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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 pediatric patients with moderate to severe seasonal rhinitis or rhinoconjunctivitis with or without asthma

    Summary
    EudraCT number
    		 2018-000548-25
    Trial protocol
    		 DE   ES   PL  
    Global end of trial date
    25 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jan 2020
    First version publication date
    01 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AL1605av
    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, +49 40427650,
    Scientific contact
    Clinical Trials Information, Allergopharma GmbH & Co. KG, +49 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
    28 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this therapeutic phase II trial was to evaluate the safety and tolerability of an accelerated high dose escalation schedule with one strength for allergen immunotherapy with Allergovit® 6-Grasses compared to the standard escalation schedule with two strengths. Children and adolescents with rhinitis or rhinoconjunctivitis caused by grass pollen, with or without allergic asthma on a well controlled level, will be enrolled. The trial consisted of a dose escalation phase (T1 to T3) for the accelerated dose escalation (One Strength) or (T1 to T7) for the standard dose escalation (Standard). Maintenance treatment phase T4-T5 (One Strength) and T8-T9 (Standard), and a follow-up phase of 30 days after the last IMP (final visit [FV]). The whole treatment duration (escalation phase + maintenance phase) lasted for approx. 9 weeks and 13 weeks, respectively, for the two treatment groups. Data are presented as subgroups: children and adolescents per treatment group.
    Protection of trial subjects
    The study 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. 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 min 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 (Pulse 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 to the study 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, 2017) to control their asthma. 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 kU/L=kilo Units per Litre IMP=Investigational medicinal product IS=Injection site MedDRA=Medical Dictionary for Regulatory Activities P. pratense=Phleum pratense RBC=Red blood cells T=Treatment (as in T1 =Treatment visit 1, etc.) TEAE=Treatment-emergent adverse event TU=Therapeutic units WAO=World Allergy Organization y=year
    Actual start date of recruitment
    02 Oct 2018
    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
    Russian Federation: 5
    Country: Number of subjects enrolled
    Poland: 68
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Germany: 10
    Worldwide total number of subjects
    87
    EEA total number of subjects
    82
    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)
    50
    Adolescents (12-17 years)
    37
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 115 adult male and female subjects (5 to <18 y) were screened for eligibility; of these, 87 were randomised to treatment according to the exclusion and inclusion criteria.

    Pre-assignment
    Screening details
    		 Study subjects (outpatients) were included if they were suffering from immunoglobulin (Ig) E-mediated seasonal moderate to severe allergic rhinitis or rhinoconjunctivitis, with or without allergic asthma, caused by grass pollen documented by skin prick test (SPT) wheal for grass pollen and specific IgE value of ≥ 0.70 kU/L to grass pollen.

    Period 1
    Period 1 title
    Treatment (Overall trial) (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. Duration of the treatment was approximately 9 weeks.
    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
    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 at 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: (1,000; 3,000; 6,000 TU) Maintenance 2 weeks after last dose: 6,000 TU, then 4 weeks after last dose: 6,000 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, 88.9% of subjects reached the 1st IMP injection of the maintenance phase without dose adjustment.

    Arm title
    		 Standard
    Arm description
    		 Patients randomized to standard dose escalation scheme ('Standard') received 7 injections with two strengths of the IMP (A: 1,000 TU/mL; B: 10,000 TU/mL), followed by 2 injections with the maximum recommended dose. Duration of the treatment was approximately 13 weeks.
    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
    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'. 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, 85.7% of subjects reached the 1st IMP injection of the maintenance phase without dose adjustment.

    Number of subjects in period 1
    		One Strength Standard
    Started
    45
    42
    Completed
    43
    39
    Not completed
    2
    3
         Adverse event, non-fatal
    2
    3

    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. Duration of the treatment was approximately 9 weeks.

    Reporting group title
    Standard
    Reporting group description
    		 Patients randomized to standard dose escalation scheme ('Standard') received 7 injections with two strengths of the IMP (A: 1,000 TU/mL; B: 10,000 TU/mL), followed by 2 injections with the maximum recommended dose. Duration of the treatment was approximately 13 weeks.

    Reporting group values
    		 One Strength Standard Total
    Number of subjects
    		 45 42 87
    Age categorical
    Units: Subjects
        Children (5 to <12 y)
    		 25 25 50
        Adolescents (12 to <18 y)
    		 20 17 37
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.1 ( 2.99 ) 11.2 ( 3.20 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 16 32
        Male
    		 29 26 55
    Race
    Units: Subjects
        White
    		 45 42 87
    Subject analysis sets

    Subject analysis set title
    Children (5 to <12 y) One Strength
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Children (5 to <12 y), randomised to One Strength treatment group.

    Subject analysis set title
    Children (5 to <12 y) Standard
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Children (5 to <12 y), randomised to the Standard treatment group.

    Subject analysis set title
    Adolescents (12 to <18 y) One Strength
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adolescents (12 to <18 y), randomised to the One Strength treatment group.

    Subject analysis set title
    Adolescents (12 to <18 y) Standard
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adolescents (12 to <18 y), randomised to the Standard treatment group.

    Subject analysis sets values
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects
    25
    25
    20
    17
    Age categorical
    Units: Subjects
        Children (5 to <12 y)
        Adolescents (12 to <18 y)
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.9 ( 1.76 )
    8.9 ( 1.32 )
    13.9 ( 1.41 )
    14.6 ( 1.80 )
    Gender categorical
    Units: Subjects
        Female
    10
    8
    6
    8
        Male
    15
    17
    14
    9
    Race
    Units: Subjects
        White
    25
    25
    20
    17

    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. Duration of the treatment was approximately 9 weeks.

    Reporting group title
    Standard
    Reporting group description
    		 Patients randomized to standard dose escalation scheme ('Standard') received 7 injections with two strengths of the IMP (A: 1,000 TU/mL; B: 10,000 TU/mL), followed by 2 injections with the maximum recommended dose. Duration of the treatment was approximately 13 weeks.

    Subject analysis set title
    Children (5 to <12 y) One Strength
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Children (5 to <12 y), randomised to One Strength treatment group.

    Subject analysis set title
    Children (5 to <12 y) Standard
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Children (5 to <12 y), randomised to the Standard treatment group.

    Subject analysis set title
    Adolescents (12 to <18 y) One Strength
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adolescents (12 to <18 y), randomised to the One Strength treatment group.

    Subject analysis set title
    Adolescents (12 to <18 y) Standard
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Adolescents (12 to <18 y), randomised to the Standard treatment group.

    Primary: 1_Treatment-emergent adverse events - Overall

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    End point title
    		 1_Treatment-emergent adverse events - Overall [1]
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation subject 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 intake of trial medication until 30 days after the last IMP administration or trial-related procedure. Results in the table below summarize the number of subjects affected by a TEAE; the number of the respective events (n) 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. Approx. 9 weeks for patients in One Strength and approx. 13 weeks for patients in Standard treatment group.
    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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [2]
    25 [3]
    20 [4]
    17 [5]
    Units: subjects
        1_Subjects with TEAE
    18
    16
    9
    8
        2_Subjects with serious TEAE
    0
    0
    1
    1
        3_Subjects with TEAEs related to IMP
    13
    10
    7
    6
        4_Subjects with TEAE leading to discontinuation
    1
    1
    1
    0
    Notes
    [2] - Safety analysis set was used for all treatment groups 1_n=59 2_n=0 3_n=21 4_n=3
    [3] - 1_n=58 2_n=0 3_n=27 4_n=1
    [4] - 1_n=55 2_n=1 3_n=39 4_n=1
    [5] - 1_n=43 2_n=5 3_n=32 4_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 [6]
    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
    [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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [7]
    25
    20
    17
    Units: subjects
        Mild
    13
    12
    5
    5
        Moderate
    5
    4
    4
    3
        Severe
    0
    0
    0
    0
    Notes
    [7] - Safety analysis set was used for all treatment groups
    No statistical analyses for this end point

    Primary: 3_Treatment-emergent adverse events - Causal relationship (IMP-related)

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    End point title
    		 3_Treatment-emergent adverse events - Causal relationship (IMP-related) [8]
    End point description
    TEAEs -- causal relationship to IMP. Results in the table below show the number of subjects with at least one TEAE related to IMP, as assessed by the investigator. The number of the respective events (n) is also shown. The actual number of TEAEs are listed under the section 'Adverse events'. Most of the related TEAEs were mild in intensity in both treatment groups (>85% children and >69% adolescent). The related TEAEs included: Injection site swelling, Injection site erythema, Injection site pruritus, Injection site pain, Injection site discomfort, Injection site oedema, FEV1 decreased, Pain in extremity, Headache, Dermatitis allergic, Somnolence, Conjunctival oedema, Rhinitis, Swelling, Cough, Rhinitis allergic, Sneezing, Urticaria, Pruritus.
    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
    [8] - 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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [9]
    25 [10]
    20 [11]
    17 [12]
    Units: subjects
        1_Subjects with TEAEs related to IMP
    13
    10
    7
    6
        2_Subjects with serious TEAEs related to IMP
    0
    0
    1
    1
    Notes
    [9] - Safety analysis set was used for all treatment groups 1_n=21 2_n=0
    [10] - 1_n=27 2_n=0
    [11] - 1_n=39 2_n=1
    [12] - 1_n=32 2_n=5
    No statistical analyses for this end point

    Secondary: 4_Treatment-emergent adverse event - Systemic allergic reactions according to the WAO

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    End point title
    		 4_Treatment-emergent adverse event - Systemic allergic reactions according to the WAO
    End point description
    Systemic allergic reaction: TEAE graded by the investigator according to the WAO grading system, which is based on the organ systems involved and the severity of the reaction. 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. All systemic allergic reactions were assessed by the investigator as IMP-related. All systemic allergic reactions had a WAO grade of 1; for children, all were non-serious; for adolescents all were serious. Children: FEV1 decreased, Dermatitis allergic; Adolescents: Urticaria, Conjunctival oedema, Cough, Pruritus, Rhinitis;
    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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25
    25
    20
    17
    Units: Sytemic TEAEs related to IMP
        Grade 1
    2
    0
    1
    1
    No statistical analyses for this end point

    Secondary: 5_Treatment-emergent adverse event - Local reactions at the injection site

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    End point title
    		 5_Treatment-emergent adverse event - Local reactions at the injection site
    End point description
    Treatment-emergent adverse event - Local reactions at the injection site Results in the table below summarize the number of subjects affected by TEAEs 'local reactions at the injection site' (IS), that were assessed by the investigators as related to the IMP. The number of the respective events (n) is also shown. The TEAEs 'local reactions at the injection site' were: Children: IS erythema, IS oedema, IS pain, IS pruritus, IS swelling; Adolescents: IS discomfort, IS erythema, IS pain, IS pruritus, IS swelling;
    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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [13]
    25 [14]
    20 [15]
    17 [16]
    Units: subjects
    10
    10
    6
    5
    Notes
    [13] - Safety analysis set was used for all treatment groups n=16
    [14] - n=27
    [15] - n=36
    [16] - n=25
    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 TEAE.
    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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [17]
    25
    20
    17
    Units: subjects
    23
    21
    17
    15
    Notes
    [17] - Safety analysis set was used for all treatment groups
    No statistical analyses for this end point

    Secondary: 7_Vital signs - Heart rate (Pulse rate)

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    End point title
    		 7_Vital signs - Heart rate (Pulse rate)
    End point description
    Vital signs (BP, heart rate, resp. rate) were assessed at: screening, during treatment visits / any unscheduled visit, and at the final visit. Vital signs are summarized by a representative parameter Heart rate (Pulse rate). Results are shown as the change from pre- to 30 min post administration of IMP on the first- (T1), last escalation dose visit (T3/T7), and last maintenance visit (T5/T9). Laboratory parameters measured (at the Screening and Final visit): • Clin. chem: creatinine, total bilirubin, asp. aminotransferase, ala. aminotransferase, gamma-glutamyltransferase • Blood sugar: Glucose (fasting or non-fasting; status assessed for decision on in-/exclusion of patient) • Hematol: differential blood cell count, hemoglobin (RBC), leukocytes, platelets • Urinalysis: protein, glucose, blood (hemoglobin), leukocytes, beta-human chorionic gonadotropin (females of childbearing potential) There were no clinically relevant differences seen 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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [18]
    25 [19]
    20 [20]
    17 [21]
    Units: bpm
    median (full range (min-max))
        1_T1 First escalation dose
    -1.0 (-30 to 12)
    -2.0 (-21 to 12)
    0 (-14 to 7)
    0 (-8 to 14)
        2_T3/T7 Last escalation dose
    -0.5 (-18 to 8)
    -1.0 (-8 to 13)
    -2.0 (-19 to 8)
    -2 (-5 to 6)
        3_T5/T9 Last maintenance dose
    -0.5 (-27 to 4)
    0 (-9 to 17)
    2 (-2 to 6)
    2 (-13 to 10)
    Notes
    [18] - Safety analysis set was used for all treatment groups 1_N=25 2_N=24 3_N=24
    [19] - The number of subjects contributing to the data is shown for all groups. 1_N=25 2_N=24 3_N=23
    [20] - 1_N=20 2_N=19 3_N=19
    [21] - 1_N=17 2_N=17 3_N=16
    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 IMP injection, otherwise no injection was 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 first escalation dose visit (T1), at the last escalation dose visit (T3/T7), and at the last maintenance dose visit (T5/T9); before and 30 min after injection of IMP. The number of subjects contributing to the data at each visit is also shown. Neither for children nor for adolescents systematic differences were detected between groups.
    End point type
    Secondary
    End point timeframe
    30 min bfr, 30, 60, 120 min aftr each treatment (T) Accelerated dose esct: 3 visits, sep by 7 d Standard dose esct: 7 visits, sep by 7 d Maintenance dose: 2 visits: 2 wks after last esct. dose, 4 wks after the last maintence dose
    End point values
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [22]
    25 [23]
    20 [24]
    17 [25]
    Units: % predicted
    arithmetic mean (standard deviation)
        1_T1 First escalation visit, before IMP
    102.5 ( 14.21 )
    98.5 ( 12.76 )
    102.7 ( 11.12 )
    103.5 ( 12.03 )
        2_T1_First escalation visit, 30 min after IMP
    101.9 ( 14.11 )
    98.4 ( 12.06 )
    104.2 ( 12.24 )
    102.2 ( 11.91 )
        3_T3/T7 Last escalation visit, before IMP
    99.5 ( 14.60 )
    103.4 ( 13.19 )
    101.2 ( 10.39 )
    101.8 ( 14.70 )
        4_T3/T7 Last escalation visit, 30 min after IMP
    99.1 ( 12.96 )
    103.5 ( 12.60 )
    101.9 ( 11.13 )
    100.8 ( 15.49 )
        5_T5/T9 Last maintenace visit, before IMP
    101.8 ( 15.62 )
    104.1 ( 13.56 )
    105.2 ( 14.18 )
    104.5 ( 13.29 )
        6_T5/T9 Last maintenace visit, 30 min after IMP
    102.0 ( 14.88 )
    102.9 ( 12.35 )
    106.0 ( 13.35 )
    103.6 ( 13.89 )
    Notes
    [22] - Safety analysis set for all treatment groups 1_N=25 2_N=25 3_N=24 4_N=24 5_N=24 6_N=24
    [23] - 1_N=25 2_N=25 3_N=24 4_N=24 5_N=23 6_N=23
    [24] - 1_N=20 2_N=20 3_N=19 4_N=19 5_N=19 6_N=19
    [25] - 1_N=17 2_N=17 3_N=17 4_N=17 5_N=16 6_N=16
    No statistical analyses for this end point

    Secondary: 9a_Tolerability: Likert scale after last dose of escalation phase (Investigator)

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    End point title
    		 9a_Tolerability: Likert scale after last dose of escalation 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 dose escalation phase.
    End point values
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [26]
    25
    20
    17
    Units: score
    number (not applicable)
        Missing
    1
    1
    1
    0
        Very Bad
    0
    0
    0
    0
        Bad
    0
    0
    0
    0
        Average
    0
    0
    2
    0
        Good
    9
    3
    3
    2
        Very Good
    15
    21
    14
    15
    Notes
    [26] - Safety analysis set was used for all treatment groups
    No statistical analyses for this end point

    Secondary: 9b_Tolerability: Likert scale at the final visit (Investigator)

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    End point title
    		 9b_Tolerability: Likert scale at the final visit (Investigator)
    End point description
    Assessment of the overall tolerability by the investigator at the final visit, 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
    At the final visit. Approximately 9 weeks for patients randomized to One Strength and approximately 13 weeks for patients randomized to Standard treatment group.
    End point values
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [27]
    25
    20
    17
    Units: score
    number (not applicable)
        Missing
    1
    1
    0
    0
        Very Bad
    0
    0
    1
    0
        Bad
    0
    0
    1
    0
        Average
    0
    0
    0
    0
        Good
    4
    3
    3
    2
        Very Good
    20
    21
    15
    15
    Notes
    [27] - Safety analysis set was used for all treatment groups
    No statistical analyses for this end point

    Secondary: 10a_Tolerability: Likert scale after last dose of escalation phase (Patient)

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    End point title
    		 10a_Tolerability: Likert scale after last dose of escalation phase (Patient)
    End point description
    Assessment of the overall tolerability by the patient 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 patient.
    End point type
    Secondary
    End point timeframe
    After the last IMP administration during the dose escalation phase.
    End point values
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [28]
    25
    20
    17
    Units: score
    number (not applicable)
        Missing
    1
    1
    1
    0
        Very Bad
    0
    0
    0
    0
        Bad
    0
    0
    0
    0
        Average
    0
    0
    1
    0
        Good
    3
    3
    5
    1
        Very Good
    21
    21
    13
    16
    Notes
    [28] - Safety analysis set was used for all treatment groups
    No statistical analyses for this end point

    Secondary: 10b_Tolerability: Likert scale at the final visit (Patient)

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    End point title
    		 10b_Tolerability: Likert scale at the final visit (Patient)
    End point description
    Assessment of the overall tolerability by the patient at the final visit, 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 patient.
    End point type
    Secondary
    End point timeframe
    At the final visit. Approximately 9 weeks for patients randomized to One Strength and approximately 13 weeks for patients randomized to Standard treatment group.
    End point values
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [29]
    25
    20
    17
    Units: score
    number (not applicable)
        Missing
    1
    1
    0
    0
        Very Bad
    0
    0
    0
    0
        Bad
    0
    0
    1
    0
        Average
    0
    0
    1
    0
        Good
    1
    1
    2
    2
        Very Good
    23
    23
    16
    15
    Notes
    [29] - Safety analysis set was used for all treatment groups
    No statistical analyses for this end point

    Secondary: 11a_Treatment-emergent adverse events related to IMP (All) - Time to onset

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    End point title
    		 11a_Treatment-emergent adverse events related to IMP (All) - Time to onset
    End point description
    Results show time to onset of all IMP-related 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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [30]
    25
    20
    17
    Units: TEAEs related to IMP
        ≤ 30 min
    3
    8
    5
    12
        > 30 min. ≤ 6 h
    9
    10
    23
    8
        > 6 h ≤ 24 h
    6
    8
    10
    9
        > 24 h
    3
    1
    1
    3
    Notes
    [30] - Safety analysis set was used for all treatment groups
    No statistical analyses for this end point

    Secondary: 11b_Treatment-emergent adverse events related to IMP (Local) - Time to onset

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    End point title
    		 11b_Treatment-emergent adverse events related to IMP (Local) - Time to onset
    End point description
    Results show time to onset of all local IMP-related 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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [31]
    25
    20
    17
    Units: Local TEAEs related to IMP
        ≤ 30 min
    3
    8
    5
    7
        > 30 min ≤ 6 h
    7
    10
    21
    8
        > 6 h ≤ 24 h
    4
    8
    9
    7
        > 24 h
    2
    1
    1
    3
    Notes
    [31] - Safety analysis set was used for all treatment groups
    No statistical analyses for this end point

    Secondary: 11c_Treatment-emergent adverse events related to IMP (Systemic) - Time to onset

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    End point title
    		 11c_Treatment-emergent adverse events related to IMP (Systemic) - Time to onset
    End point description
    Results show time to onset of all systemic IMP-related 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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [32]
    25
    20
    17
    Units: Systemic TEAEs related to IMP
        ≤ 30 min
    0
    0
    0
    5
        > 30 min ≤ 6 h
    1
    0
    1
    0
        > 6 h ≤ 24 h
    0
    0
    0
    0
        > 24 h
    1
    0
    0
    0
    Notes
    [32] - Safety analysis set was used for all treatment groups
    No statistical analyses for this end point

    Other pre-specified: 12_Immunologic parameter (IgG4 specific against grass-pollen)

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    End point title
    		 12_Immunologic parameter (IgG4 specific against grass-pollen)
    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-pollens pecific IgG4 antibody concentrations provide 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 the mean concentration of IgG4 against P. pratense (Timothy grass) pollen increased notably over time in both treatment groups (p-value < 0.0001). The number of subjects contributing to the data is also shown.
    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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Number of subjects analysed
    25 [33]
    25 [34]
    20 [35]
    17 [36]
    Units: mg/l
        arithmetic mean (full range (min-max))
    5.781 (0.17 to 28.97)
    8.008 (0.07 to 27.96)
    4.119 (0 to 21.47)
    7.419 (0.18 to 28.61)
    Notes
    [33] - Safety analysis set was used for all treatment groups N=24
    [34] - N=24
    [35] - N=20
    [36] - N=17
    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 analysis set. Results show treatment emergent adverse event (TEAE): 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. Further clarification of AEs is in the 'Description' section for end point 1.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Children (5 to <12 y) One Strength
    Reporting group description
    		 Children (5 to <12 y) who were randomised to the One Strength treatment. 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
    Children (5 to <12 y) Standard
    Reporting group description
    		 Children (5 to <12 y) who were randomised to the Standard treatment. Patient randomized to 'standard dose escalation' (Standard) received 7 injections with two strengths (A: 1,000 TU/mL; B: 10, 000 TU/mL), followed by 2 injections with the maximum recommended dose. Duration of treatment was approximately 13 weeks.

    Reporting group title
    Adolescents (12 to <18 y) One Strength
    Reporting group description
    		 Adolescents (12 to <18 y) who were randomised to the One Strength treatment. 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
    Adolescents (12 to <18 y) Standard
    Reporting group description
    		 Adolescents (12 to <18 y) who were randomised to the Standard treatment. Patient randomized to 'standard dose escalation' (Standard) received 7 injections with two strengths (A: 1,000 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
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Eye disorders
    Conjunctival oedema
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Children (5 to <12 y) One Strength Children (5 to <12 y) Standard Adolescents (12 to <18 y) One Strength Adolescents (12 to <18 y) Standard
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 25 (72.00%)
    16 / 25 (64.00%)
    8 / 20 (40.00%)
    7 / 17 (41.18%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 25 (20.00%)
    1 / 25 (4.00%)
    1 / 20 (5.00%)
    2 / 17 (11.76%)
         occurrences all number
    12
    1
    1
    5
    Somnolence
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 25 (12.00%)
    3 / 20 (15.00%)
    3 / 17 (17.65%)
         occurrences all number
    3
    11
    11
    7
    Injection site pruritus
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 25 (12.00%)
    4 / 20 (20.00%)
    2 / 17 (11.76%)
         occurrences all number
    2
    3
    8
    8
    Injection site swelling
         subjects affected / exposed
    9 / 25 (36.00%)
    8 / 25 (32.00%)
    5 / 20 (25.00%)
    4 / 17 (23.53%)
         occurrences all number
    12
    11
    13
    10
    Injection site pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    3 / 20 (15.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Fatigue
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection site discomfort
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Cough
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
    1 / 20 (5.00%)
    1 / 17 (5.88%)
         occurrences all number
    3
    1
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 20 (10.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    2
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dysphonia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    2
    Sneezing
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 25 (20.00%)
    3 / 25 (12.00%)
    0 / 20 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    7
    3
    0
    2
    Rhinitis
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    3
    2
    0
    Viral infection
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tonsillitis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2019
    Screening phase: postponed, treatment phase: postponed. This amendment was submitted in Germany, Poland, and Russia (all on 23 Jan 2019). There were country-specific differences in postponement time: Germany (23 Jan 2019), after trial start: screening phase: postponed by 1 month; treatment phase: postponed by 1 month. Poland (23 Jan 2019), prior to trial start: screening phase: postponed by 4 months; treatment phase: postponed by 5 months. Russia (23 Jan 2019), prior to trial start: screening phase: postponed by 4 months; treatment phase: postponed by 4 months.
    24 Jun 2019
    Substantial amendment regarding the adaptation of sample size was submitted to all Competent Authorities and Independent Ethics Committees (Germany, Poland, Russia, Spain), in September 2019. The date on which this amendment was submitted to the Competent Authorities (September 2019) is after the end of the trial (i.e. after LPLV = 25 Jun 2019). However, due to technical set-up of the EudraCT database, which would generate an error message during the validation process, the date of this substantial amendment is set here to 24-Jun-2019 (i.e. one day before the LPLV of this study).

    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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