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    Clinical Trial Results:
    An open-label, prospective, multicenter study investigating clinical efficacy, safety, and pharmacokinetic properties of the human normal immunoglobulin for intravenous administration BT595 as replacement therapy in patients with primary immunodeficiency disease (PID)

    Summary
    EudraCT number
    2015-003652-52
    Trial protocol
    DE   ES   GB  
    Global end of trial date
    01 Apr 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Aug 2021
    First version publication date
    27 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    991
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02810444
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biotest AG
    Sponsor organisation address
    Landsteinerstr. 5, Dreieich, Germany, 63303
    Public contact
    Dr med Andrea Wartenberg-Demand, Biotest AG, +49 61038010, andrea.wartenberg-demand@biotest.com
    Scientific contact
    Dr med Andrea Wartenberg-Demand, Biotest AG, +49 61038010, andrea.wartenberg-demand@biotest.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002092-PIP01-16
    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
    07 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to demonstrate that the rate of acute serious bacterial infections (i.e., the mean number of acute serious bacterial infections per subject year) is less than 1.0 to provide substantial evidence of efficacy.
    Protection of trial subjects
    To monitor the safety data from adult subjects and provide advice and recommendations on the enrollment of pediatric subjects, a DSMB consisting of independent experts has been implemented.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Oct 2016
    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
    Germany: 4
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Russian Federation: 11
    Worldwide total number of subjects
    67
    EEA total number of subjects
    35
    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)
    12
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    44
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Date of first enrolment: 04-Oct-2016; First IMP administration: 03-Nov-2016; Date of last completed: 01-Apr-2020

    Pre-assignment
    Screening details
    Male or female, aged 2 through 75 years. Diagnosis of PID with impaired antibody production. Established replacement therapy with any intravenous immunoglobulin (IVIg) reference preparation during the previous 6 months. Established replacement therapy with a single IVIg reference preparation for at least 3 months prior to treatment start.

    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
    Full analysis set (FAS)
    Arm description
    3- or 4-week schedule for a treatment period of approximately 12 months according to the subject’s prestudy IVIg treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    IgG Next Generation
    Investigational medicinal product code
    BT595
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BT595 will be administered at 3- or 4-week intervals for a treatment period of approximately 12 months. The initial dose and dosage intervals must be consistent with the subject’s prestudy IVIg treatment and the initial dose and dosage interval will only be changed if medically indicated. The planned dose of BT595 is 0.2 to 0.8 g/kg body weight (bw) (2 to 8 mL/kg bw) administered as intravenous infusions at 3- or 4-week intervals for a treatment period of approximately 12 months.

    Number of subjects in period 1
    Full analysis set (FAS)
    Started
    67
    Completed
    60
    Not completed
    7
         Adverse event, non-fatal
    3
         Consent withdrawn by subject
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Full analysis set (FAS)
    Reporting group description
    3- or 4-week schedule for a treatment period of approximately 12 months according to the subject’s prestudy IVIg treatment.

    Reporting group values
    Full analysis set (FAS) Total
    Number of subjects
    67 67
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    6 6
        Adults (18-75 years)
    49 49
        Children (6-11 years)
    9 9
        Young Children (2-5 years)
    3 3
    Gender categorical
    Units: Subjects
        Female
    30 30
        Male
    37 37
    Subject analysis sets

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects following the principle of intention to treat. The FAS comprised all subjects who received ≥1 dose of study medication. Subjects were analyzed according to the treatment planned. The FAS was used for all analyses of efficacy endpoints. For this nonrandomized study, FAS and SAF were identical and included all subjects who received ≥1 dose of BT595.

    Subject analysis sets values
    Full analysis set (FAS)
    Number of subjects
    67
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    6
        Adults (18-75 years)
    49
        Children (6-11 years)
    9
        Young Children (2-5 years)
    3
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    30
        Male
    37

    End points

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    End points reporting groups
    Reporting group title
    Full analysis set (FAS)
    Reporting group description
    3- or 4-week schedule for a treatment period of approximately 12 months according to the subject’s prestudy IVIg treatment.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects following the principle of intention to treat. The FAS comprised all subjects who received ≥1 dose of study medication. Subjects were analyzed according to the treatment planned. The FAS was used for all analyses of efficacy endpoints. For this nonrandomized study, FAS and SAF were identical and included all subjects who received ≥1 dose of BT595.

    Primary: Number of acute serious bacterial infections (SBI)

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    End point title
    Number of acute serious bacterial infections (SBI)
    End point description
    The primary endpoint of this study was the SBI rate, defined as the mean number of acute serious bacterial infections (SBIs) per subject-year, according to EMA and FDA guidance for IVIg studies. Acute serious bacterial infections included the following (based on specific diagnostic criteria as per FDA guidance (FDA, 2008): • Bacteremia or sepsis. • Bacterial meningitis. • Osteomyelitis/septic arthritis. • Bacterial pneumonia. • Visceral abscess.
    End point type
    Primary
    End point timeframe
    Start of treatment until close out.
    End point values
    Full analysis set (FAS) Full analysis set (FAS)
    Number of subjects analysed
    67
    67
    Units: Number of SBI
    1
    1
    Statistical analysis title
    Rate of SBI
    Statistical analysis description
    According to EMA and FDA guidelines for IVIG studies: The null hypothesis (SBI rate ≥1.0 per subject-year at the 1% level of significance using a computed one-sample Poisson model) was tested. Therefore, the full analysis set was compared only to a fixed rate.
    Comparison groups
    Full analysis set (FAS) v Full analysis set (FAS)
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.01 [2]
    Method
    one-sample Poisson CI
    Parameter type
    annual rate (SBI)
    Point estimate
    0.015
    Confidence interval
         level
    99%
         sides
    1-sided
         lower limit
    -
         upper limit
    0.151
    Notes
    [1] - According to EMA and FDA guidelines for IVIG studies: The null hypothesis (SBI rate ≥1.0 per subject-year at the 1% level of significance using a computed one-sample Poisson model) was tested
    [2] - Rate of SBI was tested according to Guidelines against 1.0. Only upper Confidence Limit was calculated.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Only Treatment-emergent AEs (TEAEs) are displayed. TEAEs were recorded from start of Treatment until Follow-up visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Full analysis set (FAS)
    Reporting group description
    All subjects following the principle of intention to treat. The FAS comprised all subjects who received ≥1 dose of study medication. Subjects were analyzed according to the treatment planned. The FAS was used for all analyses of efficacy endpoints. For this nonrandomized study, FAS and SAF were identical and included all subjects who received ≥1 dose of BT595.

    Serious adverse events
    Full analysis set (FAS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 67 (13.43%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Meniscus injury
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatitis toxic
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Systemic scleroderma
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Full analysis set (FAS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 67 (89.55%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    4
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    10
    Pyrexia
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    4
    Chills
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    3
    Psychiatric disorders
    Mood swings
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    3
    Injury, poisoning and procedural complications
    Extra dose administered
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Ligament sprain
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Investigations
    Blood pressure increased
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    3
    C-reactive protein increased
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    3
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    9
    Rhinorrhoea
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    5
    Cough
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    5
    Epistaxis
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    28
    Asthma
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Nasal congestion
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    3
    Nasal polyps
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Sinus congestion
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Nervous system disorders
    headache
         subjects affected / exposed
    17 / 67 (25.37%)
         occurrences all number
    41
    Eye disorders
    Noninfective conjunctivitis
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    3
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 67 (10.45%)
         occurrences all number
    8
    Nausea
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    6
    Vomiting
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Abdominal pain
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    4
    Dental caries
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Gastrointestinal inflammation
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    5
    Back pain
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Joint swelling
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 67 (23.88%)
         occurrences all number
    24
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 67 (19.40%)
         occurrences all number
    24
    Bronchitis
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    12
    Sinusitis
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    11
    Pharyngitis
         subjects affected / exposed
    7 / 67 (10.45%)
         occurrences all number
    8
    Viral upper respiratory tract infection
         subjects affected / exposed
    7 / 67 (10.45%)
         occurrences all number
    7
    Influenza
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    6
    Urinary tract infection
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    8
    Conjunctivitis
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    6
    Oral herpes
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    9
    Acute sinusitis
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2
    Ear infection
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    3
    Gastroenteritis viral
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    3
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    4
    Skin infection
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    3
    Viral infection
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2016
    The requirement for additional blood sampling for Coombs test and serum haptoglobin for the first 10 (adult) subjects who received ≥2 BT595 infusions was added (due to DSMB request)
    02 Jun 2017
    The option of homecare service for the PK sampling in pediatric subjects was added. An additional specification regarding vital sign assessment was added: In any case where a change in infusion rate occurred sooner than within a 15 minute interval, vital signs had to be measured prior to the change (to avoid further protocol deviations). A clarification that every infusion had to start at an initial rate of 0.3 mL/kg/h was added (to avoid further protocol deviations).
    21 Mar 2018
    The IND Number was corrected from 128413 to 17046. Note: Former IND number was mistakenly assigned by the Center for Drug Evaluation and Research (CDER) and not by the Center for Biologics Evaluation and Research (CBER). The number of planned subjects was increased from approximately 60 to approximately 70 subjects, to ensure a sufficient number of pediatric subjects was enrolled and to meet the FDA and EMA requirements for the clinical studies of immunoglobulins for intravenous administration. The date for the expected last subject last visit was moved from FEB 2018 to NOV 2019 due to shifted timelines.

    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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