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    Clinical Trial Results:
    A prospective, randomized, open, multi-centre study to assess safety of PURETHAL Birch given with a rush up-dosing regimen to patients with allergic rhinitis/rhinoconjunctivitis.

    Summary
    EudraCT number
    		 2013-000086-36
    Trial protocol
    		 PL  
    Global end of trial date
    28 Mar 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    25 Jan 2017
    First version publication date
    18 Jun 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Changes related to Sponsor Contact data

    Trial information

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    Trial identification
    Sponsor protocol code
    PB/0040
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01918956
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    HAL Allergy
    Sponsor organisation address
    J.H. Oortweg 15-17, Leiden, Netherlands, NL-2333 CH
    Public contact
    Head Department of Clinical Development & Pharmacovigilance, HAL Allergy, +31 (0)88 1959000, pjdkam@hal-allergy.com
    Scientific contact
    Head Department of Clinical Development & Pharmacovigilance, HAL Allergy, +31 (0)88 1959000, pjdkam@hal-allergy.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Mar 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the study is to show that reaching the maintenance dose of 0.5 ml PURETHAL Birch following a rush regimen of three injections in weekly intervals is as safe as a conventional regimen of six injections in weekly intervals.
    Protection of trial subjects
    In the conventional up-dosing arm the common clinical protocol was followed for immunotherapy with this preparation. On site monitoring during the first 30 minutes after injection and the direct availability of emergency medication are standard. In the rush up-dosing arm, except for the up-dosing, the same clinical protocol was followed. No specific additional protection measures were taken in either arm.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Aug 2013
    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
    Poland: 123
    Worldwide total number of subjects
    123
    EEA total number of subjects
    123
    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)
    0
    Adolescents (12-17 years)
    42
    Adults (18-64 years)
    81
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Enrollment from 03SEP2013 till 28OCT2013

    Pre-assignment
    Screening details
    		 Outpatients consulting (paediatric) allergists or other specialists for their complaints related to birch pollen allergy and that fulfilled the more general in- and exclusion criteria, like age, symptoms, SPT results and/or ssIgE level or positive provocation test, were informed about the study and requested to participate.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 conventional
    Arm description
    		 Up-dosing according to conventional (= registered) regimen: 0.05, 0.1, 0.2, 0.3, 0.4 and 0.5 ml PURETHAL Birch at weekly intervals. Maintenance dosing : three doses of 0.5 ml PURETHAL Birch biweekly
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PURETHAL Birch
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Up-dosing: sequential steps of 0.05, 0.1, 0,2, 0.3, 0.4 and 0.5 ml PURETHAL Birch at weekly time intervals Maintenance dosing: three doses of 0.5 ml PURETHAL Birch biweekly

    Arm title
    		 rush up-dosing
    Arm description
    		 Up-dosing according to a rush regimen: 0.1, 0.3 and 0.5 ml PURETHAL Birch at weekly intervals. Maintenance dosing : three doses of 0.5 ml PURETHAL Birch biweekly
    Arm type
    		 Experimental

    Investigational medicinal product name
    PURETHAL Birch
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Up-dosing: sequential steps of 0.1, 0.3 and 0.5 ml PURETHAL Birch at weekly time intervals Maintenance dosing: three doses of 0.5 ml PURETHAL Birch biweekly

    Number of subjects in period 1
    		conventional rush up-dosing
    Started
    61
    62
    maintenance phase succesfully reached
    59 [1]
    61
    Completed
    60
    61
    Not completed
    1
    1
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The endpoint on number of patients reaching the maintenance dose has a denominator which is 1 patient less than the patients completing the study

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    conventional
    Reporting group description
    		 Up-dosing according to conventional (= registered) regimen: 0.05, 0.1, 0.2, 0.3, 0.4 and 0.5 ml PURETHAL Birch at weekly intervals. Maintenance dosing : three doses of 0.5 ml PURETHAL Birch biweekly

    Reporting group title
    rush up-dosing
    Reporting group description
    		 Up-dosing according to a rush regimen: 0.1, 0.3 and 0.5 ml PURETHAL Birch at weekly intervals. Maintenance dosing : three doses of 0.5 ml PURETHAL Birch biweekly

    Reporting group values
    		 conventional rush up-dosing Total
    Number of subjects
    		 61 62 123
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 21 21 42
        Adults (18-64 years)
    		 40 41 81
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 26.6 (12 to 59) 27.9 (12 to 59) -
    Gender categorical
    Units: Subjects
        Female
    		 29 30 59
        Male
    		 32 32 64

    End points

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    End points reporting groups
    Reporting group title
    conventional
    Reporting group description
    		 Up-dosing according to conventional (= registered) regimen: 0.05, 0.1, 0.2, 0.3, 0.4 and 0.5 ml PURETHAL Birch at weekly intervals. Maintenance dosing : three doses of 0.5 ml PURETHAL Birch biweekly

    Reporting group title
    rush up-dosing
    Reporting group description
    		 Up-dosing according to a rush regimen: 0.1, 0.3 and 0.5 ml PURETHAL Birch at weekly intervals. Maintenance dosing : three doses of 0.5 ml PURETHAL Birch biweekly

    Primary: proportion of patients succesfully reaching the maintenance dose

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    End point title
    		 proportion of patients succesfully reaching the maintenance dose
    End point description
    End point type
    Primary
    End point timeframe
    milestone during treatment
    End point values
    		 conventional rush up-dosing
    Number of subjects analysed
    61
    62
    Units: subjects
        Maintenance phase reached succesfully (Y/N)
    59
    61
    Statistical analysis title
    		 non-inferiority testing
    Comparison groups
    conventional v rush up-dosing
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.038
         upper limit
    		 0.071

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    treatment
    Adverse event reporting additional description
    During 30 minutes after injection adverse event monitoring under supervision at site, during 24 hrs after injection by use of patient diary (focus on local reactions). Other general adverse events reported by patient at visit for next injection.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    conventional
    Reporting group description
    		 up-dosing according to conventional (= registered) regimen

    Reporting group title
    rush up-dosing
    Reporting group description
    		 up-dosing according to a rush regimen

    Serious adverse events
    		 conventional rush up-dosing
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 conventional rush up-dosing
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 61 (63.93%)
    38 / 62 (61.29%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 61 (6.56%)
    5 / 62 (8.06%)
         occurrences all number
    4
    10
    Dizziness
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Somnolence
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    5 / 61 (8.20%)
    6 / 62 (9.68%)
         occurrences all number
    9
    8
    Injection site pruritus
         subjects affected / exposed
    5 / 61 (8.20%)
    8 / 62 (12.90%)
         occurrences all number
    10
    12
    Injection site swelling
         subjects affected / exposed
    5 / 61 (8.20%)
    5 / 62 (8.06%)
         occurrences all number
    8
    5
    Injection site hypersensitivity
         subjects affected / exposed
    4 / 61 (6.56%)
    2 / 62 (3.23%)
         occurrences all number
    8
    4
    Local swelling
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 62 (3.23%)
         occurrences all number
    2
    3
    Injection site erythema
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 62 (3.23%)
         occurrences all number
    1
    3
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 62 (4.84%)
         occurrences all number
    1
    3
    Eye irritation
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Eye pruritus
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Sneezing
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 62 (3.23%)
         occurrences all number
    6
    2
    Oropharyngeal pain
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 62 (3.23%)
         occurrences all number
    4
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 62 (4.84%)
         occurrences all number
    1
    4
    Dyspnoea
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 62 (3.23%)
         occurrences all number
    1
    2
    Nasal discomfort
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    3
    Nasal oedema
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    3
    Throat irritation
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 62 (1.61%)
         occurrences all number
    3
    2
    Erythema
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Rash
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 61 (8.20%)
    4 / 62 (6.45%)
         occurrences all number
    7
    5
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 61 (9.84%)
    5 / 62 (8.06%)
         occurrences all number
    7
    5
    Pharyngitis
         subjects affected / exposed
    5 / 61 (8.20%)
    5 / 62 (8.06%)
         occurrences all number
    5
    5
    Rhinitis
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 62 (4.84%)
         occurrences all number
    2
    4

    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? 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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