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    Clinical Trial Results:
    Pharmacokinetics, efficacy, tolerability and safety evaluation of the therapy with subcutaneous immunoglobulin in the treatment of hypo or agammaglobulinaemic patients. Open label phase II/III study

    Summary
    EudraCT number
    		 2010-020167-20
    Trial protocol
    		 IT  
    Global end of trial date
    22 Apr 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Aug 2016
    First version publication date
    07 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KB047
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kedrion S.p.A.
    Sponsor organisation address
    Località Ai Conti, Barga, Lucca, Italy, 55051
    Public contact
    Roberta Macchia, Kedrion SpA, +39 0583767326, r.macchia@kedrion.com
    Scientific contact
    Roberta Macchia, Kedrion SpA, +39 0583767326, r.macchia@kedrion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000454-PIP01-08
    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
    22 Apr 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Evaluation of pharmacokinetics, efficacy, and safety of Kedrion 16% subcutaneous immunoglobulin preparation (Kedrion SCIg)
    Protection of trial subjects
    A Data Safety Monitoring Board (DSMB) was established and maintained active for the total study duration to have an independent scrutiny of the study and to guarantee of safety for those subjects who were recruited in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Aug 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 33
    Worldwide total number of subjects
    33
    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)
    5
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    23
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 33
    Number of subjects completed
    		 33

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

    Arms
    Arm title
    		 Single arm
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    SCIg 16%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Following the enrolment in the study, each patient was treated with the IMP, at a dose of 100 mg/kg BW/week for 6 months (26 weeks).

    Number of subjects in period 1
    		Single arm
    Started
    33
    Completed
    20
    Not completed
    13
         Physician decision
    5
         Consent withdrawn by subject
    1
         Study interruption
    6
         Pregnancy
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 33 33
    Age categorical
    Males or females aged between 2 and 60 years (≥ 2 and ≤ 60 years).
    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)
    		 5 5
        Adolescents (12-17 years)
    		 5 5
        Adults (18-64 years)
    		 23 23
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Males and females
    Units: Subjects
        Female
    		 13 13
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 -

    Subject analysis set title
    Intention to Treat Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-treat (ITT) population defined as all patients who received the first infusion of IMP and who had at least one efficacy assessment, i.e. patients with availability of data on bacterial infections at any clinical visit

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol (PP) population, defined as all patients included in the ITT population who did not have any major protocol violation

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population defined as all enrolled patients who received the first infusion of IMP

    Primary: Annualized rate of acute severe bacterial infections (SBIs)

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    End point title
    		 Annualized rate of acute severe bacterial infections (SBIs) [1]
    End point description
    The number of severe acute bacterial infections and the number of patients with severe acute bacterial infection during the study were summarized using descriptive statistics and the severe acute bacterial infections annualized rate was presented. The limit of acceptability was 1 severe infection/patient/year.
    End point type
    Primary
    End point timeframe
    For all the study period
    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: Statistical Analysis conducted for the Trial was descriptive only and for this reason we cannot fill in the fields related to this section
    End point values
    		 Single arm Intention to Treat Population Per Protocol Population
    Number of subjects analysed
    32
    32
    32
    Units: Acute SBIs
        number (not applicable)
    0.223
    0.223
    0.223
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For all the study period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    safety population
    Reporting group description
    		 -

    Serious adverse events
    		 safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 33 (12.12%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchial pneumonia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 33 (90.91%)
    Vascular disorders
    Cyanosis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Pallor
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Presyncope
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Chills
         subjects affected / exposed
    5 / 33 (15.15%)
         occurrences all number
    19
    Fatigue
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Induration
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Infusion site erythema
         subjects affected / exposed
    15 / 33 (45.45%)
         occurrences all number
    139
    Infusion site induration
         subjects affected / exposed
    10 / 33 (30.30%)
         occurrences all number
    117
    Infusion site pain
         subjects affected / exposed
    14 / 33 (42.42%)
         occurrences all number
    54
    Infusion site pruritus
         subjects affected / exposed
    11 / 33 (33.33%)
         occurrences all number
    74
    Infusion site swelling
         subjects affected / exposed
    24 / 33 (72.73%)
         occurrences all number
    310
    Infusion site warmth
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    31
    Injection site urticaria
         subjects affected / exposed
    4 / 33 (12.12%)
         occurrences all number
    13
    Local swelling
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    2
    Malaise
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    7 / 33 (21.21%)
         occurrences all number
    8
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    4
    Dyspnoea
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Nasal obstruction
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Oropharyngeal pain
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Productive cough
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Investigations
    Blood pressure decreased
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Body temperature increased
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 33 (15.15%)
         occurrences all number
    22
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Abdominal pain upper
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    8
    Dyspepsia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 33 (15.15%)
         occurrences all number
    10
    Cystitis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    4 / 33 (12.12%)
         occurrences all number
    4
    Influenza
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Oral herpes
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    4 / 33 (12.12%)
         occurrences all number
    5
    Sinusitis
         subjects affected / exposed
    4 / 33 (12.12%)
         occurrences all number
    4
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    22 Apr 2013
    Following the occurrence of the study discontinuation in 4 paediatric patients due to expected ADRs (3 of them possibly caused by allergic reactions, 1 of them was serious), the study sponsor examined, together with the DSMB and the study coordinator, the nature and the possible causes of the ADRs. Released tests were repeated on the IMP (anti-D antibodies, character, protein composition, molecular size distribution, IgA and IgM determination, Fc function of immunoglobulin, anti-A and anti-B haemagglutinins, pyrogens) and toxicity tests on the devices used for the SC administration were performed; they confirmed results in compliance with finished product specifications. In addition to the above tests, further non-routine tests (IgE determination, anticomplementary activity, prekallikrein activator, abnormal toxicity) have shown an IgE content of the batches used by patients with the above ADRs that was higher than that used in the other patients. Due to the impossibility of establishing a clear relationship between the batch used in the study and the occurrence of these ADRs (at that time the results of all analyses were not available) and that no other IMP batches for replacement of the only batch used in patients with ADRs would be rapidly available, the sponsor, in agreement with the DSMB and the study coordinator, decided to prematurely interrupt the study in order to maximise the patients protection and integrity. The decision on the interruption of the study was taken before all above analyses that led to the exclusion of causes linked with the used batch were completed. Additional comparative analyses have shown an even higher content of IgE in marketed SCIg products; for this reason Kedrion considers that this parameter was not responsible for the adverse reactions.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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