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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled (DBPC), parallel group study to assess the clinical efficacy and safety of SUBLIVAC FIX Birch immunotherapy in patients suffering from allergic rhinitis/rhinoconjunctivitis caused by birch pollen.

    Summary
    EudraCT number
    		 2013-005550-30
    Trial protocol
    		 CZ   DE   SK   BE   PL  
    Global end of trial date
    01 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Aug 2017
    First version publication date
    17 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SB/0042
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    HAL Allergy
    Sponsor organisation address
    J.H. Oortweg 15-17, Leiden, Netherlands, NL-2333 CH
    Public contact
    Head Department of Clinical Development & Pharmacovigilance, HAL Allergy, + 31 881959000, pjdkam@hal-allergy.com
    Scientific contact
    Head Department of Clinical Development & Pharmacovigilance, HAL Allergy, + 31 881959000, pjdkam@hal-allergy.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
    23 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess clinical efficacy of sublingual immunotherapy with SUBLIVAC FIX Birch (40.000 AUN/ml), compared to placebo, in patients suffering from birch pollen induced rhinitis/rhinoconjunctivitis, measured by a combined rhinoconjunctivitis symptoms score and medication score during the birch pollen season.
    Protection of trial subjects
    The trial is performed in accordance with GCP and with all applicable governmental regulations. Independent approval for the study conduct was obtained from the IECs. Informed consent was obtained from each subject participating in the trial after explanation of the aims, design, methods, benefits and potential hazards of the trial before any trial-specific procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2014
    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: 158
    Country: Number of subjects enrolled
    Slovakia: 42
    Country: Number of subjects enrolled
    Belgium: 50
    Country: Number of subjects enrolled
    Czech Republic: 83
    Country: Number of subjects enrolled
    Germany: 73
    Worldwide total number of subjects
    406
    EEA total number of subjects
    406
    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)
    404
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The actual recruitment period was from September until end October 2014. Patients fulfilling all the inclusion criteria and none of the exclusion criteria have been recruited at outpatient clinics, private practices or site management organization/research clinics from regular patient visits, database screening and advertisement.

    Pre-assignment
    Screening details
    		 501 patients were screened, 95 were not randomized. The three main reasons for screen failure were the absence of a sufficiently high serum specific anti-birch IgE response (n=46), a positive SPT to allergens other than birch pollen (may aggravate clinical symptoms during birch pollen season (n=30)) and a negative SPT for birch allergen (n=8).

    Period 1
    Period 1 title
    Double-blind period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Subject, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SUBLIVAC Placebo
    Arm description
    		 Subjects treated with Placebo during the double blind study period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Sublingual use
    Dosage and administration details
    Start with 1 drop daily of SUBLIVAC Placebo (0 AUN/mL) and increase by 1 drop daily, until the maintenance dose of 5 drops is reached. Mode of administration: Sublingual administration.

    Arm title
    		 SUBLIVAC FIX Birch
    Arm description
    		 Subjects treated with SUBLIVAC FIX during the double blind study period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    SUBLIVAC FIX Birch
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Sublingual use
    Dosage and administration details
    Start with 1 drop daily of SUBLIVAC FIX Birch (40,000 AUN/ml) and increase by 1 drop daily, until the maintenance dose of 5 drops is reached. Mode of administration: Sublingual administration.

    Number of subjects in period 1
    		SUBLIVAC Placebo SUBLIVAC FIX Birch
    Started
    198
    208
    Completed
    186
    188
    Not completed
    12
    20
         Consent withdrawn by subject
    3
    4
         Physician decision
    1
    -
         Adverse event, non-fatal
    5
    10
         Other
    -
    2
         Protocol violation, <75% treatment compliance
    1
    -
         Lost to follow-up
    2
    2
         Not able to reach maintenance dose within 14 days
    -
    2
    Period 2
    Period 2 title
    open-label extension period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SUBLIVAC Placebo origin
    Arm description
    		 Subjects participating in the safety extension period who were previously randomized to the Placebo treatment arm during the double blind study period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    SUBLIVAC FIX Birch
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Sublingual use
    Dosage and administration details
    Start with 1 drop daily of SUBLIVAC FIX Birch (40,000 AUN/ml) and increase by 1 drop daily, until the maintenance dose of 5 drops is reached. Mode of administration: Sublingual administration.

    Arm title
    		 SUBLIVAC FIX Birch origin
    Arm description
    		 Subjects participating in the safety extension period who were previously randomized to the SUBLIVAX FIX active treatment arm during the double blind study period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sublivac FIX Birch
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Sublingual use
    Dosage and administration details
    Dose: Start with 1 drop daily of SUBLIVAC FIX Birch and increase by 1 drop daily, until the maintenance dose of 5 drops is reached. Mode of administration: Sublingual administration.

    Number of subjects in period 2 [1]
    		SUBLIVAC Placebo origin SUBLIVAC FIX Birch origin
    Started
    174
    169
    Completed
    174
    169
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects who completed the double-blind part of the study and were willing to proceed were included in the open-label safety extension period and treated with SB . In total 343 subjects participated in this extension period; 174 subjects originally randomized to placebo group and 169 subjects originally randomized to the SUBLIVAC FIX Birch group.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SUBLIVAC Placebo
    Reporting group description
    		 Subjects treated with Placebo during the double blind study period.

    Reporting group title
    SUBLIVAC FIX Birch
    Reporting group description
    		 Subjects treated with SUBLIVAC FIX during the double blind study period.

    Reporting group values
    		 SUBLIVAC Placebo SUBLIVAC FIX Birch Total
    Number of subjects
    		 198 208 406
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 198 206 404
        From 65-84 years
    		 0 2 2
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 36 (18 to 61) 37 (18 to 65) -
    Gender categorical
    Units: Subjects
        Female
    		 118 106 224
        Male
    		 80 102 182
    Subject analysis sets

    Subject analysis set title
    ITT SUBLIVAC FIX Birch
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-Treat population (ITT): all patients who were randomized and received at least one dose of study medication and for whom at least one post-baseline (post-screening) measurement for the primary efficacy parameter was available.

    Subject analysis set title
    ITT Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-Treat population (ITT): all patients who were randomized and received at least one dose of study medication and for whom at least one post-baseline (post-screening) measurement for the primary efficacy parameter was available.

    Subject analysis sets values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects
    179
    178
    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)
    177
    178
        From 65-84 years
    2
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    35 (18 to 65)
    Gender categorical
    Units: Subjects
        Female
    89
        Male
    90

    End points

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    End points reporting groups
    Reporting group title
    SUBLIVAC Placebo
    Reporting group description
    		 Subjects treated with Placebo during the double blind study period.

    Reporting group title
    SUBLIVAC FIX Birch
    Reporting group description
    		 Subjects treated with SUBLIVAC FIX during the double blind study period.
    Reporting group title
    SUBLIVAC Placebo origin
    Reporting group description
    		 Subjects participating in the safety extension period who were previously randomized to the Placebo treatment arm during the double blind study period.

    Reporting group title
    SUBLIVAC FIX Birch origin
    Reporting group description
    		 Subjects participating in the safety extension period who were previously randomized to the SUBLIVAX FIX active treatment arm during the double blind study period.

    Subject analysis set title
    ITT SUBLIVAC FIX Birch
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-Treat population (ITT): all patients who were randomized and received at least one dose of study medication and for whom at least one post-baseline (post-screening) measurement for the primary efficacy parameter was available.

    Subject analysis set title
    ITT Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-to-Treat population (ITT): all patients who were randomized and received at least one dose of study medication and for whom at least one post-baseline (post-screening) measurement for the primary efficacy parameter was available.

    Primary: Mean CSMS during the pollen season

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    End point title
    		 Mean CSMS during the pollen season
    End point description
    Difference in mean Combined Symptom Medication Score (CSMS) between the SUBLIVAC FIX and placebo treatment group, assessed during birch pollen season in ITT population.
    End point type
    Primary
    End point timeframe
    Assessed during birch pollen season.
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: CSMS
        least squares mean (standard error)
    1 ( 0.08 )
    1.45 ( 0.08 )
    Statistical analysis title
    		 Analysis of mean CSMS during the pollen season
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.66
         upper limit
    		 -0.26

    Secondary: Mean CSMS during the Peak Pollen Season

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    End point title
    		 Mean CSMS during the Peak Pollen Season
    End point description
    Difference in mean Combined Symptom and Medication Score (CSMS) between the SUBLIVAC FIX and placebo treatment group, assessed during the peak pollen season in the ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed during the peak pollen season.
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: CSMS
        least squares mean (standard error)
    0.96 ( 0.1 )
    1.56 ( 0.1 )
    Statistical analysis title
    		 Analysis of mean CSMS during peak pollen season
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 -0.33

    Secondary: Mean Symptom Score during the Pollen Season

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    End point title
    		 Mean Symptom Score during the Pollen Season
    End point description
    Difference In mean Symptom Scores between the SUBLIVAC FIX and placebo treatment group, assessed during the pollen season in the ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed during the pollen season.
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: Symptom score
        least squares mean (standard error)
    0.55 ( 0.04 )
    0.82 ( 0.04 )
    Statistical analysis title
    		 Analysis of mean symptom score: pollen season
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 -0.16

    Secondary: Mean Medication Score during the Pollen Season

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    End point title
    		 Mean Medication Score during the Pollen Season
    End point description
    Difference in mean Medication Scores between the SUBLIVAC FIX and placebo treatment group, assessed during birch pollen season in the ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed during the pollen season.
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: Medication score
        least squares mean (standard error)
    0.45 ( 0.05 )
    0.64 ( 0.05 )
    Statistical analysis title
    		 Analysis of mean medication score: pollen season
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 -0.06

    Secondary: Mean Symptom score during the Peak Pollen Season

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    End point title
    		 Mean Symptom score during the Peak Pollen Season
    End point description
    Difference in mean Symptom Scores between the active vs. placebo treatment group, assessed during the peak pollen season in the ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed during the peak pollen season.
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: Symptom score
        least squares mean (standard error)
    0.55 ( 0.04 )
    0.82 ( 0.04 )
    Statistical analysis title
    		 Analysis of mean symptom score: peak pollen season
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 -0.23

    Secondary: Mean Medication Score during the Peak Pollen Season

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    End point title
    		 Mean Medication Score during the Peak Pollen Season
    End point description
    Mean Symptom scores during the Peak Pollen Season for ITT population, comparing Placebo and Sublivac Birch group.
    End point type
    Secondary
    End point timeframe
    During the peak pollen season
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: Medication score
        least squares mean (standard error)
    0.43 ( 0.06 )
    0.66 ( 0.06 )
    Statistical analysis title
    		 Analysis mean medication score: peak pollen season
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.06

    Secondary: RQLQ-S during the pollen season and at EOT/ET visit

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    End point title
    		 RQLQ-S during the pollen season and at EOT/ET visit
    End point description
    Rhinoconjunctivitis Quality of Life Questionnaire Score (RQLQ-S) during the pollen-season and at end of trial (EOT)/ early termination (ET) visit in the ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed at baseline, at pollen-season visit and at end of trial/ early termination visit.
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: RQLQ-S
    least squares mean (standard error)
        during the pollen season
    0.53 ( 0.09 )
    1.06 ( 0.09 )
        at EOT/ET
    0.41 ( 0.08 )
    0.49 ( 0.08 )
    Statistical analysis title
    		 Analysis of RQLQ during the pollen season
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.75
         upper limit
    		 -0.32
    Statistical analysis title
    		 Analysis of RQLQ at EOT/ET
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.11

    Secondary: EQ-5D during the pollen season and at EOT/ET

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    End point title
    		 EQ-5D during the pollen season and at EOT/ET
    End point description
    Quality of life Questionnaire Score (EQ-5D) during the pollen season and at the end of trial (EOT)/ early termination (ET) in ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed at baseline and at pollen season visit and at the end of trial (EOT)/ early termination (ET)
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: EQ-5D
    least squares mean (standard error)
        during the pollen season
    -0.59 ( 0.2 )
    -1.3 ( 0.2 )
        at EOT/ET
    -0.26 ( 0.17 )
    -0.13 ( 0.17 )
    Statistical analysis title
    		 Analysis of EQ-5D during pollen season
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 1.2
    Statistical analysis title
    		 Analysis of EQ-5D at EOT/ET
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.49
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.25

    Secondary: ACQ during the pollen season and EOT/ET visit

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    End point title
    		 ACQ during the pollen season and EOT/ET visit
    End point description
    Asthma Control Questionnaire (ACQ) during the pollen-season (mid-season visit) and at end of the trial (EOT)/ early termination (ET) visit in ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed during the pollen season (mid-season visit) and at end of the trial (EOT)/ early termination (ET) visit
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    44
    38
    Units: ACQ
    least squares mean (standard error)
        Mid-season visit
    0.21 ( 0.1 )
    0.21 ( 0.11 )
        EOT/ET visit
    0.06 ( 0.09 )
    0.19 ( 0.09 )
    Statistical analysis title
    		 Analysis of ACQ at mid-season visit
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 0.29
    Statistical analysis title
    		 Analysis of ACQ at EOT/ET visit
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 0.13

    Secondary: Specific Bet v1 IgE at 12 weeks and at EOT/ET visit

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    End point title
    		 Specific Bet v1 IgE at 12 weeks and at EOT/ET visit
    End point description
    Change from baseline in logarithmic scale of Bet v1 (t215) specific IgE at 12 weeks and at end of trial (EOT)/ early termination (ET) visit in ITT population.
    End point type
    Secondary
    End point timeframe
    After 12 weeks treatment and at end of trial/ early termination.
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: ratio
    geometric mean (confidence interval 95%)
        12 weeks after treatment start
    2.5 (2.23 to 2.79)
    1.08 (0.97 to 1.21)
        EOT/ ET visit
    1.85 (1.62 to 2.11)
    1.35 (1.18 to 1.54)
    Statistical analysis title
    		 Analysis of Specific Bet v1 IgE at 12 weeks
    Statistical analysis description
    Presented in SB/ placebo ratio.
    Comparison groups
    ITT Placebo v ITT SUBLIVAC FIX Birch
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric mean ratio
    Point estimate
    2.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.99
         upper limit
    		 2.68
    Statistical analysis title
    		 Analysis of Specific Bet v1 IgE at EOT/ET
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 1.64

    Secondary: Specific Birch pollen IgE at 12 weeks and EOT/ET visit

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    End point title
    		 Specific Birch pollen IgE at 12 weeks and EOT/ET visit
    End point description
    Change from baseline in logarithmic scale of Birch pollen (t3) specific IgE at 12 weeks and at end of trial (EOT)/ early termination (ET) visit in ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed after 12 weeks of treatment and at end of trial/ early termination.
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: ratio
    geometric mean (confidence interval 95%)
        12 weeks after treatment start
    2.34 (2.11 to 2.59)
    1.02 (0.92 to 1.12)
        EOT/ET visit
    1.31 (1.1 to 1.55)
    0.99 (0.83 to 1.17)
    Statistical analysis title
    		 Analysis of Specific Birch pollen IgE at 12 weeks
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.02
         upper limit
    		 2.62
    Statistical analysis title
    		 Analysis of Specific Birch pollen IgE at EOT/ET
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 1.67

    Secondary: Specific Bet v1 IgG at 12 weeks and at EOT/ET visit

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    End point title
    		 Specific Bet v1 IgG at 12 weeks and at EOT/ET visit
    End point description
    Change from baseline in logarithmic scale of Bet v1 (t215) specific IgG at 12 weeks and at end of trial (EOT)/ early termination (ET) visit in ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed after 12 weeks of treatment and at end of trial/early termination visit
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: ratio
    geometric mean (confidence interval 95%)
        12 weeks after treatment start
    1.9 (1.77 to 2.04)
    1.01 (0.94 to 1.08)
        EOT/ET visit
    2.32 (2.11 to 2.54)
    0.94 (0.86 to 1.03)
    Statistical analysis title
    		 Analysis of Specific Bet v1 IgG at 12 weeks
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    1.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.71
         upper limit
    		 2.08
    Statistical analysis title
    		 Analysis of Specific Bet v1 IgG at EOT/ET
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    2.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.17
         upper limit
    		 2.8

    Secondary: Specific Birch pollen IgG at 12 weeks and EOT/ET visit

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    End point title
    		 Specific Birch pollen IgG at 12 weeks and EOT/ET visit
    End point description
    Change from baseline in logarithmic scale of Birch pollen (t3) specific IgG at 12 weeks and at end of trial (EOT)/ early termination (ET) visit in ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed after 12 weeks of treatment and at end of trial/early termination visit
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: ratio
    geometric mean (confidence interval 95%)
        12 weeks after treatment start
    1.93 (1.78 to 2.08)
    1.09 (1.01 to 1.18)
        EOT/ET visit
    2.46 (2.25 to 2.68)
    1.03 (0.94 to 1.12)
    Statistical analysis title
    		 Analysis of Specific Birch pollen IgG at 12 weeks
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 1.95
    Statistical analysis title
    		 Analysis of Specific Birch pollen IgG at EOT/ET
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    2.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.13
         upper limit
    		 2.67

    Secondary: Specific Bet v1 IgG4 at 12 weeks and at EOT/ET visit

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    End point title
    		 Specific Bet v1 IgG4 at 12 weeks and at EOT/ET visit
    End point description
    Change from baseline in logarithmic scale of Bet v1 (t215) specific IgG4 at 12 weeks and at end of trial (EOT)/ early termination (ET) visit in ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed after 12 weeks of treatment and at end of trial/early termination visit
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: ratio
    arithmetic mean (confidence interval 95%)
        12 weeks after treatment start
    3.73 (3.3 to 4.23)
    1.03 (0.91 to 1.17)
        EOT / ET visit
    6.71 (5.81 to 7.75)
    1.03 (0.89 to 1.19)
    Statistical analysis title
    		 Analysis of Specific Bet v1 IgG4 at 12 weeks
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    3.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.1
         upper limit
    		 4.2
    Statistical analysis title
    		 Analysis of Specific Bet v1 IgG4 at EOT/ET
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.42
         upper limit
    		 7.81

    Secondary: Specific Birch pollen IgG4 at 12 weeks and EOT/ET visit

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    End point title
    		 Specific Birch pollen IgG4 at 12 weeks and EOT/ET visit
    End point description
    Change from baseline in logarithmic scale of Birch pollen (t3) specific IgG4 at 12 weeks and at end of trial (EOT)/ early termination (ET) visit in ITT population.
    End point type
    Secondary
    End point timeframe
    Assessed after 12 weeks of treatment and at end of study/early termination visit
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: ratio
    geometric mean (confidence interval 95%)
        12 weeks after treatment start
    2.73 (2.45 to 3.05)
    0.91 (0.81 to 1.01)
        EOT/ET visit
    4.86 (4.27 to 5.53)
    0.99 (0.87 to 1.13)
    Statistical analysis title
    		 Analysis of Specific Birch pollen IgG4 at 12 weeks
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    3.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.63
         upper limit
    		 3.44
    Statistical analysis title
    		 Analysis of Specific Birch pollen IgG4 at EOT/ET
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 SB / Placebo Geometric mean ratio
    Point estimate
    4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.15
         upper limit
    		 5.78

    Secondary: Percentage well days during the pollen season

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    End point title
    		 Percentage well days during the pollen season
    End point description
    Percentage of well days days during the pollen season in ITT population. Well days were defined as days with no rescue medication and a symptom score of no larger than 2. The percentage of well days has been calculated as the number of well days divided by the number of days the patient completed e-diary during the birch pollen season, times 100, respectively.
    End point type
    Secondary
    End point timeframe
    Assessed during the pollen season.
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: percentage
        arithmetic mean (standard error)
    67.53 ( 3.31 )
    52.26 ( 3.32 )
    Statistical analysis title
    		 Aanalysis of well days during the pollen season
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    15.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.64
         upper limit
    		 22.89

    Secondary: Percentage severe days during the pollen season

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    End point title
    		 Percentage severe days during the pollen season
    End point description
    Percentage of severe days during the pollen season in ITT population. Severe days were defined as days with a symptom score of 3 in any of the six rhinoconjunctivitis symptoms. The percentage of severe days has been calculated as the number of severe days divided by the number of days the patient completed e-diary during the birch pollen season, times 100, respectively.
    End point type
    Secondary
    End point timeframe
    Assessed during the pollen season
    End point values
    		 ITT SUBLIVAC FIX Birch ITT Placebo
    Number of subjects analysed
    179
    178
    Units: precentage
        arithmetic mean (standard error)
    4.04 ( 1.32 )
    9.47 ( 1.32 )
    Statistical analysis title
    		 Analysis of severe days during the pollen season
    Comparison groups
    ITT SUBLIVAC FIX Birch v ITT Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.89
         upper limit
    		 -1.97

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event monitoring was done during the double-blind period as well as during the safety-extension period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo (Double-blind period)
    Reporting group description
    		 Safety population during the double-blind study period allocated to Placebo treatment.

    Reporting group title
    SUBLIVAC FIX Birch (Double-blind period)
    Reporting group description
    		 Safety population during the double-blind study period allocated to SUBLIVAC FIX Birch active treatment.

    Reporting group title
    Former Placebo (Open label extension period)
    Reporting group description
    		 Subjects participating in the safety extension period who were previously randomized to the Placebo treatment arm during the double blind study period.

    Reporting group title
    Former SUBLIVAC FIX Birch (Open label extension period)
    Reporting group description
    		 Subjects participating in the safety extension period who were previously randomized to the SUBLIVAC FIX treatment arm during the double blind study period.

    Serious adverse events
    		 Placebo (Double-blind period) SUBLIVAC FIX Birch (Double-blind period) Former Placebo (Open label extension period) Former SUBLIVAC FIX Birch (Open label extension period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 198 (2.02%)
    5 / 208 (2.40%)
    2 / 174 (1.15%)
    3 / 169 (1.78%)
         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
    Joint dislocation
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 208 (0.48%)
    1 / 174 (0.57%)
    0 / 169 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 208 (0.00%)
    0 / 174 (0.00%)
    1 / 169 (0.59%)
         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
    Surgical and medical procedures
    Tonsillectomy
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 208 (0.00%)
    0 / 174 (0.00%)
    0 / 169 (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
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 208 (0.48%)
    0 / 174 (0.00%)
    0 / 169 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 208 (0.00%)
    1 / 174 (0.57%)
    0 / 169 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menstrual disorder
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 208 (0.00%)
    0 / 174 (0.00%)
    1 / 169 (0.59%)
         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
    Respiratory, thoracic and mediastinal disorders
    Throat oedema
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 208 (0.48%)
    0 / 174 (0.00%)
    0 / 169 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 208 (0.48%)
    0 / 174 (0.00%)
    0 / 169 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 208 (0.00%)
    0 / 174 (0.00%)
    1 / 169 (0.59%)
         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
    Skin and subcutaneous tissue disorders
    Atopic dermatitis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 208 (0.00%)
    0 / 174 (0.00%)
    0 / 169 (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
    Angioedema
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 208 (0.48%)
    0 / 174 (0.00%)
    0 / 169 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 208 (0.00%)
    0 / 174 (0.00%)
    0 / 169 (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
    Pilonidal sinus
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 208 (0.00%)
    0 / 174 (0.00%)
    0 / 169 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo (Double-blind period) SUBLIVAC FIX Birch (Double-blind period) Former Placebo (Open label extension period) Former SUBLIVAC FIX Birch (Open label extension period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 198 (56.57%)
    159 / 208 (76.44%)
    99 / 174 (56.90%)
    55 / 169 (32.54%)
    Ear and labyrinth disorders
    Ear pruritus
         subjects affected / exposed
    2 / 198 (1.01%)
    18 / 208 (8.65%)
    11 / 174 (6.32%)
    2 / 169 (1.18%)
         occurrences all number
    2
    19
    11
    3
    Gastrointestinal disorders
    Oedema mouth
         subjects affected / exposed
    1 / 198 (0.51%)
    20 / 208 (9.62%)
    10 / 174 (5.75%)
    1 / 169 (0.59%)
         occurrences all number
    1
    21
    10
    1
    Oral discomfort
         subjects affected / exposed
    5 / 198 (2.53%)
    11 / 208 (5.29%)
    11 / 174 (6.32%)
    4 / 169 (2.37%)
         occurrences all number
    5
    14
    14
    4
    Oral pruritus
         subjects affected / exposed
    14 / 198 (7.07%)
    54 / 208 (25.96%)
    39 / 174 (22.41%)
    21 / 169 (12.43%)
         occurrences all number
    15
    59
    44
    24
    Oropharyngeal pain
         subjects affected / exposed
    5 / 198 (2.53%)
    13 / 208 (6.25%)
    4 / 174 (2.30%)
    1 / 169 (0.59%)
         occurrences all number
    5
    15
    4
    1
    Paraesthesia oral
         subjects affected / exposed
    1 / 198 (0.51%)
    13 / 208 (6.25%)
    9 / 174 (5.17%)
    3 / 169 (1.78%)
         occurrences all number
    1
    14
    11
    4
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    11 / 198 (5.56%)
    7 / 208 (3.37%)
    3 / 174 (1.72%)
    0 / 169 (0.00%)
         occurrences all number
    13
    8
    3
    0
    Pharyngeal oedema
         subjects affected / exposed
    3 / 198 (1.52%)
    13 / 208 (6.25%)
    5 / 174 (2.87%)
    0 / 169 (0.00%)
         occurrences all number
    3
    13
    6
    0
    Rhinorrhoea
         subjects affected / exposed
    10 / 198 (5.05%)
    6 / 208 (2.88%)
    2 / 174 (1.15%)
    0 / 169 (0.00%)
         occurrences all number
    12
    6
    2
    0
    Sneezing
         subjects affected / exposed
    10 / 198 (5.05%)
    8 / 208 (3.85%)
    2 / 174 (1.15%)
    0 / 169 (0.00%)
         occurrences all number
    11
    10
    2
    0
    Throat irritation
         subjects affected / exposed
    6 / 198 (3.03%)
    22 / 208 (10.58%)
    21 / 174 (12.07%)
    6 / 169 (3.55%)
         occurrences all number
    7
    24
    23
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    42 / 198 (21.21%)
    36 / 208 (17.31%)
    6 / 174 (3.45%)
    6 / 169 (3.55%)
         occurrences all number
    62
    53
    6
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2015
    In version 4 of the protocol, the study was amended with a safety extension period.

    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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