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    Clinical Trial Results:
    A one-year placebo-controlled phase III trial evaluating the efficacy and safety of the house dust mite (HDM) SLIT-tablet in children (5-11 years of age) with HDM allergic rhinitis/rhinoconjunctivitis with or without asthma

    Summary
    EudraCT number
    		 2019-000560-22
    Trial protocol
    		 FR   SK   DE   PL   ES   BG   LT  
    Global end of trial date
    21 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Nov 2023
    First version publication date
    04 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MT-12
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04145219
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ALK-Abelló A/S
    Sponsor organisation address
    Bøge Allé 6-8, Hørsholm, Denmark, 2970
    Public contact
    Global pharmacovigilance and Clinical Development, ALK-Abelló A/S, 45 45747576, clinicaltrials@alk.net
    Scientific contact
    Global pharmacovigilance and Clinical Development, ALK-Abelló 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-001258-PIP01-11
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate the efficacy of the HDM sublingual immunotherapy (SLIT)-tablet compared to placebo in the treatment of HDM allergic rhinitis (AR) in children (5-11 years of age) based on total combined rhinitis symptoms and medication use (TCRS) during the primary efficacy assessment period.
    Protection of trial subjects
    Safety surveillance. Access to rescue/reliever medication.
    Background therapy
    		 Rescue medication: Subjects were provided with medication to treat rhinitis/rhinoconjunctivitis symptoms (antihistamine/intranasal corticosteroid) and asthma symptoms (short-acting β2-agonist, SABA), and, in countries where required, adrenaline auto-injector to treat severe allergic reactions. Asthma controller and reliever medication: Subjects with a diagnosis of asthma and using low or medium daily dose inhaled corticosteroids (ICS) (with or without long-acting β2-agonists, [LABA]) for asthma control, were allowed to continue with the same medication during the trial. In addition, the use of leukotriene receptor antagonists was permitted as concomitant medication for continued use on same dose only.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Oct 2019
    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
    Poland: 353
    Country: Number of subjects enrolled
    Slovakia: 66
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Bulgaria: 181
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Lithuania: 94
    Country: Number of subjects enrolled
    Canada: 38
    Country: Number of subjects enrolled
    Russian Federation: 329
    Country: Number of subjects enrolled
    Ukraine: 330
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    1458
    EEA total number of subjects
    721
    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)
    1458
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from 95 trial sites in 11 countries (Bulgaria, Canada, France, Germany, Lithuania, Poland, Russia, Slovakia, Spain, Ukraine and United States). First subject first visit: 12-Oct-2019 Last subject last visit/contact: 21-Apr-2023

    Pre-assignment
    Screening details
    		 Main criteria: - 5-11 years of age - Clinical history of HDM allergic rhinitis/conjunctivitis (AR/C) (+/- asthma) and with AR symptoms despite having received symptom-relieving medication during 1 year prior to screening - Positive SPT and IgE against D. pteronysimus and/or D. farinae - FEV1 percent predicted ≥ 70%

    Period 1
    Period 1 title
    Overall trial (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
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo SLIT-tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    The subject was instructed to preferably take the tablet in the morning, placed under the tongue, and swallowing should be avoided for approximately 1 minute. Food and beverages should not be taken for 5 minutes after intake of IMP. When the first dose was administered, the subject was under medical supervision for a minimum of 30 minutes after the tablet intake.

    Arm title
    		 12 SQ-HDM
    Arm description
    		 HDM SLIT-tablet (12 SQ-HDM)
    Arm type
    		 Experimental

    Investigational medicinal product name
    HDM SLIT-tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    The subject was instructed to preferably take the tablet in the morning, placed under the tongue, and swallowing should be avoided for approximately 1 minute. Food and beverages should not be taken for 5 minutes after intake of IMP. When the first dose was administered, the subject was under medical supervision for a minimum of 30 minutes after the tablet intake.

    Number of subjects in period 1
    		Placebo 12 SQ-HDM
    Started
    731
    727
    Completed
    707
    691
    Not completed
    24
    36
         Consent withdrawn by subject
    8
    12
         Reason stated as "other" in CRF
    7
    7
         Adverse event, non-fatal
    6
    14
         Severe or persistent symptoms of oesophagitis
    -
    1
         Lost to follow-up
    3
    2

    Baseline characteristics

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

    Reporting group title
    12 SQ-HDM
    Reporting group description
    		 HDM SLIT-tablet (12 SQ-HDM)

    Reporting group values
    		 Placebo 12 SQ-HDM Total
    Number of subjects
    		 731 727 1458
    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)
    		 731 727 1458
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 254 241 495
        Male
    		 477 486 963
    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 who received at least 1 dose of IMP. Subjects were analysed as randomised, i.e., according to their randomised assignment of treatment.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set, defined as all randomised subjects who received at least 1 dose of IMP. Subjects were analysed as treated, i.e., according to the treatment they actually received.

    Subject analysis sets values
    		 Full analysis set Safety analysis set
    Number of subjects
    1458
    1458
    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)
    1458
    1458
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    0
    0
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    495
    495
        Male
    963
    963

    End points

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

    Reporting group title
    12 SQ-HDM
    Reporting group description
    		 HDM SLIT-tablet (12 SQ-HDM)

    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 who received at least 1 dose of IMP. Subjects were analysed as randomised, i.e., according to their randomised assignment of treatment.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set, defined as all randomised subjects who received at least 1 dose of IMP. Subjects were analysed as treated, i.e., according to the treatment they actually received.

    Primary: Average daily total combined rhinitis symptoms and medication use (TCRS) during the primary efficacy assessment period

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    End point title
    		 Average daily total combined rhinitis symptoms and medication use (TCRS) during the primary efficacy assessment period
    End point description
    The primary endpoint of the trial was the average daily total combined rhinitis symptoms and medication use (TCRS) during the primary efficacy assessment period. The average daily TCRS evaluates the treatment effect based on the reduction in daily rhinitis symptoms and medication use (on a scale of 0-24). Higher scores indicate more severe symptoms and/or more medication use.
    End point type
    Primary
    End point timeframe
    8 weeks (primary efficacy assessment period), which started 44-49 weeks after initiation of IMP
    End point values
    		 Placebo 12 SQ-HDM
    Number of subjects analysed
    706 [1]
    693 [2]
    Units: Adjusted mean
        least squares mean (standard error)
    4.4 ( 0.3 )
    3.4 ( 0.3 )
    Notes
    [1] - Subjects from the full analysis set with observations in the primary efficacy assessment period
    [2] - Subjects from the full analysis set with observations in the primary efficacy assessment period
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The average daily TCRS was analysed using a linear mixed effect (LME) model with square root transformation. The model includes the square root of the endpoint as response variable, treatment and cohort as fixed factors, the square root of the baseline value as a covariate, country/region within cohort as a random effect, and with different residual errors specified for each treatment. No missing data approach was applied.
    Comparison groups
    Placebo v 12 SQ-HDM
    Number of subjects included in analysis
    1399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effect (LME)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.4

    Secondary: Average rhinitis daily symptom score (DSS) during the primary efficacy assessment period

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    End point title
    		 Average rhinitis daily symptom score (DSS) during the primary efficacy assessment period
    End point description
    Average rhinitis daily symptom score (DSS) evaluates the treatment effect based on the reduction in daily rhinitis symptoms (on a scale of 0-12). Higher scores indicate more severe symptoms.
    End point type
    Secondary
    End point timeframe
    8 weeks (primary efficacy assessment period), which started 44-49 weeks after initiation of IMP
    End point values
    		 Placebo 12 SQ-HDM
    Number of subjects analysed
    706 [3]
    693 [4]
    Units: Adjusted mean
        least squares mean (standard error)
    1.9 ( 0.1 )
    1.5 ( 0.1 )
    Notes
    [3] - Subjects from the full analysis set with observations in the primary efficacy assessment period.
    [4] - Subjects from the full analysis set with observations in the primary efficacy assessment period.
    Statistical analysis title
    		 Analysis of key secondary endpoint
    Statistical analysis description
    The average rhinitis DSS was analysed using a linear mixed effect (LME) model with square root transformation. The model includes the square root of the endpoint as response variable, treatment and cohort as fixed factors, the square root of the baseline value as a covariate, country/region within cohort as a random effect, and with different residual errors specified for each treatment. No missing data approach was applied.
    Comparison groups
    Placebo v 12 SQ-HDM
    Number of subjects included in analysis
    1399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effect (LME)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.6

    Secondary: Average rhinitis daily medication score (DMS) during the primary efficacy assessment period

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    End point title
    		 Average rhinitis daily medication score (DMS) during the primary efficacy assessment period
    End point description
    Average rhinitis daily medication score (DMS) evaluates the treatment effect based on the reduction in daily rhinitis medication use (on a scale of 0-12). Higher scores indicate more medication use.
    End point type
    Secondary
    End point timeframe
    8 weeks (primary efficacy assessment period), which started 44-49 weeks after initiation of IMP
    End point values
    		 Placebo 12 SQ-HDM
    Number of subjects analysed
    706 [5]
    693 [6]
    Units: Adjusted mean
        least squares mean (standard error)
    1.9 ( 0.2 )
    1.4 ( 0.2 )
    Notes
    [5] - Subjects from the full analysis set with observations in the primary efficacy assessment period.
    [6] - Subjects from the full analysis set with observations in the primary efficacy assessment period.
    Statistical analysis title
    		 Analysis of key secondary endpoint
    Statistical analysis description
    The average rhinitis DMS was analysed using a linear mixed effect (LME) model with square root transformation. The model includes the square root of the endpoint as response variable, treatment and cohort as fixed factors, the square root of the baseline value as a covariate, country/region within cohort as a random effect, and with different residual errors specified for each treatment. No missing data approach was applied.
    Comparison groups
    Placebo v 12 SQ-HDM
    Number of subjects included in analysis
    1399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0016
    Method
    		 Linear mixed effect (LME)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.8

    Secondary: Average daily total combined score (TCS) during the primary efficacy assessment period

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    End point title
    		 Average daily total combined score (TCS) during the primary efficacy assessment period
    End point description
    Average rhinoconjunctivitis total combined score (TCS) evaluates the treatment effect based on the reduction in daily rhinoconjunctivitis symptoms and medication use (on a scale of 0-38). Higher scores indicate more severe symptoms and/or more medication use.
    End point type
    Secondary
    End point timeframe
    8 weeks (primary efficacy assessment period), which started 44-49 weeks after initiation of IMP
    End point values
    		 Placebo 12 SQ-HDM
    Number of subjects analysed
    706 [7]
    693 [8]
    Units: Adjusted mean
        least squares mean (standard error)
    5.2 ( 0.4 )
    4.0 ( 0.4 )
    Notes
    [7] - Subjects from the full analysis set with observations in the primary efficacy assessment period.
    [8] - Subjects from the full analysis set with observations in the primary efficacy assessment period.
    Statistical analysis title
    		 Analysis of key secondary endpoint
    Statistical analysis description
    The average rhinitis TCS was analysed using a linear mixed effect (LME) model with square root transformation. The model includes the square root of the endpoint as response variable, treatment and cohort as fixed factors, the square root of the baseline value as a covariate, country/region within cohort as a random effect, and with different residual errors specified for each treatment. No missing data approach was applied.
    Comparison groups
    Placebo v 12 SQ-HDM
    Number of subjects included in analysis
    1399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Linear mixed effect (LME)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from consent to last follow-up phone contact. Only treatment-emergent AEs are presented (AEs with start time on or after the time of first IMP administration and no later than 7 days after the last day of IMP administration).
    Adverse event reporting additional description
    For the first 28 days of treatment, subjects used an eDiary daily to capture presence/absence of 15 pre-specified signs/symptoms, identified as local side effects of sublingual immunotherapy. These were assessed and reported as AEs in the eCRF at the discretion of the investigator and are included in TEAEs presented.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    12 SQ-HDM
    Reporting group description
    		 HDM SLIT-tablet (12 SQ-HDM)

    Serious adverse events
    		 Placebo 12 SQ-HDM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 731 (0.82%)
    16 / 727 (2.20%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carbon monoxide poisoning
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 727 (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
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Immune system disorder
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular torsion
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 727 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Attention deficit hyperactivity disorder
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucinations, mixed
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 731 (0.00%)
    2 / 727 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 731 (0.27%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas bronchitis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 731 (0.00%)
    1 / 727 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 727 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 731 (0.14%)
    0 / 727 (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 12 SQ-HDM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    534 / 731 (73.05%)
    608 / 727 (83.63%)
    Nervous system disorders
    Taste disorder
         subjects affected / exposed
    116 / 731 (15.87%)
    123 / 727 (16.92%)
         occurrences all number
    218
    213
    Ear and labyrinth disorders
    Ear pruritus
         subjects affected / exposed
    135 / 731 (18.47%)
    242 / 727 (33.29%)
         occurrences all number
    299
    547
    Gastrointestinal disorders
    Oral pruritus
         subjects affected / exposed
    185 / 731 (25.31%)
    419 / 727 (57.63%)
         occurrences all number
    425
    1149
    Abdominal pain upper
         subjects affected / exposed
    164 / 731 (22.44%)
    243 / 727 (33.43%)
         occurrences all number
    320
    512
    Lip swelling
         subjects affected / exposed
    38 / 731 (5.20%)
    151 / 727 (20.77%)
         occurrences all number
    63
    282
    Glossodynia
         subjects affected / exposed
    41 / 731 (5.61%)
    142 / 727 (19.53%)
         occurrences all number
    54
    313
    Nausea
         subjects affected / exposed
    81 / 731 (11.08%)
    135 / 727 (18.57%)
         occurrences all number
    125
    260
    Mouth swelling
         subjects affected / exposed
    27 / 731 (3.69%)
    99 / 727 (13.62%)
         occurrences all number
    41
    210
    Swollen tongue
         subjects affected / exposed
    20 / 731 (2.74%)
    99 / 727 (13.62%)
         occurrences all number
    29
    203
    Diarrhoea
         subjects affected / exposed
    74 / 731 (10.12%)
    95 / 727 (13.07%)
         occurrences all number
    107
    151
    Mouth ulceration
         subjects affected / exposed
    53 / 731 (7.25%)
    93 / 727 (12.79%)
         occurrences all number
    80
    162
    Tongue ulceration
         subjects affected / exposed
    27 / 731 (3.69%)
    50 / 727 (6.88%)
         occurrences all number
    34
    82
    Vomiting
         subjects affected / exposed
    33 / 731 (4.51%)
    48 / 727 (6.60%)
         occurrences all number
    38
    76
    Tooth loss
         subjects affected / exposed
    35 / 731 (4.79%)
    40 / 727 (5.50%)
         occurrences all number
    61
    66
    Respiratory, thoracic and mediastinal disorders
    Throat irritation
         subjects affected / exposed
    236 / 731 (32.28%)
    401 / 727 (55.16%)
         occurrences all number
    504
    1072
    Pharyngeal irritation
         subjects affected / exposed
    22 / 731 (3.01%)
    68 / 727 (9.35%)
         occurrences all number
    33
    134
    Asthma
         subjects affected / exposed
    38 / 731 (5.20%)
    14 / 727 (1.93%)
         occurrences all number
    49
    16
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    164 / 731 (22.44%)
    185 / 727 (25.45%)
         occurrences all number
    206
    250
    COVID-19
         subjects affected / exposed
    38 / 731 (5.20%)
    38 / 727 (5.23%)
         occurrences all number
    38
    38
    Pharyngitis
         subjects affected / exposed
    37 / 731 (5.06%)
    38 / 727 (5.23%)
         occurrences all number
    49
    44
    Bronchitis
         subjects affected / exposed
    45 / 731 (6.16%)
    36 / 727 (4.95%)
         occurrences all number
    52
    42
    Upper respiratory tract infection
         subjects affected / exposed
    37 / 731 (5.06%)
    22 / 727 (3.03%)
         occurrences all number
    53
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2019
    The amendment was prepared to update selected inclusion criteria and the main changes were: - For subjects for whom medical records of HDM AR/C diagnosis were not available, verbal history from subject/parent/caregiver could be used - Subjects that were 7 years old or younger and did not have asthma were not required to meet the inclusion criterion of FEV1 ≥ 70%, if despite coaching they were not able to perform a reproducible FEV1 manoeuvre
    19 Mar 2021
    The trial started before the COVID-19 pandemic and ended during the pandemic. At the outbreak of the COVID-19 pandemic, measures to protect the safety and integrity of trial subjects were implemented in March and April 2020 (see also Section on Trial Interruptions). An amendment was later prepared, in which the main changes included updates to trial procedures to mitigate the risks associated with the COVID-19 pandemic.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Mar 2020
    Due to the COVID-19 pandemic, screening and randomisation of cohort 1 was stopped on 20-Mar-2020 prior to the planned deadline of 01-Apr-2020. Subjects screened in Cohort 1 (but not randomised) were screen failed and offered a re-screening in Cohort 2. Screening of subjects for Cohort 2 was initiated as planned on 07-July-2020. A cohort 3 was subsequently added to recruit a sufficient number of subjects. Generally, the following mitigations were implemented due to COVID-19: - Option to convert on-site visits to remote visits via telephone or video was introduced - Introduction of direct-to-patient shipment of IMP and rescue medication, if on-site pick-up was not possible - Option to perform remote monitoring visits over telephone was introduced
    07 Jul 2020

    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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    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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