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    Clinical Trial Results:
    Efficacy and safety of the SQ tree SLIT-tablet in subjects with moderate to severe allergic rhinitis and/or conjunctivitis induced by pollen from the birch group

    Summary
    EudraCT number
    		 2015-004821-15
    Trial protocol
    		 DK   SE   CZ   FI   DE   PL   FR  
    Global end of trial date
    20 Jun 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    31 Oct 2019
    First version publication date
    05 Jan 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Protocol status for Fr needs to be updated from 'ongoing' to 'final'; however not possible from results posting page & no changes made to result listings

    Trial information

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    Trial identification
    Sponsor protocol code
    TT-04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ALK- Abello A/S
    Sponsor organisation address
    Bøge alle 1, Hørsholm, Denmark, 2970
    Public contact
    Global pharmacovigilance & clinical development, ALK Abello A/S, +45 45747576, clinicaltrials@alk.net
    Scientific contact
    Global pharmacovigilance & clinical development, ALK Abello A/S, +45 45747576, clinicaltrials@alk.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001879-PIP01-15
    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
    01 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate superiority of the SQ tree SLIT-tablet given once daily compared to placebo in the treatment of allergic rhinoconjunctivitis induced by birch pollen.
    Protection of trial subjects
    Safety surveillance Access to rescue medication
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 2016
    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: 232
    Country: Number of subjects enrolled
    Sweden: 35
    Country: Number of subjects enrolled
    Czech Republic: 71
    Country: Number of subjects enrolled
    Denmark: 24
    Country: Number of subjects enrolled
    Finland: 24
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 198
    Country: Number of subjects enrolled
    Russian Federation: 36
    Worldwide total number of subjects
    634
    EEA total number of subjects
    598
    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)
    60
    Adults (18-64 years)
    571
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from 57 trial sites in EU (Sweden, Finland, Denmark, Poland, Germany, the Czech Republic, France) and Russia First subject first visit: 15 april 2016 Last subject last visit: 20 June 2017

    Pre-assignment
    Screening details
    		 Main selection criteria: - Adults and adolescents (12-65 years) - History of moderate to severe allergic rhinitis and or conjunctivitis caused by pollen from the birch homologous group - Positive SPT and IgE against betula verrucosa

    Period 1
    Period 1 title
    treatment period (overall period)
    Is this the baseline period?
    		 Yes
    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
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Subjects were instructed to take 1 tablet every day in the morning

    Arm title
    		 SQ tree SLIT-tablet
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    SQ tree SLIT-tablet 12 DU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Subjects were instructed to take 1 tablet every day in the morning

    Number of subjects in period 1
    		Placebo SQ tree SLIT-tablet
    Started
    314
    320
    Completed
    292
    280
    Not completed
    22
    40
         Consent withdrawn by subject
    4
    9
         Adverse event, non-fatal
    8
    26
         Pregnancy
    3
    -
         -
    4
    5
         Lost to follow-up
    1
    -
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    SQ tree SLIT-tablet
    Reporting group description
    		 -

    Reporting group values
    		 Placebo SQ tree SLIT-tablet Total
    Number of subjects
    		 314 320 634
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 32 28 60
        Adults (18-64 years)
    		 281 290 571
        From 65-84 years
    		 1 2 3
    Gender categorical
    Units: Subjects
        Female
    		 168 168 336
        Male
    		 146 152 298
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set, defined as all randomised subjects

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    634
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    60
        Adults (18-64 years)
    571
        From 65-84 years
    3
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
    336
        Male
    298

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    SQ tree SLIT-tablet
    Reporting group description
    		 -

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set, defined as all randomised subjects

    Primary: Average TCS in the birch pollen season (BPS)

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    End point title
    		 Average TCS in the birch pollen season (BPS)
    End point description
    The primary endpoint of the trial was the average daily allergic rhinoconjunctivitis total combined score (TCS) during the BPS. The TCS is the sum of the rhinoconjunctivitis symptom score (DSS) and mediction score (DMS). For the DSS a total of 6 rhinoconjunctivitis symptoms (runny nose, blocked nose, sneezing, itchy nose, gritty/red/itchy eyes and watery eyes) were measured on a scale from no symptoms (0) to severe symptoms (3) (range 0-12) For the DMS subjects recorded the use of open label rhinitis and conjunctivitis medication as needed for treatment of their rhinitis and/or conjunctivitis symptoms not controlled by the IMP. - Desloradine tablets: score per tablet 6, max daily score 6 (1 tablet) - Olopatadine eye drops: score per dose 1.5 per eye, max daily score 6 (4 doses) - Momethasone nasa spray; score per dose 2, maximum daily score 8 (4 doses) Range 0-20
    End point type
    Primary
    End point timeframe
    During the birch pollen season
    End point values
    		 Placebo SQ tree SLIT-tablet
    Number of subjects analysed
    292
    283
    Units: 0-32
        least squares mean (confidence interval 95%)
    7.62 (6.55 to 8.78)
    4.61 (3.77 to 5.52)
    Statistical analysis title
    		 Analysis of average TCS in the BPS
    Statistical analysis description
    The response variable in the analysis is: the square root of the average TCS (results were back-transformed to original scale). The analysis is based on a linear mixed effect (lme) model with treatment as fixed class effect and pollen region as a random class variable.
    Comparison groups
    Placebo v SQ tree SLIT-tablet
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.99
         upper limit
    		 4.05

    Secondary: Average TCS in the tree pollen season (TPS)

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    End point title
    		 Average TCS in the tree pollen season (TPS)
    End point description
    Average TCS measured in the alder, hazel and birch pollen seasons combined (days in-between seasons excluded) TCS is a combination of the DSS and DMS (range 0-32)
    End point type
    Secondary
    End point timeframe
    Tree pollen season (TPS)
    End point values
    		 Placebo SQ tree SLIT-tablet
    Number of subjects analysed
    292
    283
    Units: 0-32
        least squares mean (confidence interval 95%)
    6.22 (5.35 to 7.16)
    3.95 (3.26 to 4.71)
    Statistical analysis title
    		 Analysis of average TCS in the TPS
    Statistical analysis description
    The response variable in the analysis is: the square root of the average TCS (results were back-transformed to original scale). The analysis is based on a linear mixed effect (lme) model with treatment as fixed class effect and pollen region as a random class variable.
    Comparison groups
    SQ tree SLIT-tablet v Placebo
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.44
         upper limit
    		 3.11

    Secondary: Average DSS in the BPS

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    End point title
    		 Average DSS in the BPS
    End point description
    The rhiniconjunctivitis daily symptom score (DSS) consisted of 6 symptoms (rynny nose, blocked nose, sneezing, itchy nose, gritty/red/itchy eyes, and watery eyes) scored from no symptoms (0) to severe symptoms (3) Range 0-12
    End point type
    Secondary
    End point timeframe
    Birch pollen season
    End point values
    		 Placebo SQ tree SLIT-tablet
    Number of subjects analysed
    292
    283
    Units: 0-12
        least squares mean (confidence interval 95%)
    3.60 (3.15 to 4.09)
    2.28 (1.92 to 2.67)
    Statistical analysis title
    		 Analysis of DSS in the BPS
    Statistical analysis description
    The response variable in the analysis is: the square root of the average DSS (results were back-transformed to original scale). The analysis is based on a linear mixed effect (lme) model with treatment as fixed class effect and pollen region as a random class variable
    Comparison groups
    Placebo v SQ tree SLIT-tablet
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.81

    Secondary: Average DSS in the TPS

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    End point title
    		 Average DSS in the TPS
    End point description
    The rhinoconjunctivitis daily symptom score (DSS) consists of 6 symptoms (runny nose, blocked nose, sneezing, itchy nose, gritty/red/itchy eyes and watery eyes) scored from no symptoms (0) to severe symptoms (3). Range 0-12
    End point type
    Secondary
    End point timeframe
    Tree pollen season defined as the alder, hazel and birch pollen seasons combined (days in-between seasons excluded)
    End point values
    		 Placebo SQ tree SLIT-tablet
    Number of subjects analysed
    292
    283
    Units: 0-12
        least squares mean (confidence interval 95%)
    3.02 (2.66 to 3.40)
    2.03 (1.74 to 2.34)
    Statistical analysis title
    		 Analysis of DSS in the TPS
    Statistical analysis description
    The response variable in the analysis is: the square root of the average DSS (results were back-transformed to original scale). The analysis is based on a linear mixed effect (lme) model with treatment as fixed class effect and pollen region as a random class variable
    Comparison groups
    Placebo v SQ tree SLIT-tablet
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.38

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from consent to 7 days after end-of-trial or discontinuation. Only treatment-emergent AEs are presented (from first IMP intake to 7 days 7 days after end-of-trial or discontinuation)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    SQ tree SLIT-tablet 12 DU
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo SQ tree SLIT-tablet 12 DU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 314 (1.91%)
    4 / 320 (1.25%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Accidental exposure to product by child
    Additional description: child of subject ingested IMP. Subjects did not experience any AEs related to the ingestion
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Hernia
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 320 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 320 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo SQ tree SLIT-tablet 12 DU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    174 / 314 (55.41%)
    262 / 320 (81.88%)
    Ear and labyrinth disorders
    Ear pruritus
         subjects affected / exposed
    0 / 314 (0.00%)
    21 / 320 (6.56%)
         occurrences all number
    0
    25
    Gastrointestinal disorders
    Lip swelling
         subjects affected / exposed
    1 / 314 (0.32%)
    23 / 320 (7.19%)
         occurrences all number
    2
    28
    Mouth swelling
         subjects affected / exposed
    2 / 314 (0.64%)
    33 / 320 (10.31%)
         occurrences all number
    2
    38
    Oral pruritus
         subjects affected / exposed
    15 / 314 (4.78%)
    116 / 320 (36.25%)
         occurrences all number
    16
    161
    Paraesthesia oral
         subjects affected / exposed
    12 / 314 (3.82%)
    34 / 320 (10.63%)
         occurrences all number
    12
    42
    Swollen tongue
         subjects affected / exposed
    0 / 314 (0.00%)
    19 / 320 (5.94%)
         occurrences all number
    0
    19
    Tongue pruritus
         subjects affected / exposed
    6 / 314 (1.91%)
    33 / 320 (10.31%)
         occurrences all number
    7
    35
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    5 / 314 (1.59%)
    24 / 320 (7.50%)
         occurrences all number
    6
    33
    Pharyngeal oedema
         subjects affected / exposed
    1 / 314 (0.32%)
    25 / 320 (7.81%)
         occurrences all number
    1
    32
    Throat irritation
         subjects affected / exposed
    8 / 314 (2.55%)
    74 / 320 (23.13%)
         occurrences all number
    8
    96
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    58 / 314 (18.47%)
    47 / 320 (14.69%)
         occurrences all number
    84
    59

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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