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    Clinical Trial Results:
    A multi-centre, double-blind dose-ranging study to evaluate the efficacy and safety/tolerability of Birch Modified Allergen Tyrosine-adsorbed + MPL (POLLINEX Quattro® Birch) in Subjects with seasonal allergic rhinoconjunctivitis due to birch pollen

    Summary
    EudraCT number
    		 2012-004336-28
    Trial protocol
    		 DE   AT   PL  
    Global end of trial date
    27 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Mar 2016
    First version publication date
    25 Mar 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PQBirch203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allergy Therapeutics (UK) Ltd.
    Sponsor organisation address
    Dominion Way, Worthing, West Sussex, United Kingdom, BN14 8SA
    Public contact
    Head of Clinical Operations, Clinical Research Management, Bencard Allergie GmbH , +49 (0)893681198, denise.lee@allergytherapeutics.com
    Scientific contact
    Head of Clinical Operations, Clinical Research Management, Bencard Allergie GmbH , +49 (0)893681198, denise.lee@allergytherapeutics.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the differences in change (baseline to post-treatment) in total symptom scores (TSS) recorded following Conjunctival Provocation Tests (CPT), between four POLLINEX Quattro® Birch treatment arms of 600SU, 1550SU, 5100SU and 13600SU (cumulative doses). The purpose of this was to identify the most appropriate dose for POLLINEX Quattro® Birch for clinical development. Defining the most appropriate dose was to be based on clinical judgement as to balance of efficacy and safety/ tolerability outcomes of the different doses, taking into account the consistency of patterns, the extent of differences in individual parameters and the achievement of or approach towards statistical significance.
    Protection of trial subjects
    This study was conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Patients, as adopted by the General Assembly of the World Medical Association in 1996 in South Africa. Furthermore, the study was compliant with the current version of the German Drug Law (”Arzneimittelgesetz”), other national legal requirements in participating countries (Germany, Austria, and Poland) and all applicable amendments laid down by the World Medical Assemblies and the International Conference on Harmonization (ICH) guidelines for Good Clinical Practice (GCP). A written approval and/or favorable opinion of the responsible Ethics Committee (EC) as well as approval from the Competent Authority (CA) for each country was obtained before the study was initiated. Subjects gave their informed consent prior to admission to a clinical study and before any protocol specified procedures were carried out. The written consent document embodied the elements of informed consent as described in the Declaration of Helsinki and also complied with local regulations. Subjects were informed that they were free to withdraw from the study at any time at their own discretion.
    Background therapy
    		 The following medication washout periods were to be adhered to prior to screening. •Oral or parenteral corticosteroids (7 days); •Ocular corticosteroids (7 days); •Inhaled or intranasal corticosteroids (1 day); •Mast cell stabilizers, e.g. Nedocromil, Lodoxamide (5 days); •Intranasal or systemic decongestants, including cold preparations (1 day); •Leukotriene modifiers, e.g. Montelukast, Zafirlukast, Zileuton (1 day); •Afrin (oxymetazoline hydrochloride) (14 days); •Antihistamines: •Once-daily or twice-daily antihistamines, e.g. Desloratadine (7 days); •Short-acting (3 or 4 times a day) antihistamines, e.g. Dimetindene (Fenistil®) (3 days); •Hydroxyzine (7 days); •H2-blockers, e.g. Ranitidine (1 day) Other anti-inflammatory, anti-allergy and any other medications (e.g. anticholinergic agents and tricyclic antidepressants) which in the opinion of the Investigator could interfere with the study objectives were to be considered on a case-by-case basis. Subjects were to refrain from using any topical skin medication on the forearms within 7 days prior to skin testing. During the course of the study, none of the prior medications listed above were to be used for the relief of allergy symptoms. Subjects with mild asthma were permitted to use beta2-agonists as needed and Budesonide (or equivalent) up to 400 µg once daily. Other medications that had no known effect on allergy symptom relief were allowed during the study if they were taken chronically (i.e. not “as needed”) and if the medication dose had been stable for at least 30 days prior to screening. Examples of these medications included contraceptives, hormone replacement therapy, e.g. levothyroxine. Acetaminophen, non-steroidal anti-inflammatory drugs and other drugs that did not impact study participation or outcomes were allowed if taken “as needed”. Ketotifen was provided to treat any symptoms remaining after CPT.
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    09 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Austria: 30
    Country: Number of subjects enrolled
    Germany: 100
    Worldwide total number of subjects
    149
    EEA total number of subjects
    149
    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)
    149
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted in 16 investigational sites in three different countries: Austria (3), Germany (10) and Poland (3). Overall, 174 subjects were screened and 149 were randomized to receive study medication.

    Pre-assignment
    Screening details
    		 Male and female subjects (not of child-bearing potential or using adequate contraception) were included in the study aged, 18 to 60 with an allergy to birch pollen. Subjects were not included in the study if they had any acute, chronic and/or infectious ocular disorder (other than allergic conjunctivitis) or moderate/severe asthma.

    Pre-assignment period milestones
    Number of subjects started
    		 149
    Number of subjects completed
    		 149

    Period 1
    Period 1 title
    Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The identity of study medication administered was not known by the subjects, Investigators or other persons directly involved in the conduct of the clinical study. The treatment blind was not broken until the database was locked and unblinding was authorized in writing. The blind of an individual subject could have been broken if specific knowledge of the study medication administered was necessary for determination of appropriate emergency treatment required for the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 13600SU
    Arm description
    		 Received 300, 800, 2000, 3500, 3500, and 3500 SU given sequentially at weekly intervals
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Arm title
    		 5100SU
    Arm description
    		 placebo, placebo, 300SU, 800SU, 2000SU and 2000SU given sequentially at weekly intervals
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Arm title
    		 1550SU
    Arm description
    		 placebo, placebo, 150SU, 300SU, 300SU and 800SU given sequentially at weekly intervals
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Arm title
    		 600SU
    Arm description
    		 placebo, placebo, 150SU, 150SU, 150SU and 150SU given sequentially at weekly intervals
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Number of subjects in period 1
    		13600SU 5100SU 1550SU 600SU
    Started
    37
    37
    36
    39
    Completed
    36
    36
    35
    38
    Not completed
    1
    1
    1
    1
         Adverse event, non-fatal
    1
    1
    -
    1
         Lost to follow-up
    -
    -
    1
    -
    Period 2
    Period 2 title
    Follow up (Visit 8)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    As in the treatment period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 13600SU
    Arm description
    		 As in treament period
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Arm title
    		 5100SU
    Arm description
    		 As in treatment period
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Arm title
    		 1550SU
    Arm description
    		 As in treatment period
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Arm title
    		 600SU
    Arm description
    		 As in treatment period
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Number of subjects in period 2
    		13600SU 5100SU 1550SU 600SU
    Started
    36
    36
    35
    38
    Completed
    36
    36
    35
    38
    Period 3
    Period 3 title
    Follow up (6-month phone call)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    As in the treatment period

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 13600SU
    Arm description
    		 As in the treatement period
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Arm title
    		 5100SU
    Arm description
    		 As in the treatment period
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Arm title
    		 1550SU
    Arm description
    		 As in the treatment period
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Arm title
    		 600SU
    Arm description
    		 As in the treatment period
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX Quattro Birch Plus 1.0 ml 100%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigator or trained study site personnel (a physician or nurse under the supervision of a physician) as subcutaneous injections to eligible subjects in the lateral/posterior aspect of the upper arm. Each randomized subject was scheduled to receive 6 injections from Visit 2 to Visit 7, with a 7 day (+/-1 day) interval between each injection. The arms were to be alternated between injections, e.g. 1st, 3rd and 5th injection right arm, 2nd, 4th and 6th injection left arm.

    Number of subjects in period 3
    		13600SU 5100SU 1550SU 600SU
    Started
    36
    36
    35
    38
    Completed
    37
    36
    35
    37
    Not completed
    0
    0
    0
    1
         Lost to follow-up
    -
    -
    -
    1
    Joined
    1
    0
    0
    0
         Joining telephone FU after AE
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    13600SU
    Reporting group description
    		 Received 300, 800, 2000, 3500, 3500, and 3500 SU given sequentially at weekly intervals

    Reporting group title
    5100SU
    Reporting group description
    		 placebo, placebo, 300SU, 800SU, 2000SU and 2000SU given sequentially at weekly intervals

    Reporting group title
    1550SU
    Reporting group description
    		 placebo, placebo, 150SU, 300SU, 300SU and 800SU given sequentially at weekly intervals

    Reporting group title
    600SU
    Reporting group description
    		 placebo, placebo, 150SU, 150SU, 150SU and 150SU given sequentially at weekly intervals

    Reporting group values
    		 13600SU 5100SU 1550SU 600SU Total
    Number of subjects
    		 37 37 36 39 149
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 35.6 ± 12.23 36.2 ± 10.9 34.3 ± 9.66 32.5 ± 10 -
    Gender categorical
    Units: Subjects
        Female
    		 23 22 19 21 85
        Male
    		 14 15 17 18 64
    Subject analysis sets

    Subject analysis set title
    Modified full analysisi set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified Full Analysis Set (mFAS): all subjects from the Full Aanalysis (FAS) Set who received the full dose to which they are randomized and without missing values with respect to the TSS at baseline or post-treatment. FAS defined as all subjects that reported at least a baseline TSS and were treated at least once with study medication. For efficacy, subjects were analysed according to the randomised treatment regardless of whether the cumulative dose that a subject received during the course of the study was equal to the treatment group to which they were randomised.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received at least one dose of study medication. Subjects not receiving the cumulative treatment as assigned were allocated to the treatment group most closely resembling the cumulative dose aactulally received as follows: ≤600SU = 600SU, >600SY and ≤1550SU = 1550SU, >1550SU and ≤5100SU = 5100SU, >5100SU - 13600SU

    Subject analysis sets values
    		 Modified full analysisi set Safety set
    Number of subjects
    143
    149
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    34.3 ± 10.73
    ±
    Gender categorical
    Units: Subjects
        Female
    81
        Male
    62

    End points

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    End points reporting groups
    Reporting group title
    13600SU
    Reporting group description
    		 Received 300, 800, 2000, 3500, 3500, and 3500 SU given sequentially at weekly intervals

    Reporting group title
    5100SU
    Reporting group description
    		 placebo, placebo, 300SU, 800SU, 2000SU and 2000SU given sequentially at weekly intervals

    Reporting group title
    1550SU
    Reporting group description
    		 placebo, placebo, 150SU, 300SU, 300SU and 800SU given sequentially at weekly intervals

    Reporting group title
    600SU
    Reporting group description
    		 placebo, placebo, 150SU, 150SU, 150SU and 150SU given sequentially at weekly intervals
    Reporting group title
    13600SU
    Reporting group description
    		 As in treament period

    Reporting group title
    5100SU
    Reporting group description
    		 As in treatment period

    Reporting group title
    1550SU
    Reporting group description
    		 As in treatment period

    Reporting group title
    600SU
    Reporting group description
    		 As in treatment period
    Reporting group title
    13600SU
    Reporting group description
    		 As in the treatement period

    Reporting group title
    5100SU
    Reporting group description
    		 As in the treatment period

    Reporting group title
    1550SU
    Reporting group description
    		 As in the treatment period

    Reporting group title
    600SU
    Reporting group description
    		 As in the treatment period

    Subject analysis set title
    Modified full analysisi set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified Full Analysis Set (mFAS): all subjects from the Full Aanalysis (FAS) Set who received the full dose to which they are randomized and without missing values with respect to the TSS at baseline or post-treatment. FAS defined as all subjects that reported at least a baseline TSS and were treated at least once with study medication. For efficacy, subjects were analysed according to the randomised treatment regardless of whether the cumulative dose that a subject received during the course of the study was equal to the treatment group to which they were randomised.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received at least one dose of study medication. Subjects not receiving the cumulative treatment as assigned were allocated to the treatment group most closely resembling the cumulative dose aactulally received as follows: ≤600SU = 600SU, >600SY and ≤1550SU = 1550SU, >1550SU and ≤5100SU = 5100SU, >5100SU - 13600SU

    Primary: Total symptom score (TSS) at conjuntival provocation test (CPT

    		 Close Top of page
    End point title
    		 Total symptom score (TSS) at conjuntival provocation test (CPT
    End point description
    The primary efficacy variable was the change from baseline to post treatment TSS at Visit 8 recorded following CPT (with the allergen concentration eliciting TSS ≥ 6, adjusted for reference eye score, at the confirmatory CPT). The baseline value was the TSS recorded during the confirmatory CPT prior to first administration of study medication.
    End point type
    Primary
    End point timeframe
    Baseline (Visit 2 or 2a) to Visit 8. Approximately 8 weeks from beginning of treatment.
    End point values
    		 13600SU 5100SU 1550SU 600SU
    Number of subjects analysed
    36
    35
    34
    38
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    7.4 ± 1.18
    7.3 ± 1.32
    7.6 ± 1.5
    7.6 ± 1.39
        Visit 8
    4.2 ± 2.4
    5 ± 2.58
    4.9 ± 2.71
    6.1 ± 2.51
        Baseline - Visit 8
    -3.2 ± 2.81
    -2.3 ± 2.51
    -2.7 ± 2.96
    -1.5 ± 2.51
    Attachments
    		 Predicted change from baseline TSS
    Statistical analysis title
    		 Predefined first primary comparison
    Statistical analysis description
    A strict semi-hierarchical test procedure was applied to the hypotheses. The first two hypotheses were considered as the most important and were tested in parallel, using a Bonferroni adjustment for the significance level. 1. H01: Mean change TSS (13600SU) = Mean change TSS (600SU) vs. H11: Mean change TSS (13600SU) ≠ Mean change TSS (600SU) 2. H02: Mean change TSS (5100SU) = Mean change TSS (600SU) vs. H12: Mean change TSS (5100SU) ≠ Mean change TSS
    Comparison groups
    13600SU v 600SU
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 ≥ 0.025 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least square means
    Point estimate
    1.88
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 3.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.59
    Notes
    [1] - If both null hypotheses (H01 and H02) could be rejected at a significance level of 0.025, only then were further comparisons tested. The test procedure ensured that the overall significance level of 0.05 was strictly maintained for all comparisons.
    [2] - p = 0.0019
    Statistical analysis title
    		 Predefined second primary comparison
    Statistical analysis description
    A strict semi-hierarchical test procedure was applied to the hypotheses. The first two hypotheses were considered as the most important and were tested in parallel, using a Bonferroni adjustment for the significance level. 1. H01: Mean change TSS (13600SU) = Mean change TSS (600SU) vs. H11: Mean change TSS (13600SU) ≠ Mean change TSS (600SU) 2. H02: Mean change TSS (5100SU) = Mean change TSS (600SU) vs. H12: Mean change TSS (5100SU) ≠ Mean change TSS
    Comparison groups
    5100SU v 600SU
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 ≥ 0.025 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean
    Point estimate
    1.01
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 2.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6
    Notes
    [3] - If both null hypotheses (H01 and H02) could be rejected at a significance level of 0.025, only then were further comparisons tested. The test procedure ensured that the overall significance level of 0.05 was strictly maintained for all comparisons.
    [4] - p = 0.0919

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment period i.e. from first injection (Visit 2) to 3 weeks after last injection (Visit 8)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    13600SU
    Reporting group description
    		 Received 300, 800, 2000, 3500, 3500, and 3500 SU given sequentially at weekly intervals

    Reporting group title
    5100SU
    Reporting group description
    		 placebo, placebo, 300SU, 800SU, 2000SU and 2000SU given sequentially at weekly intervals

    Reporting group title
    1550SU
    Reporting group description
    		 placebo, placebo, 150SU, 300SU, 300SU AND 800SU given sequentially at weekly intervals

    Reporting group title
    600SU
    Reporting group description
    		 placebo, placebo, 150SU, 150SU, 150SU AND 150SU at weekly intervals

    Serious adverse events
    		 13600SU 5100SU 1550SU 600SU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    		 13600SU 5100SU 1550SU 600SU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 36 (72.22%)
    26 / 37 (70.27%)
    28 / 36 (77.78%)
    33 / 40 (82.50%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 36 (8.33%)
    2 / 37 (5.41%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    4
    3
    1
    1
    General disorders and administration site conditions
    Injection site swelling
         subjects affected / exposed
    19 / 36 (52.78%)
    19 / 37 (51.35%)
    16 / 36 (44.44%)
    15 / 40 (37.50%)
         occurrences all number
    53
    43
    30
    37
    Injection site erythema
         subjects affected / exposed
    17 / 36 (47.22%)
    19 / 37 (51.35%)
    14 / 36 (38.89%)
    14 / 40 (35.00%)
         occurrences all number
    48
    47
    33
    27
    Injection site pruritus
         subjects affected / exposed
    7 / 36 (19.44%)
    7 / 37 (18.92%)
    5 / 36 (13.89%)
    6 / 40 (15.00%)
         occurrences all number
    21
    9
    9
    7
    Injection site pain
         subjects affected / exposed
    4 / 36 (11.11%)
    4 / 37 (10.81%)
    1 / 36 (2.78%)
    7 / 40 (17.50%)
         occurrences all number
    6
    6
    1
    9
    Injection site induration
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 37 (5.41%)
    3 / 36 (8.33%)
    1 / 40 (2.50%)
         occurrences all number
    2
    3
    3
    1
    Injection site nodule
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 37 (5.41%)
    2 / 36 (5.56%)
    2 / 40 (5.00%)
         occurrences all number
    1
    3
    3
    2
    Injection site urticaria
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 37 (0.00%)
    3 / 36 (8.33%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    5
    1
    Injection site warmth
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    2
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    1
    2
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 37 (0.00%)
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 37 (5.41%)
    4 / 36 (11.11%)
    5 / 40 (12.50%)
         occurrences all number
    2
    2
    4
    5
    Gastroenteritis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    1
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2013
    To complete the set of procedures performed at post-treatment visit (Visit 8). For women of childbearing potential a pregnancy test was integrated, to be performed prior to the CPT. In addition, re-consent was to be given by subjects prior to the procedure via the associated updated ICF.

    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.
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