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    Clinical Trial Results:
    A prospective, multicenter, double-blind, placebo-controlled randomized study to assess efficacy and safety of LAIS® Grass pollen tablets in patients with seasonal grass pollen-induced allergic rhinoconjunctivitis

    Summary
    EudraCT number
    		 2019-001532-65
    Trial protocol
    		 IT  
    Global end of trial date
    24 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Apr 2022
    First version publication date
    22 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LGT03-19
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Lofarma Spa
    Sponsor organisation address
    Viale Cassala, 40, Milan, Italy, 20143
    Public contact
    CRO, CD PHARMA GROUP SRL, +39 02581981,
    Scientific contact
    CRO, CD PHARMA GROUP SRL, +39 02581981,
    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
    15 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the efficacy and safety of tablet-based sublingual immunotherapy (SLIT) with the monomeric allergoid LAIS® Grass tablets compared to placebo in patients with grass pollen-induced allergic rhinoconjunctivitis with or without controlled asthma.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, under the provisions of the Declaration of Helsinki, and in accordance with the International Conference on Harmonization (ICH) Consolidated Guideline on Good Clinical Practice (GCP). With the exception of those drugs listed among non-permitted medications participants were allowed to use any concomitant medication (necessary for the treatment of preexisting concomitant pathologies or for intercurrent diseases), that did not interfere with the study evaluation parameters. Decongestants (oral, nasal spray, drops) were allowed for symptom relief for short term needs (i.e. to provide relief after the TNPT, in occurrence of a cold or flu). Asthma medications not influencing the study outcomes (i.e. inhaled corticosteroids, short-acting and long acting beta-2-agonists) were admitted to maintain asthma control along the whole trial duration.
    Background therapy
    		 Standard rescue therapy with anti-symptomatic medication during the grass pollen season: Desloratadine (oral) , Levocabastine (eyedrops), Mometasone furoate (nasal) 50 mcg , Prednisone (oral) 5 mg. The score was assigned as follows: Score = 1: use of oral/ocular antihistamines; Score = 2: use of nasal corticosteroids; Score = 3: use of oral corticosteroids. The assumption of Rescue Medications was reported on the patient diary. For adolescents included in the trial, parents were responsible for the management of rescue medications and careful clinical diary completion
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Nov 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 9 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 98
    Worldwide total number of subjects
    98
    EEA total number of subjects
    98
    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)
    17
    Adults (18-64 years)
    81
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Territory: Italy The total number of partecipants in each treatment group was recruited and screened for inclusion and exclusion criteria. Recruitment was greatly slower than planned. Limitation of a reduced sample size was due to the premature termination of the study enrolment.

    Pre-assignment
    Screening details
    		 Patients with a confirmed diagnosis of moderate to severe ARC based on medical history underwent a skin prick test and nasal allergen provocation challenge with Grass pollen extract and serum specific IgE (>0.7 kU/l) for Phl p1-5.

    Period 1
    Period 1 title
    Grass pollen (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The randomization was implemented in eCRF according to an algorithm generated and validated by CINECA. A paper copy of the complete randomization list was placed in a sealed envelope and retained in a secure, fire-proof room with restricted-access at the CRO. The MED.ID was then printed on the label of the medication prescribed by the randomization list. Breaking of this code was only valid under certain circumstances

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo - Group 1
    Arm description
    		 Sublingual placebo preparation (one tablet once daily) for about 7-9 months pre-/coseasonally (from at least 16 weeks before the expected start of the pollen season to 30 June 2020) and standard rescue therapy with anti-symptomatic medication during the grass pollen season. Placebo and verum preparation were identical except of the active ingredient
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo of Lais Grass sublingual tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Independent of the assigned tratment group, the patients ingested one sublingual tablet per day. The first dose had to be self-administered at the randomization visit (V1) at study site and patient was monitored for at least 30 minutes after tablet intake.

    Arm title
    		 Lais Grass - Group 2
    Arm description
    		 Sublingual immunotherapy with grass pollen extract (one tablet of 1,000 UA once daily) for about 7-9 months pre-/co-seasonally (from at least 16 weeks before the expected start of the pollen season to 30 June 2020) and standard rescue therapy with anti-symptomatic medication during the grass pollen season.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lais Grass sublingual tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Independent of the assigned tratment group, the patients ingested one sublingual tablet per day. The first dose had to be self-administered at the randomization visit (V1) at study site and patient was monitored for at least 30 minutes after tablet intake.

    Number of subjects in period 1 [1]
    		Placebo - Group 1 Lais Grass - Group 2
    Started
    47
    47
    Completed
    38
    37
    Not completed
    9
    10
         No evaluable post-randomization data
    9
    10
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Overall, 98 patients were randomised to receive the assigned treatment: 49 patients were randomised to receive LAIS grass and 49 patients were randomised to receive placebo. Two randomised patients in each treatment group did not receive at least one dose of the study medication and there therefore excluded. The study comprised 94 patients overall (95.9% of randomized), 47 (95.9%) in each treatment group.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Grass pollen
    Reporting group description
    		 Female or male patients aged 12–64 years with a history of at least 2 years of grass pollen induced allergic rhinoconjunctivitis (ARC) with or without seasonal controlled allergic asthma; moderate/severe (interfering with usual daily activities or sleep) ARC defined according to ARIA guidelines; positive clinical history of grass pollen allergy; compliance and ability of the patient to complete a patient’s diary for self-evaluation of the symptoms and antisymptomatic medication and treatment compliance; signed and dated patient’s informed consent.

    Reporting group values
    		 Grass pollen Total
    Number of subjects
    		 94 94
    Age categorical
    Female or male patients aged 12–64 years
    Units: Subjects
        12-64 years
    		 94 94
    Age continuous
    Units: years
        median (full range (min-max))
    		 28 (12 to 54) -
    Gender categorical
    The demographic characteristics were similar in the two groups, except for a slightly higher proportion of males in the LAIS group than in the placebo group
    Units: Subjects
        Female
    		 45 45
        Male
    		 49 49
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Randomized patients who met key eligibility and evaluability criteria. This dataset was defined by the availability of evaluable post-randomization data for at least one of the primary efficacy variables (dSS and dMS during the 14-days of highest pollen load) The analysis of ITT population was based on 37 subjects in the treatment group and 38 in the control group from all investigational centers.All p-values reported refer to the analysis of variance.

    Subject analysis set title
    Per-Protocol-Set (PP-set)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients in the FAS with no major protocol deviations, which would impact the primary efficacy (defined as ‘critical’), and delivering a sufficient data set of measurements and evaluations of the primary efficacy variables: a maximum of two subsequent missing single evaluations of the rhinoconjunctivitis symptom score (dSS) was acceptable. The total number of missing single evaluations of the dSS had not to exceed 25 % over the entire course of the 14-days of highest pollen load within the peaks of the grass pollen season. The analysis was based on 31 subjects in the treatment group and 32 in the control group from all investigational centers.

    Subject analysis set title
    Safety evaluation set- SES
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety evaluation set (SES), which included all randomized patients who received at least one dose of the study medication. This population was used for all safety analyses. The analysis was based on 47 subjects in the treatment group and 47 in the control group from all investigational centers.

    Subject analysis sets values
    		 ITT population Per-Protocol-Set (PP-set) Safety evaluation set- SES
    Number of subjects
    75
    63
    94
    Age categorical
    Female or male patients aged 12–64 years
    Units: Subjects
        12-64 years
    75
    63
    94
    Age continuous
    Units: years
        median (full range (min-max))
    (12 to 54)
    (12 to 54)
    (12 to 54)
    Gender categorical
    The demographic characteristics were similar in the two groups, except for a slightly higher proportion of males in the LAIS group than in the placebo group
    Units: Subjects
        Female
    34
    31
    45
        Male
    41
    32
    49

    End points

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    End points reporting groups
    Reporting group title
    Placebo - Group 1
    Reporting group description
    		 Sublingual placebo preparation (one tablet once daily) for about 7-9 months pre-/coseasonally (from at least 16 weeks before the expected start of the pollen season to 30 June 2020) and standard rescue therapy with anti-symptomatic medication during the grass pollen season. Placebo and verum preparation were identical except of the active ingredient

    Reporting group title
    Lais Grass - Group 2
    Reporting group description
    		 Sublingual immunotherapy with grass pollen extract (one tablet of 1,000 UA once daily) for about 7-9 months pre-/co-seasonally (from at least 16 weeks before the expected start of the pollen season to 30 June 2020) and standard rescue therapy with anti-symptomatic medication during the grass pollen season.

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Randomized patients who met key eligibility and evaluability criteria. This dataset was defined by the availability of evaluable post-randomization data for at least one of the primary efficacy variables (dSS and dMS during the 14-days of highest pollen load) The analysis of ITT population was based on 37 subjects in the treatment group and 38 in the control group from all investigational centers.All p-values reported refer to the analysis of variance.

    Subject analysis set title
    Per-Protocol-Set (PP-set)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients in the FAS with no major protocol deviations, which would impact the primary efficacy (defined as ‘critical’), and delivering a sufficient data set of measurements and evaluations of the primary efficacy variables: a maximum of two subsequent missing single evaluations of the rhinoconjunctivitis symptom score (dSS) was acceptable. The total number of missing single evaluations of the dSS had not to exceed 25 % over the entire course of the 14-days of highest pollen load within the peaks of the grass pollen season. The analysis was based on 31 subjects in the treatment group and 32 in the control group from all investigational centers.

    Subject analysis set title
    Safety evaluation set- SES
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety evaluation set (SES), which included all randomized patients who received at least one dose of the study medication. This population was used for all safety analyses. The analysis was based on 47 subjects in the treatment group and 47 in the control group from all investigational centers.

    Primary: CSMS - 14D - Efficacy

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    End point title
    		 CSMS - 14D - Efficacy
    End point description
    Assessment of the efficacy on the average daily total Combined Symptom-Medication score (CSMS) based on an equal weight of the dSS and dMS (maximum score 3 + 3 = 6) for the 14 days of highest pollen load within the peaks of the grass pollen season taking into account: - Daily rhinoconjunctivitis total Symptom Score (dSS) of the six rhinoconjunctivitis symptoms over the previous 24 hours, which included itching, sneezing, rhinorrhea, obstruction, ocular itching/grittiness/redness and ocular tearing with scale from 0-3 per symptom (maximum score 18 points / divided by 6 symptoms = 3 points) - Daily Medication Score (dMS) over the previous 24 hours: 0 = no rescue medication taken 1 = use of antihistamines (oral, ophthalmic, or both); 2 = use of nasal corticosteroids; 3 = use of oral corticosteroids If more than 1 class of rescue medication was used on a particular day, the highest score was to be retained for the dMS of that day (maximum score = 3).
    End point type
    Primary
    End point timeframe
    14-days of highest pollen load within the peaks of the grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    1.04 ± 1.25
    0.84 ± 1.10
    Statistical analysis title
    		 LMSs difference (Lais-Placebo)
    Statistical analysis description
    A 2-sided 95% confidence interval (CI) for the difference in adjusted means between the 2 groups was presented as well as the coherent p-value vs. the H0 stating the null value for such difference. The adjusted difference was obtained as least squares mean (LSM) estimated within the previously cited linear mixed model framework
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 -0.16
    Notes
    [1] - The difference in LMSs was -0.30 (95% CI, -0.44 to -0.16) that corresponds to a difference of -28% relative to to placebo, and was statistically significant.

    Secondary: Average CSMS during the peak

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    End point title
    		 Average CSMS during the peak
    End point description
    Average CSMS
    End point type
    Secondary
    End point timeframe
    During the days with ≥ 50 pollen/m3
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    1.02 ± 1.29
    0.55 ± 0.96
    Statistical analysis title
    		 LMSs difference (Lais-Placebo)
    Statistical analysis description
    A 2-sided 95% confidence interval (CI) for the difference in adjusted means between the 2 groups was presented as well as the coherent p-value vs. the H0 stating the null value for such difference. The adjusted difference was obtained as least squares mean (LSM) estimated within the previously cited linear mixed model framework
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 -0.41
    Notes
    [2] - The difference in LMSs was -0.49 (95% CI, -0.58 to -0.41) and was statistically significant (p<0.0001 between groups)

    Secondary: Average CSMS during the entire grass pollen season

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    End point title
    		 Average CSMS during the entire grass pollen season
    End point description
    End point type
    Secondary
    End point timeframe
    entire grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    0.96 ± 1.25
    0.75 ± 1.04
    Statistical analysis title
    		 LMSs difference (Lais-Placebo)
    Statistical analysis description
    A 2-sided 95% confidence interval (CI) for the difference in adjusted means between the 2 groups was presented as well as the coherent p-value vs. the H0 stating the null value for such difference. The adjusted difference was obtained as least squares mean (LSM) estimated within the previously cited linear mixed model framework
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 -0.22
    Notes
    [3] - The difference in LMSs was -0.28 (95% CI, -0.33 to -0.22) and was statistically significant (p<0.0001 between groups)

    Secondary: Average dSS -14D

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    End point title
    		 Average dSS -14D
    End point description
    End point type
    Secondary
    End point timeframe
    14-days of highest pollen load within the peaks of the grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    0.47 ± 0.62
    0.44 ± 0.61
    Statistical analysis title
    		 LMSs difference (Lais-Placebo)
    Statistical analysis description
    A 2-sided 95% confidence interval (CI) for the difference in adjusted means between the 2 groups was presented as well as the coherent p-value vs. the H0 stating the null value for such difference. The adjusted difference was obtained as least squares mean (LSM) estimated within the previously cited linear mixed model framework
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0058 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 -0.01
    Notes
    [4] - The difference in LMSs was -0.08 (95% CI, -0.16 to -0.01) and was statistically significant (p=0.0058 between groups)

    Secondary: Average dSS during the peak

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    End point title
    		 Average dSS during the peak
    End point description
    End point type
    Secondary
    End point timeframe
    During the days with ≥ 50 pollen/m3
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    0.49 ± 0.67
    0.30 ± 0.52
    Statistical analysis title
    		 LMSs difference (Lais-Placebo)
    Statistical analysis description
    A 2-sided 95% confidence interval (CI) for the difference in adjusted means between the 2 groups was presented as well as the coherent p-value vs. the H0 stating the null value for such difference. The adjusted difference was obtained as least squares mean (LSM) estimated within the previously cited linear mixed model framework
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 -0.17
    Notes
    [5] - The difference in LMSs was -0.21 (95% CI, -0.26 to -0.17) and was statistically significant (p<0.0001 between groups)

    Secondary: Average dSS during the entire grass pollen season

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    End point title
    		 Average dSS during the entire grass pollen season
    End point description
    End point type
    Secondary
    End point timeframe
    entire grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    0.48 ± 0.62
    0.41 ± 0.59
    Statistical analysis title
    		 LMSs difference (Lais-Placebo)
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 -0.08
    Notes
    [6] - The difference in LMSs was -0.11 (95% CI, -0.13 to -0.08) and was statistically significant (p<0.0001 between groups)

    Secondary: Average dMS - 14D

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    End point title
    		 Average dMS - 14D
    End point description
    End point type
    Secondary
    End point timeframe
    14-days of highest pollen load within the peaks of the grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    0.57 ± 0.83
    0.40 ± 0.63
    Statistical analysis title
    		 LMSs difference (Lais-Placebo)
    Statistical analysis description
    A 2-sided 95% confidence interval (CI) for the difference in adjusted means between the 2 groups was presented as well as the coherent p-value vs. the H0 stating the null value for such difference. The adjusted difference was obtained as least squares mean (LSM) estimated within the previously cited linear mixed model framework
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 -0.12
    Notes
    [7] - The difference in LMSs was -0.21 (95% CI, -0.30 to -0.12) and was statistically significant (p=0.0004 between groups)

    Secondary: Average dMS during the peak

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    End point title
    		 Average dMS during the peak
    End point description
    End point type
    Secondary
    End point timeframe
    during the days with ≥ 50 pollen/m3
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    0.52 ± 0.82
    0.25 ± 0.65
    Statistical analysis title
    		 LMSs difference (Lais-Placebo)
    Statistical analysis description
    A 2-sided 95% confidence interval (CI) for the difference in adjusted means between the 2 groups was presented as well as the coherent p-value vs. the H0 stating the null value for such difference. The adjusted difference was obtained as least squares mean (LSM) estimated within the previously cited linear mixed model framework
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 -0.23
    Notes
    [8] - The difference in LMSs was -0.28 (95% CI, -0.34 to -0.23) and was statistically significant (p<0.0001 between groups)

    Secondary: Average dMS during the entire grass pollen season

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    End point title
    		 Average dMS during the entire grass pollen season
    End point description
    End point type
    Secondary
    End point timeframe
    entire grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    0.48 ± 0.80
    0.34 ± 0.65
    Statistical analysis title
    		 LMSs difference (Lais-Placebo)
    Statistical analysis description
    A 2-sided 95% confidence interval (CI) for the difference in adjusted means between the 2 groups was presented as well as the coherent p-value vs. the H0 stating the null value for such difference. The adjusted difference was obtained as least squares mean (LSM) estimated within the previously cited linear mixed model framework
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
    Notes
    [9] - The difference in LMSs was -0.17 (95% CI, -0.21 to -0.13) and was statistically significant (p<0.0001 between groups)

    Secondary: Average 6 individual symptom scores of dSS - 14D

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    End point title
    		 Average 6 individual symptom scores of dSS - 14D
    End point description
    Each six individual symptom score of dSS were analyzed using a general linear mixed model having the same independent variable side structure as described for CSMS to reach the primary objective (treatment group as fixed effect, pollen region as random effect).
    End point type
    Secondary
    End point timeframe
    14-days of highest pollen load within the peaks of the grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
    arithmetic mean (standard deviation)
        Nasal itching mean 14D
    0.54 ± 0.87
    0.43 ± 0.70
        Rhinorrhoea mean 14D
    0.49 ± 0.79
    0.47 ± 0.80
        Nasal obstruction 14D
    0.56 ± 0.83
    0.50 ± 0.78
        Sneezing mean 14D
    0.62 ± 0.80
    0.59 ± 0.79
        Ocular itching/grittiness/redness mean 14D
    0.39 ± 0.73
    0.42 ± 0.73
        Ocular tearing
    0.23 ± 0.60
    0.23 ± 0.64
    Statistical analysis title
    		 Nasal itching mean 14D
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6145 [10]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [10] - The difference between groups was not statistically significant
    Statistical analysis title
    		 Rhinorrhoea mean 14D
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5905 [11]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [11] - The difference between groups was not statistically significant.
    Statistical analysis title
    		 Nasal obstruction mean 14D
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7007 [12]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [12] - The difference between groups was not statistically significant.
    Statistical analysis title
    		 Sneezing mean 14D
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.829 [13]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [13] - The difference between groups was not statistically significant.
    Statistical analysis title
    		 Ocular itching/grittiness/redness mean 14D
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5564 [14]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [14] - The difference between groups was not statistically significant.
    Statistical analysis title
    		 Ocular tearing mean 14D
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4247 [15]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [15] - The difference between groups was not statistically significant.

    Secondary: Average 6 individual symptom scores of dSS - during the peak

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    End point title
    		 Average 6 individual symptom scores of dSS - during the peak
    End point description
    Average six individual symptom scores of the dSS: during the days with ≥ 50 pollen/m3
    End point type
    Secondary
    End point timeframe
    during the days with ≥ 50 pollen/m3
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
    arithmetic mean (standard deviation)
        Nasal itching mean peak
    0.59 ± 0.88
    0.32 ± 0.62
        Rhinorrhoea mean peak
    0.53 ± 0.84
    0.30 ± 0.65
        Nasal obstruction mean peak
    0.57 ± 0.90
    0.35 ± 0.66
        Sneezing mean peak
    0.60 ± 0.78
    0.41 ± 0.69
        Ocular itching/grittiness/redness mean peak
    0.42 ± 0.76
    0.29 ± 0.60
        Ocular tearing mean peak
    0.25 ± 0.62
    0.15 ± 0.49
    Statistical analysis title
    		 Nasal itching mean peak
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5722 [16]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [16] - The difference between groups was not statistically significant.
    Statistical analysis title
    		 Rhinorrhoea mean peak
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6146 [17]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [17] - The difference between groups was not statistically significant.
    Statistical analysis title
    		 Nasal obstruction mean peak
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6852 [18]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [18] - The difference between groups was not statistically significant.
    Statistical analysis title
    		 Sneezing mean peak
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7894 [19]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [19] - The difference between groups was not statistically significant.
    Statistical analysis title
    		 Ocular itching/grittiness/redness mean peak
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7014 [20]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [20] - The difference between groups was not statistically significant.
    Statistical analysis title
    		 Ocular tearing mean peak
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3058 [21]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [21] - The difference between groups was not statistically significant.

    Secondary: Average 6 individual symptom scores of dSS - during entire grass pollen season

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    End point title
    		 Average 6 individual symptom scores of dSS - during entire grass pollen season
    End point description
    Average six individual symptom scores of the dSS: over the entire grass pollen season until the study end
    End point type
    Secondary
    End point timeframe
    entire grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
    arithmetic mean (standard deviation)
        Nasal itching mean entire grass season
    0.51 ± 0.79
    0.43 ± 0.71
        Rhinorrhoea mean entire grass season
    0.51 ± 0.79
    0.46 ± 0.78
        Nasal obstruction mean entire grass season
    0.54 ± 0.85
    0.47 ± 0.75
        Sneezing mean entire grass season
    0.62 ± 0.83
    0.57 ± 0.80
        Ocular itching/grittiness/redness mean - season
    0.44 ± 0.79
    0.35 ± 0.67
        Ocular tearing mean entire grass season
    0.24 ± 0.58
    0.19 ± 0.52
    No statistical analyses for this end point

    Secondary: well days

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    End point title
    		 well days
    End point description
    The “well days”, being defined as days of the entire grass pollen season with a maximum ARC symptom score of 2 and no rescue medication use according to Dahl (Dahl et al., 2006) and Durham (Durham et al., 2006) (verum vs. placebo)
    End point type
    Secondary
    End point timeframe
    entire grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    67.33 ± 21.68
    69.56 ± 22.89
    Statistical analysis title
    		 LMSs difference (Lais-Placebo)
    Statistical analysis description
    A 2-sided 95% confidence interval (CI) for the difference in adjusted means between the 2 groups was presented as well as the coherent p-value vs. the H0 stating the null value for such difference. The adjusted difference was obtained as least squares mean (LSM) estimated within the previously cited linear mixed model framework
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1702 [22]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.11
    Notes
    [22] - The difference in LMSs was 0.04 (95% CI, -0.02 to 0.11) and was not statistically significant (p = 0.1702 between groups)

    Secondary: VAS score

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    End point title
    		 VAS score
    End point description
    The VAS on ‘nasal symptoms’ was included as a simple, reliable, and fully validated subjective psychometric response scale in adults for symptoms in many indication areas to evaluate disease severity including AR and was, therefore, recommended by the EAACI. In this study, VAS was determined during the control visits to show differences between the treatment groups. the VAS score was analysed as described for the primary endpoints (i.e. applying the hierarchical testing procedure in case of statistically significant result for CSMS). The VAS score was the distance (in millimetres) from the left end of the line to the point where the patient’s mark crossed the line
    End point type
    Secondary
    End point timeframe
    entire grass season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    19.50 ± 21.40
    22.14 ± 23.96
    Statistical analysis title
    		 Vas score
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5331 [23]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.01
         upper limit
    		 7.69
    Notes
    [23] - The difference between the groups was 1.84 mm (95% CI, -4.01 to 7.69 mm) and was not statistically significant (p = 0.5331)

    Secondary: Global evaluation for the entire grass pollen season

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    End point title
    		 Global evaluation for the entire grass pollen season
    End point description
    A global evaluation was carried out by the patient for the entire grass pollen season, to evaluate the Treatment Satisfaction (verum vs placebo) with the scale: 0 = unsatisfied, 1 = little satisfied, 2 = satisfied, 3 = very satisfied.
    End point type
    Secondary
    End point timeframe
    entire grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    3.13 ± 0.58
    2.95 ± 0.66
    Statistical analysis title
    		 Global evaluation
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2186 [24]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 0.1
    Notes
    [24] - The difference between the groups was - 0.19 (95% CI, -0.47 to 0.10) and was not statistically significant (p= 0.2186)

    Secondary: Global evaluation comparison of the current season versus the previous year

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    End point title
    		 Global evaluation comparison of the current season versus the previous year
    End point description
    A global evaluation carried out by the patient in the overall comparison of the current grass pollen season versus the previous season (previous year); in order to permit a computation of a responder analysis, this aspect was investigated at the end of the treatment period, by asking subjects the following question “Compared to your symptoms in previous grass seasons, how have you felt overall in this grass pollen season?” with possible response categories: 0 = worsening; 1 = no change; 2 = slight to moderate improvement; 3 = good to excellent improvement
    End point type
    Secondary
    End point timeframe
    entire grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: score
        arithmetic mean (standard deviation)
    3.03 ± 0.69
    2.95 ± 0.87
    Statistical analysis title
    		 Global evaluation comparison between seasons
    Comparison groups
    Placebo - Group 1 v Lais Grass - Group 2
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7184 [25]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 0.44
    Notes
    [25] - The difference between the groups was 0.08 (95% CI - 0.28 to 0.44) and was not statistically significant.

    Secondary: Excellence of rhinoconjunctivitis control during entire grass pollen season

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    End point title
    		 Excellence of rhinoconjunctivitis control during entire grass pollen season
    End point description
    Excellence of rhinoconjunctivitis control during the entire grass pollen season = more than 50% well days in the grass pollen season;
    End point type
    Secondary
    End point timeframe
    Entire grass pollen season
    End point values
    		 Placebo - Group 1 Lais Grass - Group 2
    Number of subjects analysed
    38
    37
    Units: %
        number (not applicable)
    78.9
    78.4
    Statistical analysis title
    		 Excellence of rhinoconjunctivitis control
    Comparison groups
    Lais Grass - Group 2 v Placebo - Group 1
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9688 [26]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.31
         upper limit
    		 1.26
    Notes
    [26] - The difference between groups was -0.02% (95% CI, -1.31 to 1.26%) and was not statistically significant (p= 0.9688 between groups).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 to end of follow up (observation period between V1 and V5)
    Adverse event reporting additional description
    The patient diary for the recording of the Adverse Events was dispensed to patients. All treatment emergent adverse events (TEAEs) were assigned to a Preferred Term (PT) and classified by primary System Organ Class (SOC) according to the MedDRA.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Placebo - Group 1
    Reporting group description
    		 groups of subjects to whom placebo was administered

    Reporting group title
    Lais Grass - Group 2
    Reporting group description
    		 groups of subjects to whom Lais sublingual tablets (verum) was administered

    Serious adverse events
    		 Placebo - Group 1 Lais Grass - Group 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax spontaneous
    Additional description: Patient was a male subject aged 17 years . On 02 Mar 2000, the patient had preumothorax spontaneous, which was of moderate intensity and required hospitalization. Treatment with IMP was discontinued and the event resolved on 15 Mar 2000
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo - Group 1 Lais Grass - Group 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 47 (57.45%)
    29 / 47 (61.70%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Application site pruritus
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Seasonal allergy
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Premenstrual pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    9 / 47 (19.15%)
    8 / 47 (17.02%)
         occurrences all number
    9
    8
    Cough
         subjects affected / exposed
    3 / 47 (6.38%)
    5 / 47 (10.64%)
         occurrences all number
    3
    5
    Sneezing
         subjects affected / exposed
    1 / 47 (2.13%)
    4 / 47 (8.51%)
         occurrences all number
    1
    4
    Throat irritation
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 47 (4.26%)
         occurrences all number
    1
    2
    Epistaxis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Nasal inflammation
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    Nasal discomfort
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Nasal obstruction
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Asthma
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Apnoea
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Dysphonia
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 47 (0.00%)
         occurrences all number
    3
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    1
    1
    Investigations
    Body temperature increased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Influenza virus test negative
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Arthropod sting
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 47 (8.51%)
    8 / 47 (17.02%)
         occurrences all number
    4
    8
    Migraine without aura
         subjects affected / exposed
    4 / 47 (8.51%)
    3 / 47 (6.38%)
         occurrences all number
    4
    3
    Paraesthesia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Neurological symptom
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    5 / 47 (10.64%)
    3 / 47 (6.38%)
         occurrences all number
    5
    3
    Eyelid irritation
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Eye pruritus
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 47 (0.00%)
         occurrences all number
    3
    0
    Oral pruritus
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 47 (2.13%)
         occurrences all number
    2
    1
    Anal fissure
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    1
    1
    Abdominal pain
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    Stomatitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Abdominal distension
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash erythematous
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    Eczema
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    1
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 47 (6.38%)
         occurrences all number
    1
    3
    Neck pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    1
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    4 / 47 (8.51%)
    4 / 47 (8.51%)
         occurrences all number
    4
    4
    Conjunctivitis
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    1
    1
    Pharyngitis
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 47 (2.13%)
         occurrences all number
    1
    1
    Cystitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Bacterial rhinitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    Acute sinusitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jul 2019
    The protocol initially submitted to the Italian Health Authority (‘Agenzia Italiana del Farmaco’, AIFA) was that named Version 1.3 of 23 April 2019. Then the IEC of the coordinating centre evaluated the study before AIFA and required changes and integrations that led to Protocol Version 1.4 of 12 July 2019, which was re-submitted to AIFA. Changes from Protocol Version 1.3 of 23 April 2019 to Version 1.4 of 12 July 2019 - Addition of information on the stepwise management of rescue medication; - Change of time of waiting for the next incremental dosage in case of a negative TNPT result; - Addition of specifications on the management of asthma exacerbations and on the management of treatments for asthma.
    23 Jul 2019
    AIFA examined Protocol Version 1.4 of 12 July 2019 and required further changes and integrations that led to Protocol Version 1.5 of 23 July 20219 Changes from Protocol Version 1.4 to Version 1.5 - Addition and specification of the secondary objective of the study; - Addition of phone contact control visits; - Addition of further specifications on the stepwise management of rescue medication; - Addition of a clarification on highly effective method of contraception as inclusion criterion; - Change from urine to serum pregnancy test at inclusion in the study; - Minor formal changes

    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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