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    Clinical Trial Results:
    A multi-centre, double-blind, placebo-controlled study to explore the safety and efficacy of Birch Modified Allergen Tyrosine adsorbed + MPL (POLLINEX® Quattro Plus 1.0 mL Birch [PQ Birch]) in subjects with seasonal allergic rhinoconjunctivitis due to birch pollen.

    Summary
    EudraCT number
    		 2015-000984-15
    Trial protocol
    		 DE   AT  
    Global end of trial date
    08 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Feb 2017
    First version publication date
    24 Feb 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PQBirch204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allergy Therapeutic (UK) Ltd. (ATL)
    Sponsor organisation address
    Dominion Way, Worthing, West Sussex, United Kingdom, BN14 8SA
    Public contact
    Research and Development, Allergy Therapeutics, +44 19038440, ClinicalOperations@allergytherapeutics.com
    Scientific contact
    Research and Development, Allergy Therapeutics, +44 1903844700, ClinicalOperations@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
    12 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was designed to evaluate the safety and efficacy of different cumulative doses of POLLINEX® Quattro Plus 1.0 mL Birch 100% (PQ Birch) treatment as assessed with conjunctival provocation test (CPT).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization (ICH) guideline E6: Good Clinical Practice (GCP). An informed consent form explaining the procedures of the study including the potential hazards was reviewed and approved by the responsible IEC/IRB before its use.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Sep 2015
    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
    Austria: 51
    Country: Number of subjects enrolled
    Germany: 319
    Worldwide total number of subjects
    370
    EEA total number of subjects
    370
    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)
    370
    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 28 investigational sites in two countries: Austria and Germany. Overall, 461 subjects were screened, 371 were randomized and 370 patients received study medication. One patient was randomized by mistake despite being a screening failure. This patient was not treated.

    Pre-assignment
    Screening details
    		 Male or female aged 18 to 60 with a positive history of moderate to severe seasonal allergic rhinoconjunctivitis ascribed to birch pollen exposure requiring treatment for at least the last 2 years (i.e., pollen seasons) prior to study and severe symptoms of allergic rhinoconjunctivitis in the past birch pollen season as determined by DSQ (score ≥5)

    Pre-assignment period milestones
    Number of subjects started
    		 370
    Number of subjects completed
    		 370

    Period 1
    Period 1 title
    Visit 2-7 (Visit 1=Screening)
    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.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 6 injections of Placebo given sequentially at weekly intervals
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (2% L-Tyrosine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Trained site personnel administered 6 subcutaneous injections of 1.0 mL each in eligible subjects in the lateral/posterior aspect of the upper arm.

    Arm title
    		 5100 SU
    Arm description
    		 2 injections of Placebo and 4 active injections of PQ Birch achieving 5100 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch; Placebo (2 % L-Tyrosine)
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, with 2 Placebo injections followed by active formulation at dose strenghts 300, 800, 2000 and 2000 SU/mL given sequentially at weekly intervals.

    Arm title
    		 5000 SU
    Arm description
    		 6 active injections of PQ Birch achieving 5000 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, at dose strengths 300, 300, 800, 800, 800, 2000 SU/mL given sequentially at weekly intervals.

    Arm title
    		 15300 SU
    Arm description
    		 2 injections of Placebo and 4 active injections of PQ Birch achieving 15300 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch, Placebo (2 % L-Tyrosine)
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each with 2 Placebo injections followed by active formulation at dose strengths 900, 2400, 6000 and 6000 SU/mL given sequentially at weekly intervals.

    Arm title
    		 15000 SU
    Arm description
    		 6 active injections of PQ Birch achieving 15000 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, at dose strengths 900, 900, 2400, 2400, 2400, 6000 SU/mL given sequentially at weekly intervals.

    Arm title
    		 20100 SU
    Arm description
    		 6 active injections of PQ Birch achieving 20100 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, at dose strengths 900, 2400, 2400, 2400, 6000 and 6000 SU/mL given sequentially at weekly intervals.

    Arm title
    		 27300 SU
    Arm description
    		 6 active injections of PQ Birch achieving 27300 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, at dose strengths 900, 2400, 6000, 6000, 6000, 6000 SU/mL given sequentially at weekly intervals.

    Number of subjects in period 1
    		Placebo 5100 SU 5000 SU 15300 SU 15000 SU 20100 SU 27300 SU
    Started
    53
    49
    53
    53
    55
    51
    56
    Completed
    49
    44
    50
    52
    52
    48
    54
    Not completed
    4
    5
    3
    1
    3
    3
    2
         Consent withdrawn by subject
    1
    2
    -
    -
    1
    2
    -
         Adverse event, non-fatal
    2
    2
    1
    1
    2
    -
    2
         Pregnancy
    1
    -
    -
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    1
    -
    -
    1
    -
         Protocol deviation
    -
    1
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 6 injections of Placebo given sequentially at weekly intervals
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo (2 % L-Tyrosine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Trained site personnel administered 6 subcutaneous injections of 1.0 mL each in eligible subjects in lateral/posterior aspect of the upper arm.

    Arm title
    		 5100 SU
    Arm description
    		 2 injections of Placebo and 4 active injections of PQ Birch achieving 5100 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch, Placebo (2 % L-Tyrosine)
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, with 2 placebo injections followed by active formulation at dose strengths 300, 800, 2000 and 2000 SU/mL given sequentially at weekly intervals.

    Arm title
    		 5000 SU
    Arm description
    		 6 active injections of PQ Birch achieving 5000 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, at dose strengths 300, 300, 800, 800, 800, 2000 SU/mL given sequentially at weekly intervals.

    Arm title
    		 15300 SU
    Arm description
    		 2 injections of Placebo and 4 active injections of PQ birch Birch achieving 15300 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch, Placebo (2 % L-Tyrosine)
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, with 2 placebo injections followed by active formulation at dose strengths 900, 2400, 6000 and 6000 SU/mL given sequentially at weekly intervals.

    Arm title
    		 15000 SU
    Arm description
    		 6 active injections of PQ Birch achieving 15000 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, at dose strengths 900, 900, 2400, 2400, 2400, 6000 SU/mL given sequentially at weekly intervals.

    Arm title
    		 20100 SU
    Arm description
    		 6 active injections of PQ Birch achieving 20100 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, at dose strengths 900, 2400, 2400, 2400, 6000, 6000 SU/mL given sequentially at weekly intervals.

    Arm title
    		 27300 SU
    Arm description
    		 6 active injections of PQ Birch achieving 27300 SU cumulative dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    POLLINEX® Quattro Plus 1.0 mL Birch
    Investigational medicinal product code
    Other name
    PQ Birch
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 subcutaneous injections of 1.0 mL each, at dose strengths 900, 2400, 6000, 6000, 6000, 6000 SU/mL given sequentially at weekly intervals.

    Number of subjects in period 2
    		Placebo 5100 SU 5000 SU 15300 SU 15000 SU 20100 SU 27300 SU
    Started
    49
    44
    50
    52
    52
    48
    54
    Completed
    49
    44
    50
    51
    51
    48
    54
    Not completed
    0
    0
    0
    1
    1
    0
    0
         Terminated after treatment period
    -
    -
    -
    1
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 6 injections of Placebo given sequentially at weekly intervals

    Reporting group title
    5100 SU
    Reporting group description
    		 2 injections of Placebo and 4 active injections of PQ Birch achieving 5100 SU cumulative dose

    Reporting group title
    5000 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 5000 SU cumulative dose

    Reporting group title
    15300 SU
    Reporting group description
    		 2 injections of Placebo and 4 active injections of PQ Birch achieving 15300 SU cumulative dose

    Reporting group title
    15000 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 15000 SU cumulative dose

    Reporting group title
    20100 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 20100 SU cumulative dose

    Reporting group title
    27300 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 27300 SU cumulative dose

    Reporting group values
    		 Placebo 5100 SU 5000 SU 15300 SU 15000 SU 20100 SU 27300 SU Total
    Number of subjects
    		 53 49 53 53 55 51 56 370
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 53 49 53 53 55 51 56 370
        From 65-84 years
    		 0 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.5 ( 12.19 ) 36.4 ( 11.95 ) 35.2 ( 11.35 ) 35.9 ( 12.4 ) 36.1 ( 12.63 ) 34.6 ( 12.02 ) 35.7 ( 12.48 ) -
    Gender categorical
    Units: Subjects
        Female
    		 23 34 29 25 30 21 31 193
        Male
    		 30 15 24 28 25 30 25 177
    Subject analysis sets

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who received at least one dose of study medication. Subjects were analyzed according to the treatment that they received.

    Subject analysis set title
    mFAS
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subset of the Full Analysis Set that excluded all patients who did not receive the full cumulative dose they were randomized to or who had missing values with respect to the post-treatment TSS.

    Subject analysis sets values
    		 Safety Set mFAS
    Number of subjects
    370
    346
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    370
    346
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    35.9 ( 12.09 )
    35.7 ( 12.07 )
    Gender categorical
    Units: Subjects
        Female
    193
    177
        Male
    177
    169

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 6 injections of Placebo given sequentially at weekly intervals

    Reporting group title
    5100 SU
    Reporting group description
    		 2 injections of Placebo and 4 active injections of PQ Birch achieving 5100 SU cumulative dose

    Reporting group title
    5000 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 5000 SU cumulative dose

    Reporting group title
    15300 SU
    Reporting group description
    		 2 injections of Placebo and 4 active injections of PQ Birch achieving 15300 SU cumulative dose

    Reporting group title
    15000 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 15000 SU cumulative dose

    Reporting group title
    20100 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 20100 SU cumulative dose

    Reporting group title
    27300 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 27300 SU cumulative dose
    Reporting group title
    Placebo
    Reporting group description
    		 6 injections of Placebo given sequentially at weekly intervals

    Reporting group title
    5100 SU
    Reporting group description
    		 2 injections of Placebo and 4 active injections of PQ Birch achieving 5100 SU cumulative dose

    Reporting group title
    5000 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 5000 SU cumulative dose

    Reporting group title
    15300 SU
    Reporting group description
    		 2 injections of Placebo and 4 active injections of PQ birch Birch achieving 15300 SU cumulative dose

    Reporting group title
    15000 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 15000 SU cumulative dose

    Reporting group title
    20100 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 20100 SU cumulative dose

    Reporting group title
    27300 SU
    Reporting group description
    		 6 active injections of PQ Birch achieving 27300 SU cumulative dose

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who received at least one dose of study medication. Subjects were analyzed according to the treatment that they received.

    Subject analysis set title
    mFAS
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subset of the Full Analysis Set that excluded all patients who did not receive the full cumulative dose they were randomized to or who had missing values with respect to the post-treatment TSS.

    Primary: Total Symptom Score reported during CPTs

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    End point title
    		 Total Symptom Score reported during CPTs
    End point description
    The primary efficacy variable was the change from baseline to post-treatment in TSS (comprising the categories eye redness, tearing, itching and irritation). The MCP-Mod methodology (multiple comparison procedure - modelling) was used to test for a dose-response and to estimate the dose-response shape.
    End point type
    Primary
    End point timeframe
    Approximately four weeks after the last injection.
    End point values
    		 Placebo 5100 SU 5000 SU 15300 SU 15000 SU 20100 SU 27300 SU
    Number of subjects analysed
    49
    44
    50
    50
    51
    48
    54
    Units: Score
    arithmetic mean (standard deviation)
        Post-treatment - Baseline
    -2.2 ( 2.8 )
    -3.2 ( 2.9 )
    -2.9 ( 2.5 )
    -3.6 ( 3.2 )
    -3.1 ( 2.8 )
    -2.8 ( 2.1 )
    -3.5 ( 2.8 )
    Attachments
    		 Primary Endpoint
    Statistical analysis title
    		 MCP-Mod
    Comparison groups
    Placebo v 5100 SU v 5000 SU v 15300 SU v 15000 SU v 20100 SU v 27300 SU
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.004 [2]
    Method
    		 MCP-Mod
    Confidence interval
    Notes
    [1] - The primary analysis set was the mFAS. Further Analysis was performed by MCP-Mod (three candiate models - Emax, Linear in log and Logistic), further Information on the analysis can be found in attachemnt.
    [2] - Three candidate models were used to analyze the data using the MCP-Mod and the dose response curve is presented in the Appendix.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within the time period from the first injection of study medication until Visit 8a
    Adverse event reporting additional description
    AEs were summarized by treatment group and primary SOC, preferred term, additionally by causality assessment and intensity.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 6 subcutaneous injections of 1.0 mL each given sequentially at weekly intervals

    Reporting group title
    5100 SU
    Reporting group description
    		 6 subcutaneous injections of 1.0 mL each, with 2 placebo injections followed by active formulation at dose strengths 300, 800, 2000 and 2000 SU/mL given sequentially at weekly intervals.

    Reporting group title
    5000 SU
    Reporting group description
    		 6 subcutaneous injections of 1.0 mL each, at dose strengths 300, 300, 800, 800, 800, 2000 SU/mL given sequentially at weekly intervals.

    Reporting group title
    15300 SU
    Reporting group description
    		 6 subcutaneous injections of 1.0 mL each, with 2 placebo injections followed by active formulation at dose strengths 900, 2400, 6000 and 6000 SU/mL given sequentially at weekly intervals.

    Reporting group title
    15000 SU
    Reporting group description
    		 6 subcutaneous injections of 1.0 mL each, at dose strengths 900, 900, 2400, 2400, 2400, 6000 SU/mL given sequentially at weekly intervals.

    Reporting group title
    20100 SU
    Reporting group description
    		 6 subcutaneous injections of 1.0 mL each, at dose strengths 900, 2400, 2400, 2400, 6000, 6000 SU/mL given sequentially at weekly intervals.

    Reporting group title
    27300 SU
    Reporting group description
    		 6 subcutaneous injections of 1.0 mL each, at dose strengths 900, 2400, 6000, 6000, 6000, 6000 SU/mL given sequentially at weekly intervals.

    Serious adverse events
    		 Placebo 5100 SU 5000 SU 15300 SU 15000 SU 20100 SU 27300 SU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 49 (2.04%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 51 (0.00%)
    1 / 56 (1.79%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
    Additional description: Reported adverse event was assessed as non-related to study medication.
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 49 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 51 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
    Additional description: Reported adverse event was assessed as non-related to study medication.
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 49 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 51 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
    Additional description: Reported adverse event was assessed as non-related to study medication.
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 49 (2.04%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 55 (0.00%)
    0 / 51 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo 5100 SU 5000 SU 15300 SU 15000 SU 20100 SU 27300 SU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 53 (52.83%)
    37 / 49 (75.51%)
    41 / 53 (77.36%)
    42 / 53 (79.25%)
    39 / 55 (70.91%)
    36 / 51 (70.59%)
    47 / 56 (83.93%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 49 (2.04%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
    1 / 55 (1.82%)
    4 / 51 (7.84%)
    2 / 56 (3.57%)
         occurrences all number
    2
    3
    1
    1
    2
    7
    2
    General disorders and administration site conditions
    Injection site swelling
         subjects affected / exposed
    6 / 53 (11.32%)
    24 / 49 (48.98%)
    27 / 53 (50.94%)
    31 / 53 (58.49%)
    21 / 55 (38.18%)
    21 / 51 (41.18%)
    29 / 56 (51.79%)
         occurrences all number
    14
    50
    64
    62
    62
    62
    79
    Injection site erythema
         subjects affected / exposed
    5 / 53 (9.43%)
    21 / 49 (42.86%)
    27 / 53 (50.94%)
    24 / 53 (45.28%)
    24 / 55 (43.64%)
    20 / 51 (39.22%)
    34 / 56 (60.71%)
         occurrences all number
    8
    46
    83
    50
    62
    63
    100
    Injection site pruritus
         subjects affected / exposed
    2 / 53 (3.77%)
    11 / 49 (22.45%)
    17 / 53 (32.08%)
    10 / 53 (18.87%)
    11 / 55 (20.00%)
    7 / 51 (13.73%)
    15 / 56 (26.79%)
         occurrences all number
    2
    18
    34
    21
    22
    19
    35
    Injection site pain
         subjects affected / exposed
    7 / 53 (13.21%)
    8 / 49 (16.33%)
    13 / 53 (24.53%)
    9 / 53 (16.98%)
    9 / 55 (16.36%)
    10 / 51 (19.61%)
    13 / 56 (23.21%)
         occurrences all number
    10
    12
    20
    19
    13
    16
    19
    Injection site induration
         subjects affected / exposed
    0 / 53 (0.00%)
    4 / 49 (8.16%)
    2 / 53 (3.77%)
    2 / 53 (3.77%)
    0 / 55 (0.00%)
    2 / 51 (3.92%)
    4 / 56 (7.14%)
         occurrences all number
    0
    6
    2
    3
    0
    2
    5
    Injection site haematoma
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 49 (6.12%)
    3 / 53 (5.66%)
    2 / 53 (3.77%)
    0 / 55 (0.00%)
    3 / 51 (5.88%)
    1 / 56 (1.79%)
         occurrences all number
    0
    7
    3
    2
    0
    3
    1
    Injection site urticaria
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 49 (2.04%)
    3 / 53 (5.66%)
    1 / 53 (1.89%)
    3 / 55 (5.45%)
    1 / 51 (1.96%)
    3 / 56 (5.36%)
         occurrences all number
    0
    2
    3
    2
    9
    2
    5
    Injection site nodule
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 49 (2.04%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
    3 / 55 (5.45%)
    2 / 51 (3.92%)
    2 / 56 (3.57%)
         occurrences all number
    1
    1
    4
    0
    8
    3
    4
    Injection site warmth
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 49 (0.00%)
    3 / 53 (5.66%)
    2 / 53 (3.77%)
    2 / 55 (3.64%)
    1 / 51 (1.96%)
    2 / 56 (3.57%)
         occurrences all number
    0
    0
    6
    2
    6
    1
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 53 (15.09%)
    7 / 49 (14.29%)
    5 / 53 (9.43%)
    5 / 53 (9.43%)
    7 / 55 (12.73%)
    5 / 51 (9.80%)
    6 / 56 (10.71%)
         occurrences all number
    8
    8
    6
    5
    8
    5
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2015
    To clarify the exact time point of the spirometry pre- and post-injection and further definition of the observation period post injection in case of notable worsening of the spirometry results. To correct error with respect to the top dose available for the use in the study and to change dose rationale and provide additional information on the dose rational of the study. To clarify that only treatment arms using 6 injections (the 5000 SU, 15000 SU, 201000 SU and the 273000 SU treatment arms) and the placebo arm will primarily be used to estimate the dose-response shape.
    23 Jul 2015
    To reflect changes in laboratory testing. Exploratory biomarker (lipocalin) assessment will no longer be performed due to filed collaboration with the laboratory selected to perform this specific analysis. This change does not impact any of the main objectives or safety assessments.

    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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