Study Days Analyzed = 9543
    No statistical analyses for this end point

    Secondary: Annualized Rate of Infection Episodes

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    End point title
    Annualized Rate of Infection Episodes
    End point description
    The annualized rate was based on the total number of infection episodes occurring during the efficacy period (N = 96) divided by the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days. The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 13) who had the disease under study.
    End point type
    Secondary
    End point timeframe
    Efficacy period: up to 12 months (week 13 to completion visit)
    End point values
    IgPro20
    Number of subjects analysed
    38 [8]
    Units: infection episodes per subject year
        number (confidence interval 95%)
    2.76 (2.235 to 3.37)
    Notes
    [8] - MITT population Number of Subject Study Days Analyzed = 12697
    No statistical analyses for this end point

    Secondary: Number of Infection Episodes (Serious and Non-serious)

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    End point title
    Number of Infection Episodes (Serious and Non-serious)
    End point description
    Total number of infections for the specified analysis population. The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
    End point type
    Secondary
    End point timeframe
    Efficacy period: up to 12 months (week 13 to the completion visit)
    End point values
    IgPro20
    Number of subjects analysed
    38 [9]
    Units: infections
    96
    Notes
    [9] - MITT population
    No statistical analyses for this end point

    Secondary: Annualized Rate of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections

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    End point title
    Annualized Rate of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections
    End point description
    The annualized rate was based on the total number of days out of work / school / kindergarten / day care or inability to perform normal activities due to infection (N = 71), and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days. The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 13) who had the disease under study.
    End point type
    Secondary
    End point timeframe
    Efficacy period: up to 12 months (week 13 to the completion visit)
    End point values
    IgPro20
    Number of subjects analysed
    38 [10]
    Units: days per subject year
        number (not applicable)
    2.06
    Notes
    [10] - MITT population Number of Exposure Days Analyzed = 12605
    No statistical analyses for this end point

    Secondary: Number of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections

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    End point title
    Number of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Daily Activities Due to Infections
    End point description
    Total number of days out of work / school / kindergarten / day care or unable to perform normal daily activities due to infections, for the specified analysis population. The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
    End point type
    Secondary
    End point timeframe
    Efficacy period: up to 12 months (week 13 to the completion visit)
    End point values
    IgPro20
    Number of subjects analysed
    38 [11]
    Units: Days
    71
    Notes
    [11] - MITT population
    No statistical analyses for this end point

    Secondary: Annualized Rate of Hospitalization Due to Infection

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    End point title
    Annualized Rate of Hospitalization Due to Infection
    End point description
    The annualized rate was based on the total number of days of hospitalization due to infection (N = 7) and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days. The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
    End point type
    Secondary
    End point timeframe
    Efficacy period: up to 12 months (week 13 to the completion visit)
    End point values
    IgPro20
    Number of subjects analysed
    38 [12]
    Units: days per subject year
        number (not applicable)
    0.2
    Notes
    [12] - MITT population Number of Exposure Days Analyzed = 12605
    No statistical analyses for this end point

    Secondary: Number of Days of Hospitalization Due to Infections

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    End point title
    Number of Days of Hospitalization Due to Infections
    End point description
    Total number of days of hospitalization due to infections for the specified analysis population. The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
    End point type
    Secondary
    End point timeframe
    Efficacy period: up to 12 months (week 13 to the completion visit)
    End point values
    IgPro20
    Number of subjects analysed
    38 [13]
    Units: days
    7
    Notes
    [13] - MITT population
    No statistical analyses for this end point

    Secondary: Use of Antibiotics for Infection Prophylaxis and Treatment

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    End point title
    Use of Antibiotics for Infection Prophylaxis and Treatment
    End point description
    Annualized rate of days with antibiotics for infection prophylaxis and treatment. The annualized rate was based on the total number of days of antibiotic use for infection prophylaxis and treatment in the efficacy period, and the total number of subject study days for all subjects in the specified analysis population, and adjusted to 365 days. The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
    End point type
    Secondary
    End point timeframe
    Efficacy period: up to 12 months (week 13 to the completion visit)
    End point values
    IgPro20
    Number of subjects analysed
    38 [14]
    Units: days per subject year
        number (not applicable)
    48.52
    Notes
    [14] - MITT population Number of Exposure Days Analyzed = 12697
    No statistical analyses for this end point

    Secondary: Total Serum IgG Trough Levels

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    End point title
    Total Serum IgG Trough Levels
    End point description
    The IgG trough values per subject were aggregated to a median value, and then median values across subjects were summarized using descriptive statistics. The MITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with week 13) who had the disease under study.
    End point type
    Secondary
    End point timeframe
    Every 4 weeks, throughout the 12-month efficacy period
    End point values
    IgPro20
    Number of subjects analysed
    38 [15]
    Units: g/L
        arithmetic mean (standard deviation)
    12.53 ( 3.21 )
    Notes
    [15] - MITT population
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax) of Total Serum IgG at Steady State

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    End point title
    Maximum Concentration (Cmax) of Total Serum IgG at Steady State
    End point description
    The PPK population included all subjects with the disease under study who fulfilled the requirements of the PK substudy, including PK sampling in a preceding study with IVIG (Privigen, CSL Behring), and fulfilling IgPro20 dosing requirements and providing adequate PK blood samples in the current study.
    End point type
    Secondary
    End point timeframe
    Week 28 ± 1 week of the treatment period
    End point values
    IgPro20 (PK Substudy)
    Number of subjects analysed
    18 [16]
    Units: g/L
        arithmetic mean (standard deviation)
    16.16 ( 4.93 )
    Notes
    [16] - PPK population
    No statistical analyses for this end point

    Secondary: Tmax at Steady State

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    End point title
    Tmax at Steady State
    End point description
    Timepoint of maximum concentration (Cmax). The PPK population included all subjects with the disease under study who fulfilled the requirements of the PK substudy, including PK sampling in a preceding study with IVIG (Privigen, CSL Behring), and fulfilling IgPro20 dosing requirements and providing adequate PK blood samples in the current study.
    End point type
    Secondary
    End point timeframe
    Week 28 ± 1 week of the treatment period
    End point values
    IgPro20 (PK Substudy)
    Number of subjects analysed
    18 [17]
    Units: days
        median (full range (min-max))
    3.118 (0 to 6.97)
    Notes
    [17] - PPK population
    No statistical analyses for this end point

    Other pre-specified: Minimum Concentration (Cmin) of Total Serum IgG at Steady State

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    End point title
    Minimum Concentration (Cmin) of Total Serum IgG at Steady State
    End point description
    The PPK population included all subjects with the disease under study who fulfilled the requirements of the PK substudy, including PK sampling in a preceding study with IVIG (Privigen, CSL Behring), and fulfilling IgPro20 dosing requirements and providing adequate PK blood samples in the current study.
    End point type
    Other pre-specified
    End point timeframe
    Week 28 ± 1 week of the treatment period
    End point values
    IgPro20 (PK Substudy)
    Number of subjects analysed
    18 [18]
    Units: g/L
        arithmetic mean (standard deviation)
    13.7 ( 4.39 )
    Notes
    [18] - PPK population
    No statistical analyses for this end point

    Other pre-specified: Rate of All AEs by Relatedness and Seriousness

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    End point title
    Rate of All AEs by Relatedness and Seriousness
    End point description
    The rate of AEs was the number of AEs over the number of infusions administered. At least possibly related AEs included possibly related AEs, probably related AEs, and related AEs.
    End point type
    Other pre-specified
    End point timeframe
    For the duration of the study, up to 15 months
    End point values
    IgPro20 - ITT
    Number of subjects analysed
    49 [19]
    Units: AEs per infusion
    number (not applicable)
        All
    0.773
        At least possibly related
    0.634
        Serious
    0.004
        At least possibly related and serious
    0
    Notes
    [19] - ITT population Number of infusions analyzed: 2264
    No statistical analyses for this end point

    Other pre-specified: Rate of Mild, Moderate, or Severe Local Reactions

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    End point title
    Rate of Mild, Moderate, or Severe Local Reactions
    End point description
    In addition to the standard MedDRA System Organ Class (SOC) AE assignments, the category of 'local reactions' was defined to provide the possibility for a combined analysis of local reactions and included AEs of injection site reaction, injection site bruising, infusion site scab, injection site cyst, injection site eczema, injection site irritation, injection site nodule, and injection site pain. Mild AE: Did not interfere with routine activities; Moderate AE: Interfered somewhat with routine activities; Severe AE: Impossible to perform routine activities.
    End point type
    Other pre-specified
    End point timeframe
    For the duration of the study, up to 15 months
    End point values
    IgPro20 - ITT
    Number of subjects analysed
    49 [20]
    Units: local reactions per infusion
    number (not applicable)
        All
    0.592
        Mild
    0.553
        Moderate
    0.038
        Severe
    0.002
    Notes
    [20] - ITT population Number of Infusions Analyzed = 2264
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 15 months (including the 3 month wash in/wash out period and the 12 month efficacy period).
    Adverse event reporting additional description
    For the serious AEs (SAEs), treatment-emergent SAEs are provided.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    IgPro20
    Reporting group description
    IgPro20 is a liquid formulation of normal human IgG at a concentration of 20% administered as a SC infusion at weekly intervals.

    Serious adverse events
    IgPro20
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 49 (14.29%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    IgPro20
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 49 (100.00%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 49 (26.53%)
         occurrences all number
    40
    Migraine
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    5
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    49 / 49 (100.00%)
         occurrences all number
    1314
    Fatigue
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    6
    Injection site bruising
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    19
    Pain
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    5
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 49 (14.29%)
         occurrences all number
    8
    Abdominal pain upper
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    5
    Nausea
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 49 (16.33%)
         occurrences all number
    9
    Epistaxis
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    6
    Pharyngolaryngeal pain
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    6
    Asthma
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    6
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    11
    Arthralgia
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    5
    Pain in extremity
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    7
    Myalgia
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    4
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    14 / 49 (28.57%)
         occurrences all number
    20
    Nasopharyngitis
         subjects affected / exposed
    11 / 49 (22.45%)
         occurrences all number
    15
    Bronchitis
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    9
    Acute sinusitis
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    7
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    6
    Urinary tract infection
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Viral infection
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    7
    Influenza
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Otitis media
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Nov 2006
    A health-related quality of life assessment was incorporated as Appendix 6, references to the subject diary as an electronic tool were removed, and minor changes to the schedule of assessments were incorporated. This amendment was implemented before any subject had received the first infusion of study drug.
    17 Jan 2007
    The design of the health-related quality of life assessment was changed from comparative to single group longitudinal and the assessment of local tolerability was clarified. This amendment was implemented after 2 subjects had received their first infusion of study drug.
    23 Apr 2007
    Changes associated with the switch from the electronic to the paper diary used for collecting subject information were described, references to the health-related quality of life substudy were removed, and entry criteria for new subjects regarding the number of required serum IgG Ctrough values measured prior to study entry were clarified to match the current USA standard of care. This amendment was implemented after 23 subjects had received their first infusion of study drug.
    30 Apr 2008
    The maximum number of injection sites to be infused simultaneously and maximum total body flow rate of IgPro20 were described, additional timepoints for vital signs evaluation during visits to the study site were added, several statistical concepts were clarified, completion visit procedures were updated, and the lower limit of polysorbate 80 concentration in IgPro20 was specified. In addition, a set of tests to follow a newly positive Direct Coombs’ test result was specified. This amendment was implemented after 25 subjects had received their first infusion of study drug.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/20454851
    http://www.ncbi.nlm.nih.gov/pubmed/21553933
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