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    Clinical Trial Results:
    A multicentre, randomized, open label clinical trial for safety evaluation of an accelerated high dose escalation schedule with one strength for an allergen immunotherapy with an aluminium hydroxide adsorbed allergoid preparation of 6-Grasses in patients with moderate to severe seasonal rhinitis or rhinoconjunctivitis with or without asthma

    Summary
    EudraCT number
    		 2017-000754-19
    Trial protocol
    		 DE   ES   PL  
    Global end of trial date
    31 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 May 2019
    First version publication date
    03 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AL1602av
    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-Straße 52, Reinbek, Germany, 21465
    Public contact
    Clinical Trials Information, ALLERGOPHARMA GMBH & CO. KG., 0049 40427650,
    Scientific contact
    Clinical Trials Information, ALLERGOPHARMA GMBH & CO. KG., 0049 40427650,
    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
    11 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of an accelerated high dose escalation schedule using one strength allergen immunotherapy with Allergovit® 6-Grasses compared with the standard escalation schedule using two strengths. Adults subjects with rhinitis or rhinoconjunctivitis caused by grass pollen, with or without allergic asthma on a well controlled level were enrolled into the study.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that 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. The DSMB team reviewed an update of the safety data from all treated subjects. After each administration of the IMP, each subject in the study was kept under supervision of a qualified and trained investigator for at least 30 min (in accordance with the country-specific trial protocol: 30 mins in Russia and Spain, 120 min in Germany and Poland). Safety evaluation during supervision after IMP administration consisted of: FEV1, Systolic BP, Diastolic BP, Heart rate, Respiratory rate. Other than routine care, no specific measures were implemented for the protection of trial subjects.
    Background therapy
    		 There was no background therapy planned in this study. 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 should 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 had to be treated as recommended by GINA (GINA, 2017) to control their asthma. However, the in- and exclusion criteria had to be strictly followed. Any asthma medication including medication for seasonal asthma that had been prescribed in the previous season had to be documented as concomitant medication. Restricted medication and nonpermitted medications were clearly defined in the study protocol.
    Evidence for comparator
    		 There was no comparator used in this study. Abbreviations used in this document: AE=Adverse event AIT=Allergen immunotherapy BMI=Body mass index BP=Blood pressure bpm=Beats per minute ICF=Informed consent form DSMB=Data Safety Monitoring Board FEV1=Forced expiratory volume in 1 second ICF=Informed consent form IgG=Immunoglobulin G IMP=Investigational medicinal product MedDRA=Medical Dictionary for Regulatory Activities P. pratense=Phleum pratense T=Treatment (as in T1 =Treatment visit 1, etc.) TEAE=Treatment-emergent adverse event TU=Therapeutic units WAO=World Allergy Organization
    Actual start date of recruitment
    04 Oct 2017
    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: 19
    Country: Number of subjects enrolled
    Poland: 49
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Spain: 6
    Worldwide total number of subjects
    87
    EEA total number of subjects
    74
    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)
    0
    Adults (18-64 years)
    86
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 129 adult male and female subjects (18-65 y) were screened for eligibility; of these, 87 were randomised to treatment, according to the exclusion and inclusion criteria. One subject discontinued the study this subject prior to any IMP administration, due to 'flue-like' symptoms.

    Pre-assignment
    Screening details
    		 Study subjects (outpatients) were included if they were suffering from immunoglobulin (Ig) E mediated seasonal allergic rhinitis or rhinoconjunctivitis, with or without allergic asthma, caused by grass pollen documented by skin prick test (SPT) wheal for grass pollen.

    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
    		 One Strength
    Arm description
    		 Patients randomised to the 'One Strength' dose scheme received 3 injections with one strength of the IMP (B: 10 000 therapeutic units [TU]/mL), followed by 2 injections with the maximum recommended dose. The duration of treatment was approximately 9 weeks. One subject in the 'One Strength' dose scheme discontinued the study due to 'flue-like' symptoms; this subject did not receive any IMP and was excluded from the overall analysis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Allergovit® 6-grasses
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The IMP is an aluminium hydroxide-adsorbed allergoid preparation of 6-Grasses (Allergovit® 6-grasses). IMP was available in two concentrations (A: 1,000 TU/mL; B: 10,000 TU/mL). IMP was administered subcutaneously in the upper arm as increasing doses at 7-day intervals with 3 injections in the group 'accelerated dose escalation'. IMP strength B (10,000 TU/mL) was used. Dose escalation schedule once every 7 days: 1000, 3000, 6000 TU Maintenance 2 weeks after last dose: 6000 TU, then 4 weeks after last dose 6000 TU Patients had to demonstrate an FEV1 of at least 70% of predicted normal ranges before injection, otherwise no injection was to be given and the visit was rescheduled. If the FEV1 decreased after injection compared with the value measured before injection, the investigator checked whether an AE occurred that needed documentation and medical treatment. In this group, 80% of subjects reached the 1st IMP injection of the maintenace phase without dose adjustment.

    Arm title
    		 Standard
    Arm description
    		 Patient randomized to standard dose escalation scheme ('Standard') received 7 injections with two strengths of the IMP (A: 1000 TU/mL; B: 10 000 TU/mL), followed by 2 injections with the maximum recommended dose. The duration of treatment was approximately 13 weeks. Two subject ranomized to the 'Standard' dose scheme, due to allocation error actually received the IMP of the 'One Strength' scheme. Thus, data and results of these two subjects were part of the 'One Strength' scheme analyses.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Allergovit® 6-grasses
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The IMP is an aluminium hydroxide-adsorbed allergoid preparation of 6-Grasses (Allergovit® 6-grasses). IMP was available as (A: 1,000 TU/mL; B: 10,000 TU/mL). IMP was administered subcutaneously in the upper arm as gradually increasing doses at 7-day intervals with 7 injections in the group 'standard dose escalation'. IMP strengths A and B were used. Dose escalation schedule every 7 days: 100, 200, 400, 800, 1500, 3000, 6000 TU Maintenance 2 weeks after last dose: 6000 TU, then 4 weeks after last dose 6000 TU Patients had to demonstrate an FEV1 of at least 70% of predicted normal ranges before injection, otherwise no injection was to be given and the visit was rescheduled. If the FEV1 decreased after injection compared with the value measured before injection, the investigator checked whether an AE occurred that needed documentation and medical treatment. In this group, 95% of subjects reached the 1st IMP injection of the maintenance phase without dose adjustment.

    Number of subjects in period 1
    		One Strength Standard
    Started
    46
    41
    Completed
    38
    39
    Not completed
    8
    2
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    3
    -
         Flue-like symptoms, before any IMP administration
    1
    -
         Treatment allocation error
    2
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    One Strength
    Reporting group description
    		 Patients randomised to the 'One Strength' dose scheme received 3 injections with one strength of the IMP (B: 10 000 therapeutic units [TU]/mL), followed by 2 injections with the maximum recommended dose. The duration of treatment was approximately 9 weeks. One subject in the 'One Strength' dose scheme discontinued the study due to 'flue-like' symptoms; this subject did not receive any IMP and was excluded from the overall analysis.

    Reporting group title
    Standard
    Reporting group description
    		 Patient randomized to standard dose escalation scheme ('Standard') received 7 injections with two strengths of the IMP (A: 1000 TU/mL; B: 10 000 TU/mL), followed by 2 injections with the maximum recommended dose. The duration of treatment was approximately 13 weeks. Two subject ranomized to the 'Standard' dose scheme, due to allocation error actually received the IMP of the 'One Strength' scheme. Thus, data and results of these two subjects were part of the 'One Strength' scheme analyses.

    Reporting group values
    		 One Strength Standard Total
    Number of subjects
    		 46 41 87
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 46 40 86
        From 65-84 years
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.98 ± 9.48 36.05 ± 12.21 -
    Gender categorical
    Units: Subjects
        Female
    		 19 20 39
        Male
    		 27 21 48
    Smoking status
    Units: Subjects
        Never
    		 37 31 68
        Ex-smoker
    		 6 4 10
        Current smoker
    		 3 6 9
    Ethnicity
    Units: Subjects
        American Indian or Alaskan Native
    		 1 0 1
        Asian
    		 0 1 1
        White
    		 45 40 85
    BMI
    Units: kg/m2
        median (full range (min-max))
    		 24.74 (18.73 to 35.92) 23.89 (17.93 to 43.52) -

    End points

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    End points reporting groups
    Reporting group title
    One Strength
    Reporting group description
    		 Patients randomised to the 'One Strength' dose scheme received 3 injections with one strength of the IMP (B: 10 000 therapeutic units [TU]/mL), followed by 2 injections with the maximum recommended dose. The duration of treatment was approximately 9 weeks. One subject in the 'One Strength' dose scheme discontinued the study due to 'flue-like' symptoms; this subject did not receive any IMP and was excluded from the overall analysis.

    Reporting group title
    Standard
    Reporting group description
    		 Patient randomized to standard dose escalation scheme ('Standard') received 7 injections with two strengths of the IMP (A: 1000 TU/mL; B: 10 000 TU/mL), followed by 2 injections with the maximum recommended dose. The duration of treatment was approximately 13 weeks. Two subject ranomized to the 'Standard' dose scheme, due to allocation error actually received the IMP of the 'One Strength' scheme. Thus, data and results of these two subjects were part of the 'One Strength' scheme analyses.

    Primary: 1_Treatment-emergent adverse events - Overall

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    End point title
    		 1_Treatment-emergent adverse events - Overall [1]
    End point description
    TEAE was defined as any untoward medical occurrence in a patient or clinical investigation subject who received the IMP. The TEAEs did not necessarily have to have a causal relationship with this treatment. A TEAE 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. Results in the table below summarize the number of subjects affected by a TEAE; the number of the respective events is also shown. The TEAEs (as System Organ Class and as Preferred Term) are listed under the section 'Adverse events'.
    End point type
    Primary
    End point timeframe
    Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.
    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-focused trial. No statistical analysis was performed. Results were evaluated descriptively.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    45 [2]
    41 [3]
    Units: subjects
        1_Subjects with TEAE
    37
    35
        2_Subjects with serious TEAE
    1
    0
        3_Subjects with TEAEs related to IMP
    27
    20
        4_Subjects with TEAE leading to discontinuation
    2
    0
    Notes
    [2] - Safety set 1_TEAEs N=200 2_TEAEs N=2 3_TEAEs N=129 4_TEAEs N=2
    [3] - Safety set 1_TEAEs N=244 2_TEAEs N=0 3_TEAEs N=132 4_TEAEs N=0
    No statistical analyses for this end point

    Primary: 2_Treatment-emergent adverse events - Maximum intensity

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    End point title
    		 2_Treatment-emergent adverse events - Maximum intensity [4]
    End point description
    A treatment emergent adverse event (TEAE) was defined as any AE that started or worsened after the first intake of trial medication until 30 days after the last IMP administration or trial related procedure. The intensity of the TEAE was assessed by the the investigator. Mild=Transient symptoms, no interference with the patient’s daily activities. Moderate=Marked symptoms, moderate interference with the patient’s daily activities. Severe=Considerable interference with the patient’s daily activities.
    End point type
    Primary
    End point timeframe
    Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.
    Notes
    [4] - 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-focused trial. No statistical analysis was performed. Results were evaluated descriptively.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    45 [5]
    41
    Units: subjects
        Mild
    22
    24
        Moderate
    13
    11
        Severe
    2
    0
    Notes
    [5] - Safety set was used for the analyses of both treatment groups
    No statistical analyses for this end point

    Primary: 3_Treatment-emergent adverse events - Causal relationship

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    End point title
    		 3_Treatment-emergent adverse events - Causal relationship [6]
    End point description
    TEAEs, assessed as related to IMP. Relatedness of TEAEs to the IMP was assessed by the the investigator. Most of the related TEAEs were mild in intensity (85% in the accelerated escalation dose and 91% in the standard escalation dose group). The TEAEs included Injection site swelling, Injection site erythema, Injection site pruritus, Injection site pain, Injection site warmth, Injection site haemorrhage, FEV1 decrease, and Headache and are listed under the section 'Adverse events'. Results in the table below summarize the number of subjects affected by an TEAEs or serious TEAEs related to IMP; the number of the respective events is also shown.
    End point type
    Primary
    End point timeframe
    Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.
    Notes
    [6] - 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-focused trial. No statistical analysis was performed. Results were evaluated descriptively.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    45 [7]
    41 [8]
    Units: subjects
        Subjects with adverse events
    27
    20
        Subjects with serious adverse events
    1
    0
    Notes
    [7] - Safety set was used for the analyses of both treatment groups Number of events AE=127 SAE=2
    [8] - Number of events AE=132 SAE=0
    No statistical analyses for this end point

    Secondary: 5_Treatment-emergent adverse event - Systemic allergic reactions according to WAO

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    End point title
    		 5_Treatment-emergent adverse event - Systemic allergic reactions according to WAO
    End point description
    A systemic allergic reaction was defined as an AE graded by the investigator according to the WAO grading system that is based on the organ systems involved and the severity of the reaction (Cox et al 2010)*. Dose reductions for systemic reactions acc. to WAO : • Grade 1: reduction by 1 dose step of the last applied dose. • Grade 2: reduction by 2 dose steps of the last applied dose. For WAO Grade 1 and WAO Grade 2: if the 1st dose reduction was not tolerated, a 2nd dose reduction by 1 dose step of the last applied dose was administered. The systemic allergic reaction AEs were: Tachycardia, Eye pruritus, Malaise, Rhinitis, FEV1 decreased, Restlessness, Asthma, Dyspnoea, Rhinorrhoea, Throat tightness, Erythema. All systemic allergic reactions were assessed by the investigator as non-serious *Cox L, Speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol 2010; 125(3): 569-57
    End point type
    Secondary
    End point timeframe
    Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    45 [9]
    41
    Units: subjects
        Grade 1
    2
    1
        Grade 2
    3
    0
    Notes
    [9] - Safety set was used for the analyses of both treatment groups
    No statistical analyses for this end point

    Secondary: 6_Number of subjects reaching the maintenance dose without dose adjustment due to TEAE

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    End point title
    		 6_Number of subjects reaching the maintenance dose without dose adjustment due to TEAE
    End point description
    Number of patients reaching the maintenance dose without dose adjustment due to treatment-emergent adverse event. In the 'accelerated dose escalation' group, 5 patients did not reach the maintenance phase without dose adjustment due to a TEAE: 3 had TEAEs leading to dose reduction and 2 patients terminated the trial prematurely due to TEAEs.
    End point type
    Secondary
    End point timeframe
    Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    45 [10]
    41
    Units: subjects
    40
    39
    Notes
    [10] - Safety set was used for the analyses of both treatment groups
    No statistical analyses for this end point

    Secondary: 7_Vital signs - Heart rate

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    End point title
    		 7_Vital signs - Heart rate
    End point description
    Clinical chemistry, vital signs, and physical examination are summarized by a representative parameter 'Heart rate'. Results are shown as the change (at 30 min) from pre-IMP administration on the first (T1), last (T3/T7) escalation dose visit and the last maintenance (M2) visit. Vital signs measured: Arterial BP, diastolic BP, heart rate, respiratory rate Laboratory parameters measured (at the screening visit and Final visit): • Clinical chemistry: creatinine, total bilirubin, aspartate, liver enzymes aminotransferase, alanine aminotransferase, gamma-glutamyltransferase • Blood sugar: Glucose (fasting or non-fasting; status assessed for decision on in-/exclusion of patient) • Hematology: differential blood cell count, hemoglobin, leukocytes, platelets • Urinalysis: protein, glucose, blood (hemoglobin), leukocytes, beta-human chorionic gonadotropin (women of childbearing potential). There were no clinical relevant differences noted between the treatment groups.
    End point type
    Secondary
    End point timeframe
    At IMP treatment visits (escalation and maintenance dose phase): before and after 30, 60, 120 min administration of IMP.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    45 [11]
    41 [12]
    Units: bpm
    median (full range (min-max))
        T1 visit 30 min after
    -2 (-19 to 12)
    0 (-21 to 12)
        T3/T7 visit after
    -2 (-28 to 21)
    -2 (-20 to 9)
        M2 visit 30 min after
    -4 (-23 to 38)
    -3 (-22 to 9)
    Notes
    [11] - Safety set Patients contributing data T1 aft N=45 T3 aft N=38 M2 aft N=38
    [12] - Safety set Patients contributing data T1 aft N=41 T7 aft N=41 M2 aft N=39
    No statistical analyses for this end point

    Secondary: 8_Lung function test - FEV1

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    End point title
    		 8_Lung function test - FEV1
    End point description
    Subjects had to demonstrate FEV1 of at least 70% of predicted normal ranges before injection, otherwise no injection was to be given and the visit was rescheduled. If the FEV1 decreased after injection compared to the value measured before injection, the investigator checked if an AE had to be documented and adequate medical treatment initiated. An FEV1 decrease of ≥ 20% after injection as compared to the value measured before injection, was documented as an AE. Results shown are representative for the study visits at the start (screening), at the end of the escalation dose (T3/T7), at the end of the maintenance dose (M2), and at the final visit (30 days after the last IMP injection). At all time points, the mean and median results for FEV1 were similar. There were no trends or systematic differences in changes of FEV1 from baseline during the trial between or within the treatment groups. The number of patients contributing to the data at each visits is also shown.
    End point type
    Secondary
    End point timeframe
    30 min bfr, 30, 60, 120 min aftr each treatment (T) Accelerated dose escalat: 3 visits, separtd by 7 d Standard dose escalat: 7 visits, separtd by 7 d Maintenance dose: 2 visits separated by 2 wk; 2 wk after escalat Final visit: 30 d after last IMP
    End point values
    		 One Strength Standard
    Number of subjects analysed
    45 [13]
    41 [14]
    Units: % predicted
    arithmetic mean (standard deviation)
        Screening
    102.9 ± 12.53
    100.2 ± 11.90
        T3/T7 before
    103.8 ± 14.44
    98.6 ± 12.54
        T3/T7 30 min after
    101.8 ± 15.84
    98.9 ± 13.58
        M2 before
    103.7 ± 13.38
    100.5 ± 15.57
        M2 30 min after
    103.4 ± 13.37
    102.0 ± 21.53
        Final visit
    102.3 ± 13.79
    96.6 ± 12.23
    Notes
    [13] - Safety set Scrng=45 T3 bfr=38 T3 aft=37 M2 bfr=38 M2 aft=38 Final=42
    [14] - Safety set Scrng=41 T7 bfr=41 T7 aft=40 M2 bfr=39 M2 aft=39 Final=40
    No statistical analyses for this end point

    Secondary: 9_Tolerability: Likert scale after escalation dose phase (Investigator)

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    End point title
    		 9_Tolerability: Likert scale after escalation dose phase (Investigator)
    End point description
    Assessment of the overall tolerability by the investigator using a 5-point Likert scale. Likert scale score system: 1=Very bad; 2=Bad; 3=Average; 4=Good; 5=Very good. Table below shows the number of subjects in each tolerability category of the Likert scale, as assessed by the investigator.
    End point type
    Secondary
    End point timeframe
    After the last IMP administration during the escalation dose phase (T3/T7 visit) and at the Final visit.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    38 [15]
    38
    Units: score
        Missing (T3/T7 visit)
    7
    3
        Very Bad (T3/T7 visit)
    0
    0
        Bad (T3/T7 visit)
    0
    0
        Average (T3/T7 visit)
    4
    0
        Good (T3/T7 visit)
    11
    9
        Very Good (T3/T7 visit)
    23
    29
    Notes
    [15] - Safety set was used for the analyses of both treatment groups
    No statistical analyses for this end point

    Secondary: 9a_Tolerability: Likert scale Final visit (Investigator)

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    End point title
    		 9a_Tolerability: Likert scale Final visit (Investigator)
    End point description
    Assessment of the overall tolerability by the investigator using a 5-point Likert scale. Likert scale score system: 1=Very bad; 2=Bad; 3=Average; 4=Good; 5=Very good. Table below shows the number of subjects in each tolerability category of the Likert scale, as assessed by the investigator.
    End point type
    Secondary
    End point timeframe
    After the last IMP administration during the escalation dose phase and at the Final visit.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    45 [16]
    40
    Units: score
        Missing (Final visit)
    0
    1
        Very Bad (Final visit)
    1
    0
        Bad (Final visit)
    2
    0
        Average (Final visit)
    3
    0
        Good (Final visit)
    11
    8
        Very Good (Final visit)
    28
    32
    Notes
    [16] - Safety set was used for the analyses of both treatment groups
    No statistical analyses for this end point

    Secondary: 10_Tolerability: Likert scale after escalation dose phase (Subject)

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    End point title
    		 10_Tolerability: Likert scale after escalation dose phase (Subject)
    End point description
    Assessment of the overall tolerability by the investigator using a 5-point Likert scale. Likert scale score system: 1=Very bad; 2=Bad; 3=Average; 4=Good; 5=Very good. Table below shows the number of subjects in each tolerability category of the Likert scale, as assessed by the subject.
    End point type
    Secondary
    End point timeframe
    After the last IMP administration during the escalation dose phase (T3/T7 visit) and at the Final visit.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    38 [17]
    38
    Units: score
        Missing (T3/T7 visit)
    7
    3
        Very Bad (T3/T7 visit)
    0
    0
        Bad (T3/T7 visit)
    0
    0
        Average (T3/T7 visit)
    3
    1
        Good (T3/T7 visit)
    17
    14
        Very Good (T3/T7 visit)
    18
    23
    Notes
    [17] - Safety set was used for the analyses of both treatment groups
    No statistical analyses for this end point

    Secondary: 10a_Tolerability: Likert scale Final visit (Subject)

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    End point title
    		 10a_Tolerability: Likert scale Final visit (Subject)
    End point description
    Assessment of the overall tolerability by the investigator using a 5-point Likert scale. Likert scale score system: 1=Very bad; 2=Bad; 3=Average; 4=Good; 5=Very good. Table below shows the number of subjects in each tolerability category of the Likert scale, as assessed by the subject.
    End point type
    Secondary
    End point timeframe
    After the last IMP administration during the escalation dose phase (T3/T7 visit) and at the Final visit.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    45 [18]
    40
    Units: score
        Missing (Final visit)
    0
    1
        Very Bad (Final visit)
    0
    0
        Bad (Final visit)
    3
    0
        Average (Final visit)
    3
    1
        Good (Final visit)
    15
    15
        Very Good (Final visit)
    24
    24
    Notes
    [18] - Safety set was used for the analyses of both treatment groups
    No statistical analyses for this end point

    Other pre-specified: 11_Immunologic parameter (IgG4 specific against grass-pollen from P. pratense)

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    End point title
    		 11_Immunologic parameter (IgG4 specific against grass-pollen from P. pratense)
    End point description
    According to the study inclusion criteria, all patients had IgE-mediated seasonal allergic rhinitis or rhinoconjunctivitis with or without allergic asthma, caused by grass pollen. Changes in grass-pollen-specific IgG4 antibody concentrations provide valuable information and evidence for the immunogenic activity of the active preparations. Changes in IgG4 were analyzed as an exploratory parameter. In particular, the results indicate that the mean change from baseline to the final visit in IgG4 against the pollen from P. pratense (Timothy-grass) was similar between the treatment groups and is summarized in the table below.
    End point type
    Other pre-specified
    End point timeframe
    To determine the immunologic parameters, blood was taken at screening (baseline) and the final visit/premature termination of the study.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    42 [19]
    40
    Units: mg/l
        arithmetic mean (full range (min-max))
    5.229 (-0.45 to 28.88)
    5.311 (0.00 to 28.81)
    Notes
    [19] - Safety set was used for the analyses of both treatment groups
    No statistical analyses for this end point

    Post-hoc: 4_Treatment-emergent adverse events related to IMP - Time to onset

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    End point title
    		 4_Treatment-emergent adverse events related to IMP - Time to onset
    End point description
    End point type
    Post-hoc
    End point timeframe
    Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.
    End point values
    		 One Strength Standard
    Number of subjects analysed
    45 [20]
    41 [21]
    Units: TEAEs related to IMP
        ≤ 30 min
    23
    22
        > 30 min, ≤ 6 h
    56
    50
        > 6 h, ≤ 24 h
    36
    46
        > 24 h
    14
    14
    Notes
    [20] - Safety set TEAE related to IMP N=129
    [21] - Safety set TEAE related to IMP N=132
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.
    Adverse event reporting additional description
    Results are shown for the Safety set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    One Strength
    Reporting group description
    		 Patients randomised to the 'accelerated dose escalation scheme' received 3 injections with one strength (B: 10 000 therapeutic units [TU]/mL), followed by 2 injections with the maximum recommended dose. Duration of treatment was approximately 9 weeks.

    Reporting group title
    Standard
    Reporting group description
    		 Patient randomized to 'standard dose escalation' ( Standard) received 7 injections with two strengths (A: 1000 TU/mL; B: 10 000 TU/mL), followed by 2 injections with the maximum recommended dose. Duration of treatment was approximately 13 weeks.

    Serious adverse events
    		 One Strength Standard
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 41 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site swelling
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 One Strength Standard
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 45 (82.22%)
    35 / 41 (85.37%)
    Investigations
    Forced expiratory volume decreased
         subjects affected / exposed
    2 / 45 (4.44%)
    6 / 41 (14.63%)
         occurrences all number
    3
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 45 (20.00%)
    10 / 41 (24.39%)
         occurrences all number
    15
    20
    General disorders and administration site conditions
    Injection site swelling
         subjects affected / exposed
    21 / 45 (46.67%)
    14 / 41 (34.15%)
         occurrences all number
    49
    38
    Injection site erythema
         subjects affected / exposed
    13 / 45 (28.89%)
    15 / 41 (36.59%)
         occurrences all number
    28
    51
    Injection site pruritus
         subjects affected / exposed
    14 / 45 (31.11%)
    7 / 41 (17.07%)
         occurrences all number
    24
    26
    Injection site pain
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 41 (7.32%)
         occurrences all number
    2
    7
    Injection site warmth
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 41 (0.00%)
         occurrences all number
    5
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 41 (7.32%)
         occurrences all number
    2
    6
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    6 / 45 (13.33%)
    9 / 41 (21.95%)
         occurrences all number
    9
    14
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 41 (7.32%)
         occurrences all number
    3
    3

    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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