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    Clinical Trial Results:
    A multicenter, randomized, open label clinical trial for safety evaluation of an allergen immunotherapy with an accelerated dose escalation schedule using one strength of an aluminium hydroxide adsorbed allergoid preparation of birch pollen allergens in adult and pediatric patients with moderate to severe seasonal allergic rhinitis or rhinoconjunctivitis with or without bronchial asthma.

    Summary
    EudraCT number
    		 2021-002317-34
    Trial protocol
    		 DE   PL  
    Global end of trial date
    29 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2024
    First version publication date
    06 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AL2101av
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allergopharma GmbH & Co. KG
    Sponsor organisation address
    Hermann-Körner-Str. 52 , Reinbek, Germany, 21465
    Public contact
    Clinical Development, Allergopharma GmbH & Co. KG, +49 40 727650, clinicaltrials@allergopharma.com
    Scientific contact
    Clinical Development, Allergopharma GmbH & Co. KG, +49 40 727650, clinicaltrials@allergopharma.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
    15 Aug 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Mar 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of a One strength dose escalation scheme using one strength of Allergovit Birch for allergen immunotherapy (AIT) compared to the standard escalation scheme using 2 strength of Allergovit Birch in adults, adolescents, and children with allergic rhinitis/rhinoconjunctivitis caused by birch pollen allergens with or without allergic asthma on a well-controlled level
    Protection of trial subjects
    The trial was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (ICH) guidance for Good Clinical Practice (GCP) and the applicable regulatory requirements. Data Safety Monitoring Board (DSMB) was in place throughout the trial; DSMB consisted of 3 independent physicians, experienced in the field of allergy. The primary function of the DSMB was to ensure the subjects’ safety. During the whole course of the trial, the DSMB team regularly reviewed an update of the safety data from all treated patients. After each administration of the IMP, each patient in the study was kept under supervision of a qualified and trained investigator for at least 120 min. Safety evaluation during supervision after IMP administration consisted of: FEV1, Systolic BP, Diastolic BP, Heart rate (Pulse rate), Respiratory rate.
    Background therapy
    		 No background therapy was generally planned in this trial. Concomitant medication was defined as any medication other than the IMP that was taken during the clinical trial. Any relevant medication taken before entering the clinical trial was considered as “previous medication”. All anti-allergic medication administered in the last 2 years and other medication used during the last 6 weeks prior to enrollment to the trial had to be documented at the screening visit. Medication against rhinitis and rhinoconjunctivitis was permitted, but had to be documented as concomitant medication. Patients with bronchial asthma who required regular basic treatment of their allergic asthma were treated as recommended by GINA (GINA, 2021) to control their asthma. Any asthma medication had to be documented as concomitant medication. Restricted medication and nonpermitted medications were clearly defined in the trial protocol.
    Evidence for comparator
    		 There was no comparator used in this trial. Abbreviations used in this document: AE=Adverse event, AIT=Allergen immunotherapy, BP=Blood pressure, bpm=Beats per minute, DSMB=Data Safety Monitoring Board, FEV1=Forced expiratory volume in 1 second, GINA=Global Initiative for Asthma, ICF=Informed consent form, IgE = Immunoglobulin E, IgG=Immunoglobulin G, IMP=Investigational medicinal product, MedDRA=Medical Dictionary for Regulatory Activities, RBC=Red blood cells, TEAE=Treatment-emergent adverse event, TU=Therapeutic units, WAO=World Allergy Organization, y=year
    Actual start date of recruitment
    16 Mar 2022
    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
    Poland: 206
    Country: Number of subjects enrolled
    Germany: 39
    Worldwide total number of subjects
    245
    EEA total number of subjects
    245
    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)
    69
    Adolescents (12-17 years)
    63
    Adults (18-64 years)
    113
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 245 patients were screened for eligibility; of these 201 patients were randomized and 200 patients (87 adults, 51 adolescents, and 62 children) were actually treated with at least one dose of IMP (103 in the One Strength group and 97 in the Standard group).

    Pre-assignment
    Screening details
    		 Trial patients (outpatients) were included if they were suffering from immunoglobulin (Ig)E-mediated moderate to severe allergic rhinitis or rhinoconjunctivitis, with or without allergic asthma, triggered by house dust mite (HDM) allergens documented by skin prick test (SPT) wheal for HDM and specific IgE value of ≥ 0.70 kU/L to HDM.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 One Strength
    Arm description
    		 Patients randomized and treated into the One Strength group (accelerated dose escalation) received 3 injections with increasing doses of only strength B of Allergovit Birch (10 000 TU/mL), followed by 2 injections with the maximum recommended dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Allergovit Fagales (100% Birch)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IMP is an aluminium hydroxide adsorbed allergoid preparation of birch pollen allergens. IMP is available in 2 concentrations (A: 1 000 TU/ml and B: 10 000 TU/ml). In the One Strength group only strength B was used for 3 dose escalation injections (0.1ml, 0.3ml and 0.6ml), followed by 2 maintenance injections of the maximum recommended dose (0.6ml of strength B: 10 000TU).

    Arm title
    		 Standard
    Arm description
    		 Patients randomized and treated into the Standard group (standard dose escalation) received 7 injections with increasing doses of two strengths of Allergovit Birch (strength A: 1 000 TU/mL; strength B: 10 000 TU/mL), followed by 2 injections of the maximum recommended dose. Note: 98 patients were randomized into the Standard group, but one patient withdraw consent before first treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Allergovit Fagales (100% Birch)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IMP is an aluminium hydroxide adsorbed allergoid preparation of birch pollen allergens. IMP is available in 2 concentrations (A: 1 000 TU/ml and B: 10 000 TU/ml). In the standard group both concentrations were used for 7 dose escalation injections (0.1ml, 0.2ml, 0.4ml, 0.8ml of strength A and 0.15ml, 0.3ml, 0.6ml of strength B), followed by 2 maintenance injections of the maximum recommended dose (0.6ml of strength B: 10 000TU).

    Number of subjects in period 1 [1]
    		One Strength Standard
    Started
    103
    97
    Completed
    96
    92
    Not completed
    7
    5
         Consent withdrawn by subject
    1
    1
         Physician decision
    1
    -
         Adverse event, non-fatal
    3
    2
         Other reason(s)
    1
    1
         Sponsor/DSMB Desicion
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of patients enrolled worldwide includes screening failures (i.e. patients that signed the informed consent form, but were not randomized; N=44) and patients that were randomized, but never treated (N= 1). The number of patients in the baseline period equals the number of patients who were actually treated with IMP (= number of patients in the safety set, which was used for all analyses of this trial).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    One Strength
    Reporting group description
    		 Patients randomized and treated into the One Strength group (accelerated dose escalation) received 3 injections with increasing doses of only strength B of Allergovit Birch (10 000 TU/mL), followed by 2 injections with the maximum recommended dose.

    Reporting group title
    Standard
    Reporting group description
    		 Patients randomized and treated into the Standard group (standard dose escalation) received 7 injections with increasing doses of two strengths of Allergovit Birch (strength A: 1 000 TU/mL; strength B: 10 000 TU/mL), followed by 2 injections of the maximum recommended dose. Note: 98 patients were randomized into the Standard group, but one patient withdraw consent before first treatment.

    Reporting group values
    		 One Strength Standard Total
    Number of subjects
    		 103 97 200
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 31 31 62
        Adolescents (12-17 years)
    		 25 26 51
        Adults (18-64 years)
    		 47 40 87
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 22.6 ( 14.8 ) 21.7 ( 14.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 49 42 91
        Male
    		 54 55 109
    Subject analysis sets

    Subject analysis set title
    Adults (18 to ≤ 65 years), One Strength
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adults (18 to ≤ 65 years) treated according to the One Strength dose escalation scheme

    Subject analysis set title
    Adults (18 to ≤ 65 years), Standard
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adults (18 to ≤ 65 years) treated according to the Standard dose escalation scheme

    Subject analysis set title
    Adolescents (12 to < 18 years), One Strength
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adolescents (12 to < 18 years) treated according to the One Strength dose escalation scheme

    Subject analysis set title
    Adolescents (12 to < 18 years), Standard
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adolescents (12 to < 18 years) treated according to the Standard dose escalation scheme

    Subject analysis set title
    Children (5 to < 12 years), One Strength
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Children (5 to < 12 years) treated according to the One Strength dose escalation scheme

    Subject analysis set title
    Children (5 to < 12 years), Standard
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Children (5 to < 12 years) treated according to the Standard dose escalation scheme

    Subject analysis sets values
    		 Adults (18 to ≤ 65 years), One Strength Adults (18 to ≤ 65 years), Standard Adolescents (12 to < 18 years), One Strength Adolescents (12 to < 18 years), Standard Children (5 to < 12 years), One Strength Children (5 to < 12 years), Standard
    Number of subjects
    47
    40
    25
    26
    31
    31
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    31
    31
        Adolescents (12-17 years)
    0
    0
    25
    26
    0
    0
        Adults (18-64 years)
    47
    40
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    36.2 ( 11.1 )
    37.2 ( 9.4 )
    14.2 ( 1.4 )
    14.2 ( 1.4 )
    8.7 ( 2.0 )
    7.9 ( 1.7 )
    Gender categorical
    Units: Subjects
        Female
    19
    20
    17
    10
    13
    12
        Male
    28
    20
    8
    16
    18
    10

    End points

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    End points reporting groups
    Reporting group title
    One Strength
    Reporting group description
    		 Patients randomized and treated into the One Strength group (accelerated dose escalation) received 3 injections with increasing doses of only strength B of Allergovit Birch (10 000 TU/mL), followed by 2 injections with the maximum recommended dose.

    Reporting group title
    Standard
    Reporting group description
    		 Patients randomized and treated into the Standard group (standard dose escalation) received 7 injections with increasing doses of two strengths of Allergovit Birch (strength A: 1 000 TU/mL; strength B: 10 000 TU/mL), followed by 2 injections of the maximum recommended dose. Note: 98 patients were randomized into the Standard group, but one patient withdraw consent before first treatment.

    Subject analysis set title
    Adults (18 to ≤ 65 years), One Strength
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adults (18 to ≤ 65 years) treated according to the One Strength dose escalation scheme

    Subject analysis set title
    Adults (18 to ≤ 65 years), Standard
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adults (18 to ≤ 65 years) treated according to the Standard dose escalation scheme

    Subject analysis set title
    Adolescents (12 to < 18 years), One Strength
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adolescents (12 to < 18 years) treated according to the One Strength dose escalation scheme

    Subject analysis set title
    Adolescents (12 to < 18 years), Standard
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adolescents (12 to < 18 years) treated according to the Standard dose escalation scheme

    Subject analysis set title
    Children (5 to < 12 years), One Strength
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Children (5 to < 12 years) treated according to the One Strength dose escalation scheme

    Subject analysis set title
    Children (5 to < 12 years), Standard
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Children (5 to < 12 years) treated according to the Standard dose escalation scheme

    Primary: Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Treatment Emergent Adverse Events (TEAEs) [1]
    End point description
    Number, incidence, time of onset, type and intensity of AEs and serious adverse events (SAE). An adverse event (AE) was defined as any untoward medical occurrence in a patient administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an IMP, whether or not related to the IMP. A treatment emergent adverse event (TEAE) was defined as any AE that started or worsened after the first use of trial medication until and including final visit or premature termination visit. Results in the table below summarize the number of patients affected by one or more events events (TEAEs).
    End point type
    Primary
    End point timeframe
    Between first IMP injection and the final visit. Approximately 9 weeks for patients randomized to One Strength (accelerated dose escalation) and approximately 13 weeks for patients randomized to Standard (standard dose escalation).
    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: This was a safety trial with descriptive results evaluation. Descriptive evaluation of group differences. CI for the difference (One Strength - Standard): exact 95%-confidence intervals for the difference in proportions of patients with events (%).
    End point values
    		 One Strength Standard Adults (18 to ≤ 65 years), One Strength Adults (18 to ≤ 65 years), Standard Adolescents (12 to < 18 years), One Strength Adolescents (12 to < 18 years), Standard Children (5 to < 12 years), One Strength Children (5 to < 12 years), Standard
    Number of subjects analysed
    103
    97
    47
    40
    25
    26
    31
    31
    Units: Patients with at least one event of
        TEAEs
    68
    54
    30
    18
    16
    15
    22
    21
        TEAEs related to IMP
    50
    31
    24
    8
    15
    11
    11
    12
        serious TEAEs
    1
    0
    1
    0
    0
    0
    0
    0
        serious TEAEs related to IMP
    0
    0
    0
    0
    0
    0
    0
    0
        TEAEs leading to dose reduction
    13
    4
    10
    2
    1
    0
    2
    3
        TEAEs leading to discontinuation
    3
    2
    2
    1
    1
    0
    0
    0
        Local reactions related to IMP
    47
    31
    22
    8
    14
    11
    11
    12
        Systemic allergic reactions related to IMP
    3
    1
    1
    0
    1
    0
    1
    1
        Other type of events related to IMP
    5
    3
    2
    3
    1
    0
    2
    1
        TEAEs related to IMP with intensity mild
    49
    30
    24
    8
    14
    10
    11
    12
        TEAEs related to IMP with intensity moderate
    8
    3
    5
    2
    2
    1
    1
    1
        TEAEs related to IMP with intensity severe
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Systemic allergic reactions according to the WAO grading system

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    End point title
    		 Systemic allergic reactions according to the WAO grading system [2]
    End point description
    Incidence and intensity of systemic allergic reactions after injections according to the WAO grading system.
    End point type
    Primary
    End point timeframe
    Between first IMP injection and the final visit. Approximately 9 weeks for patients randomized to One Strength (accelerated dose escalation) and approximately 13 weeks for patients randomized to Standard (standard dose escalation).
    Notes
    [2] - 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: This was a safety trial with descriptive results evaluation. Descriptive evaluation of group differences. CI for the difference (One Strength - Standard): exact 95%-confidence intervals for the difference in proportions of patients with events (%).
    End point values
    		 One Strength Standard Adults (18 to ≤ 65 years), One Strength Adults (18 to ≤ 65 years), Standard Adolescents (12 to < 18 years), One Strength Adolescents (12 to < 18 years), Standard Children (5 to < 12 years), One Strength Children (5 to < 12 years), Standard
    Number of subjects analysed
    103
    97
    47
    40
    25
    26
    31
    31
    Units: Systemic TEAEs related to IMP
        Grade 1
    2
    5
    1
    0
    0
    0
    1
    5
        Grade 2
    1
    1
    0
    0
    1
    0
    0
    1
        Grade 3, 4 and 5
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: TEAEs related to IMP - Time to onset

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    End point title
    		 TEAEs related to IMP - Time to onset
    End point description
    Onset of IMP-related TEAEs after IMP injection.
    End point type
    Secondary
    End point timeframe
    Between first IMP injection and the final visit. Approximately 9 weeks for patients randomized to One Strength (accelerated dose escalation) and approximately 13 weeks for patients randomized to Standard (standard dose escalation).
    End point values
    		 One Strength Standard Adults (18 to ≤ 65 years), One Strength Adults (18 to ≤ 65 years), Standard Adolescents (12 to < 18 years), One Strength Adolescents (12 to < 18 years), Standard Children (5 to < 12 years), One Strength Children (5 to < 12 years), Standard
    Number of subjects analysed
    103
    97
    47
    40
    25
    26
    31
    31
    Units: Number of TEAEs related to IMP
        <= 30 min
    15
    12
    5
    1
    2
    1
    8
    10
        > 30 min and <= 2 h
    32
    23
    10
    0
    16
    0
    6
    23
        > 2 h and <= 6 h
    60
    33
    33
    16
    16
    3
    11
    14
        > 6 h and <= 24 h
    91
    85
    57
    19
    21
    26
    13
    40
        > 24 h
    13
    18
    5
    5
    8
    5
    0
    8
    No statistical analyses for this end point

    Secondary: Tolerability assessed by Patient

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    End point title
    		 Tolerability assessed by Patient
    End point description
    Assessment of the overall tolerability using a 5-point Likert scale. Table shows the number of patients in tolerability category (1=Very Bad, 2=Bad, 3= Average, 4=Good, 5=Very good) assessed by the patient.
    End point type
    Secondary
    End point timeframe
    Between first IMP injection and the final visit. Approximately 9 weeks for patients randomized to One Strength (accelerated dose escalation) and approximately 13 weeks for patients randomized to Standard (standard dose escalation).
    End point values
    		 One Strength Standard Adults (18 to ≤ 65 years), One Strength Adults (18 to ≤ 65 years), Standard Adolescents (12 to < 18 years), One Strength Adolescents (12 to < 18 years), Standard Children (5 to < 12 years), One Strength Children (5 to < 12 years), Standard
    Number of subjects analysed
    103
    97
    47
    40
    25
    26
    31
    31
    Units: Number of patients
        Very Bad
    0
    0
    1
    0
    1
    0
    0
    0
        Bad
    0
    1
    1
    0
    0
    0
    0
    0
        Average
    3
    0
    0
    3
    0
    0
    0
    0
        Good
    13
    7
    8
    4
    2
    2
    3
    1
        Very good
    85
    86
    36
    33
    22
    24
    27
    29
    No statistical analyses for this end point

    Secondary: Tolerability assessed by Investigator

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    End point title
    		 Tolerability assessed by Investigator
    End point description
    Assessment of the overall tolerability using a 5-point Likert scale. Table shows the number of patients in tolerability category (1=Very Bad, 2=Bad, 3= Average, 4=Good, 5=Very good) assessed by the investigator.
    End point type
    Secondary
    End point timeframe
    Between first IMP injection and the final visit. Approximately 9 weeks for patients randomized to One Strength (accelerated dose escalation) and approximately 13 weeks for patients randomized to Standard (standard dose escalation).
    End point values
    		 One Strength Standard Adults (18 to ≤ 65 years), One Strength Adults (18 to ≤ 65 years), Standard Adolescents (12 to < 18 years), One Strength Adolescents (12 to < 18 years), Standard Children (5 to < 12 years), One Strength Children (5 to < 12 years), Standard
    Number of subjects analysed
    103
    97
    47
    40
    25
    26
    31
    31
    Units: Number of patients
        Very bad
    0
    0
    0
    0
    0
    0
    0
    0
        Bad
    2
    1
    2
    1
    0
    0
    0
    0
        Average
    2
    1
    1
    1
    1
    0
    0
    0
        Good
    4
    2
    2
    0
    1
    1
    1
    1
        Very good
    93
    90
    42
    36
    22
    25
    29
    29
    No statistical analyses for this end point

    Secondary: Systemic allergic reactions related to IMP - Time to onset

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    End point title
    		 Systemic allergic reactions related to IMP - Time to onset
    End point description
    Onset of IMP-related TEAEs after IMP injection.
    End point type
    Secondary
    End point timeframe
    Between first IMP injection and the final visit. Approximately 9 weeks for patients randomized to One Strength (accelerated dose escalation) and approximately 13 weeks for patients randomized to Standard (standard dose escalation).
    End point values
    		 One Strength Standard
    Number of subjects analysed
    103
    97
    Units: Number of TEAEs related to IMP
        <= 30 min
    0
    1
        > 30 min and <= 2 h
    0
    2
        > 2 h and <= 6 h
    1
    1
        > 6 h and <= 24 h
    1
    2
        > 24 h
    1
    0
    No statistical analyses for this end point

    Other pre-specified: Immunological profile (Treatment-induced change in birch specific IgG4)

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    End point title
    		 Immunological profile (Treatment-induced change in birch specific IgG4)
    End point description
    Changes in the immunological profile of birch-specific IgG4 provides valuable information and evidence for the immunogenic activity of the active preparation. Changes in IgG4 were analyzed as an exploratory parameter. The results (shown as changes from baseline) indicate that for all patients (adults, adolescents and children), during the course of the trial, the median levels of IgG4 specific for Birch pollen (Betula verrucosa) increased notably over time in both treatment groups [p-values < 0.0001 between baseline and final visit, for all age groups].
    End point type
    Other pre-specified
    End point timeframe
    To determine the immunological profile, blood was taken at baseline visit and final visit/premature termination of the study.
    End point values
    		 Adults (18 to ≤ 65 years), One Strength Adults (18 to ≤ 65 years), Standard Adolescents (12 to < 18 years), One Strength Adolescents (12 to < 18 years), Standard Children (5 to < 12 years), One Strength Children (5 to < 12 years), Standard
    Number of subjects analysed
    47
    40
    25
    26
    31
    31
    Units: mg/L
        median (full range (min-max))
    2.490 (-0.32 to 29.35)
    2.460 (-0.15 to 19.26)
    4.075 (0.01 to 24.24)
    3.780 (0.17 to 14.62)
    6.355 (-0.01 to 25.84)
    6.830 (0.37 to 19.10)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The collection of adverse events starts at the day of the patient's signature on the patient informed consent form and is performed until and including the final visit or premature termination visit.
    Adverse event reporting additional description
    Results are shown for the safety set (SAF), which includes all patients treated at least with one dose of IMP. Only TEAES (Treatment-emergent Adverse Events) are shown. PT of Non-serious TEAEs are listed, if at least one age group is above the frequency treshold of 2%.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Adults (18 to ≤ 65 years), One Strength
    Reporting group description
    		 Patients treated according to the One Strength dose escalation scheme (One strength group). Patients in the One Strength group received 3 injections with increasing doses of only strength B of Allergovit Birch (10000 TU/mL), followed by 2 injections with the individual maximum recommended dose.

    Reporting group title
    Adults (18 to ≤ 65 years), Standard
    Reporting group description
    		 Patients treated according to the Standard dose escalation scheme (Standard group). Patients in the Standard group received 7 injections with increasing doses of two strengths of Allergovit Birch (strength A: 1000 TU/mL; strength B: 10000 TU/mL), followed by 2 injections with the maximum recommended dose.

    Reporting group title
    Adolescents (12 to < 18 years), One Strength
    Reporting group description
    		 Patients treated according to the One Strength dose escalation scheme (One strength group). Patients in the One Strength group received 3 injections with increasing doses of only strength B of Allergovit Birch (10000 TU/mL), followed by 2 injections with the individual maximum recommended dose.

    Reporting group title
    Adolescents (12 to < 18 years), Standard
    Reporting group description
    		 Patients treated according to the Standard dose escalation scheme (Standard group). Patients in the Standard group received 7 injections with increasing doses of two strengths of Allergovit Birch (strength A: 1000 TU/mL; strength B: 10000 TU/mL), followed by 2 injections with the maximum recommended dose.

    Reporting group title
    Children (5 to < 12 years), One Strength
    Reporting group description
    		 Patients treated according to the One Strength dose escalation scheme (One strength group). Patients in the One Strength group received 3 injections with increasing doses of only strength B of Allergovit Birch (10000 TU/mL), followed by 2 injections with the individual maximum recommended dose.

    Reporting group title
    Children (5 to < 12 years), Standard
    Reporting group description
    		 Patients treated according to the Standard dose escalation scheme (Standard group). Patients in the Standard group received 7 injections with increasing doses of two strengths of Allergovit Birch (strength A: 1000 TU/mL; strength B: 10000 TU/mL), followed by 2 injections with the maximum recommended dose.

    Serious adverse events
    		 Adults (18 to ≤ 65 years), One Strength Adults (18 to ≤ 65 years), Standard Adolescents (12 to < 18 years), One Strength Adolescents (12 to < 18 years), Standard Children (5 to < 12 years), One Strength Children (5 to < 12 years), Standard
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Immune system disorders
    Food allergy
    Additional description: One patient (1.0%) in the One Strength group experienced one treatment-emergent SAE. The SAE was classified as other type of event and was not related to IMP.
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Adults (18 to ≤ 65 years), One Strength Adults (18 to ≤ 65 years), Standard Adolescents (12 to < 18 years), One Strength Adolescents (12 to < 18 years), Standard Children (5 to < 12 years), One Strength Children (5 to < 12 years), Standard
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 47 (63.83%)
    18 / 40 (45.00%)
    16 / 25 (64.00%)
    15 / 26 (57.69%)
    22 / 31 (70.97%)
    21 / 31 (67.74%)
    Investigations
    Forced expiratory volume decreased
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 40 (2.50%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    3 / 31 (9.68%)
    3 / 31 (9.68%)
         occurrences all number
    1
    1
    0
    0
    6
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 47 (12.77%)
    7 / 40 (17.50%)
    1 / 25 (4.00%)
    5 / 26 (19.23%)
    5 / 31 (16.13%)
    6 / 31 (19.35%)
         occurrences all number
    14
    11
    1
    20
    7
    6
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    8 / 47 (17.02%)
    2 / 40 (5.00%)
    4 / 25 (16.00%)
    0 / 26 (0.00%)
    2 / 31 (6.45%)
    7 / 31 (22.58%)
         occurrences all number
    22
    2
    10
    0
    7
    9
    Injection site oedema
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 40 (2.50%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    5
    2
    0
    1
    1
    2
    Injection site pain
         subjects affected / exposed
    7 / 47 (14.89%)
    1 / 40 (2.50%)
    5 / 25 (20.00%)
    5 / 26 (19.23%)
    3 / 31 (9.68%)
    3 / 31 (9.68%)
         occurrences all number
    10
    1
    6
    5
    3
    8
    Injection site pruritus
         subjects affected / exposed
    11 / 47 (23.40%)
    5 / 40 (12.50%)
    7 / 25 (28.00%)
    5 / 26 (19.23%)
    2 / 31 (6.45%)
    8 / 31 (25.81%)
         occurrences all number
    30
    10
    18
    15
    5
    15
    Injection site urticaria
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 40 (0.00%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    0
    2
    9
    Injection site swelling
         subjects affected / exposed
    17 / 47 (36.17%)
    5 / 40 (12.50%)
    12 / 25 (48.00%)
    5 / 26 (19.23%)
    8 / 31 (25.81%)
    11 / 31 (35.48%)
         occurrences all number
    37
    18
    23
    13
    17
    22
    Pyrexia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    3 / 31 (9.68%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    0
    3
    2
    Fatigue
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 40 (5.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    0
    5
    0
    0
    2
    5
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 40 (2.50%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    1
    4
    Diarrhoea
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    0 / 31 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Abdominal pain
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    2 / 26 (7.69%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    2
    1
    1
    Nausea
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    3
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 40 (0.00%)
    1 / 25 (4.00%)
    1 / 26 (3.85%)
    4 / 31 (12.90%)
    7 / 31 (22.58%)
         occurrences all number
    2
    0
    1
    1
    11
    16
    Oropharyngeal pain
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 40 (2.50%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    2 / 31 (6.45%)
    2 / 31 (6.45%)
         occurrences all number
    1
    1
    0
    1
    2
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 40 (2.50%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
         occurrences all number
    1
    3
    2
    0
    1
    2
    Nasal pruritus
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 40 (2.50%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    2
    2
    0
    0
    1
    3
    Sneezing
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 40 (2.50%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    1
    0
    0
    0
    3
    Pruritus
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 40 (2.50%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    1
    1
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 47 (6.38%)
    7 / 40 (17.50%)
    5 / 25 (20.00%)
    4 / 26 (15.38%)
    2 / 31 (6.45%)
    5 / 31 (16.13%)
         occurrences all number
    6
    8
    5
    7
    2
    14
    Rhinitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 40 (2.50%)
    0 / 25 (0.00%)
    3 / 26 (11.54%)
    2 / 31 (6.45%)
    3 / 31 (9.68%)
         occurrences all number
    0
    1
    0
    3
    2
    6
    Bronchitis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    2 / 31 (6.45%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 40 (0.00%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    2 / 31 (6.45%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    1
    0
    3
    4
    Gastroenteritis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    2
    1
    1
    Pharyngitis
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 40 (2.50%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    1
    0
    1
    1
    Viral infection
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 40 (2.50%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    1
    1
    0
    1
    2
    1
    COVID-19
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 40 (5.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Ear infection
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 40 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    0
    0
    0
    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? 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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