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    Clinical Trial Results:
    Efficacy and Safety of sublingual immunotherapy with Allergoid LAIS Birch tablets for patients with tree pollen-induced allergic rhinoconjunctivitis with or without mild controlled asthma

    Summary
    EudraCT number
    		 2018-002596-18
    Trial protocol
    		 IT  
    Global end of trial date
    30 Jun 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Apr 2023
    First version publication date
    21 Apr 2022
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    A correction is needed after data checking.

    Trial information

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    Trial identification
    Sponsor protocol code
    Lais-Birch-Alder-18-19
    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
    Allergy and Immunology Specialist - Scientific Direction & Clinical Trials, Scientific Direction & Clinical Trials LOFARMA S.p.A. 20143. Milano. Italy, +39 02581981,
    Scientific contact
    Allergy and Immunology Specialist - Scientific Direction & Clinical Trials , Scientific Direction & Clinical Trials LOFARMA S.p.A. 20143. Milano. Italy, +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
    30 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess the efficacy and safety of tablet-based SLIT with the allergoid LAIS Birch tablets compared to placebo in patients with tree pollen-induced allergic rhinoconjunctivitis with or without mild asthma.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles which have their origin in the Declaration of Helsinki,, protocol, Guideline for Good Clinical Practice (GCP) CPMP/ICH/135/95 as well as the requirements of national drug and data protection. Investigators informed trial participants prior to their inclusion in the study about the nature of the trial, of its aims, of the methods and means to be used, and of the estimated duration of the study. All patients were informed of the possible risks linked with administration of the products and of the possible effects which to his/her knowledge might occur. Patients were allowed to ask question. Written informed consent forms were signed by patients prior to their enrolment in the clinical trial, name filled in and personally dated by the patient. The Patient Information and the Informed Consent Form was previously approved by the local Ethics Committee. Two copies per patient were provided to the sites and both were signed by the Investigator and the patient. One copy of the written Patient Informed Consent Form and of Patient Information Form was handed out to the patient. One copy was kept with the Investigator. All patients were informed that they had the right to withdraw from the study at any time without prejudicing future medical care.
    Background therapy
    		 The assumption of Rescue Medications was expected as needed. Escalation scheme for their intake is the following: Step 1 Loratadine (oral) and/or Levocabastine (eyedrops) 1 x 10 mg 2 x 1 drop per eye Step 2 Beclomethasone(nasal) 1 x 0,05 mg /side nose Step 3 Prednisone (oral) 5 mg The assumption of Rescue Medications was reported on the patient diary.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 116
    Worldwide total number of subjects
    116
    EEA total number of subjects
    116
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    109
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Territory: Italy The total number of patients were recruited and screened for inclusion and exclusion criteria.

    Pre-assignment
    Screening details
    		 88 patients were randomized. 6 patients for both groups didn't complete the study: 1 protocol deviation, 4 adverse event non -fatal and 1 consent withdrawn by subject for verum group and 1 physician decision, 1 adverse event, non-fatal, 1 consent withdrawn by subject and 3 lost to follow-up for placebo . Finally 76 patients finished the study

    Pre-assignment period milestones
    Number of subjects started
    		 116
    Number of subjects completed
    		 88

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Reason: Number of subjects
    		 screening failure: 21
    Reason: Number of subjects
    		 site suspended: 4
    Period 1
    Period 1 title
    Tree pollen (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    Sealed envelopes have been provided to the investigators. The sealed envelopes have been returned to the sponsor at the end of the study. CRO and Sponsor were blinded at treatments as the Investigators. A copy of the list of randomization codes was kept at the CRO. The sealed envelopes would be opened only in case of any patient-related event that requires unblinding even if knowledge of treatment may influence gement of this event. The opened envelope should be signed and adated on the top.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LAIS® Birch/Alder
    Arm description
    		 Treatment group 1 (1,000 UA): Patients receiving sublingual immunotherapy with monomeric allergoids of tree pollen extract (one tablet of 1,000 UA once daily) pre-/co-seasonally and standard rescue therapy with antisymptomatic medication during the tree pollen season.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LAIS® Birch/Alder sublingual tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Every patient received 1 tablet of IMP immediately after the randomization, waiting in the Center, for at least 60 minutes, in order to be assisted in case of some allergic drug reaction. The tablet was placed under the tongue and retained until its complete dissolution, i.e. 1 or 2 minutes before swallowing. The patients were instructed to assume a tablet of treatment every day, without food, until the End of Study (Visit 5). The assumption of the treatment was reported on a patient diary.

    Arm title
    		 Placebo
    Arm description
    		 Treatment group 2 (placebo): Patients receiving sublingual placebo preparation (one tablet once daily) pre-/co-seasonally and standard rescue therapy with anti-symptomatic medication during the tree pollen season. The study medication was provided in form of identical containers of the LAIS® Birch/Alder tablets. All containers or content were identical in shape, size, weight, color, taste, and smell to ensure blinding.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Every patient received 1 tablet of Placebo immediately after the randomization, waiting in the Center, for at least 60 minutes, in order to be assisted in case of some allergic drug reaction. The tablet was placed under the tongue and retained until its complete dissolution, i.e. 1 or 2 minutes before swallowing. The patients were instructed to assume a tablet of treatment every day, without food, until the End of Study (Visit 5). The assumption of the treatment was reported on a patient diary.

    Number of subjects in period 1 [1]
    		LAIS® Birch/Alder Placebo
    Started
    42
    46
    Completed
    36
    40
    Not completed
    6
    6
         Consent withdrawn by subject
    1
    1
         Physician decision
    -
    1
         Adverse event, non-fatal
    4
    1
         Lost to follow-up
    -
    3
         Protocol deviation
    1
    -
    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: Worldwide number enrolled correspond to screened subjects. In subjects in the baseline period are the assigned subjects.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tree pollen
    Reporting group description
    		 -

    Reporting group values
    		 Tree pollen Total
    Number of subjects
    		 88 88
    Age categorical
    Units: Subjects
        Adults (18-75)
    		 88 88
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.9 ± 12.2 -
    Gender categorical
    Units: Subjects
        Female
    		 57 57
        Male
    		 31 31
    Subject analysis sets

    Subject analysis set title
    Per-Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Evaluable subjects who comply with the protocol in all points, delivering a complete data set of measurements and evaluations of the primary efficacy variable. A maximum of two successive missing single evaluations of the rhinoconjunctivitis total symptom score (RTSS) is acceptable; the total number of missing single evaluations of the RTSS must not exceed 25% over the entire course of the peak pollen period. The missing values are established by using the Last Value Option as described in the next section. An additional confirmatory analysis of the primary efficacy variable will be performed on this subgroup.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) incorporated all patients who received at least 1 dose of investigational treatment and filled -in diary data during the peak period.

    Subject analysis set title
    SES
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety evaluation set (SES) comprised all randomized subjects having received at least 1 dose of the investigational product.

    Subject analysis sets values
    		 Per-Protocol FAS SES
    Number of subjects
    43
    73
    88
    Age categorical
    Units: Subjects
        Adults (18-75)
    43
    73
    88
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    47.9 ± 12.2
    Gender categorical
    Units: Subjects
        Female
    57
        Male
    31

    End points

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    End points reporting groups
    Reporting group title
    LAIS® Birch/Alder
    Reporting group description
    		 Treatment group 1 (1,000 UA): Patients receiving sublingual immunotherapy with monomeric allergoids of tree pollen extract (one tablet of 1,000 UA once daily) pre-/co-seasonally and standard rescue therapy with antisymptomatic medication during the tree pollen season.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment group 2 (placebo): Patients receiving sublingual placebo preparation (one tablet once daily) pre-/co-seasonally and standard rescue therapy with anti-symptomatic medication during the tree pollen season. The study medication was provided in form of identical containers of the LAIS® Birch/Alder tablets. All containers or content were identical in shape, size, weight, color, taste, and smell to ensure blinding.

    Subject analysis set title
    Per-Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Evaluable subjects who comply with the protocol in all points, delivering a complete data set of measurements and evaluations of the primary efficacy variable. A maximum of two successive missing single evaluations of the rhinoconjunctivitis total symptom score (RTSS) is acceptable; the total number of missing single evaluations of the RTSS must not exceed 25% over the entire course of the peak pollen period. The missing values are established by using the Last Value Option as described in the next section. An additional confirmatory analysis of the primary efficacy variable will be performed on this subgroup.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) incorporated all patients who received at least 1 dose of investigational treatment and filled -in diary data during the peak period.

    Subject analysis set title
    SES
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety evaluation set (SES) comprised all randomized subjects having received at least 1 dose of the investigational product.

    Primary: TCS 14D Efficacy

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    End point title
    		 TCS 14D Efficacy
    End point description
    Assessment of the efficacy of the sublingual immunotherapy with the allergoid LAIS® Birch tablets on a “Total Combined Score (TCS)” for the consecutive 14-days of maximum pollen load within the peak of the birch pollen season taking into account: - a “Rhinoconjunctivitis Total Symptom Score (RTSS)”, of the six rhinoconjunctivitis symptoms sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus and watery eyes (as sum of the symptoms daily evaluated by the patient, using a score from 0 to 3, divided by the number of symptoms (6): - a “Total Rescue Medication Score (TRMS)”, taking into account the use of oral antihistamines, Levocabastine eye drops and nasal corticosteroids, oral corticosteroids (according to the following point values for scoring use: Step 1 Loratadine (oral, 1 x 10 mg) and/or Levocabastine (eyedrops, 2 x 1 drop per eye), score 1 Step 2 Beclomethasone (nasal, 1 x 0,05 mg /side nose), score 2 Step 3 Prednisone (oral, 5 mg), score 3.
    End point type
    Primary
    End point timeframe
    for the consecutive 14-days of maximum pollen load within the peak of the birch pollen season
    End point values
    		 LAIS® Birch/Alder Placebo FAS
    Number of subjects analysed
    36
    40
    73
    Units: Score
        arithmetic mean (confidence interval 95%)
    1.0579 (0.8447 to 1.2710)
    1.7240 (1.5574 to 1.8905)
    -0.70 (-0.94 to -0.40)
    Statistical analysis title
    		 TCS Difference (LAIS – Placebo) between means
    Statistical analysis description
    Values as determined by the patients in their diary are combined to a daily TCS by adding up RTSS and TRMS. An analysis of variance for repeated measures. The multiple test procedure was applied based on the between-subject factor p-values obtained from this model. Treatment specific means were estimated from this model as least sqaures means. Statistical tests were set on two-side and at the 5% level of significance.
    Comparison groups
    LAIS® Birch/Alder v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - Compared to placebo, the treatment group had lower symptom score RTSS (P=0.0150) and made less use of rescue medication ( P<0.0001). TCS values were significantly lower in the treatment group compared to placebo (P<0.0001).

    Primary: Subgroup TCS 14D

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    End point title
    		 Subgroup TCS 14D
    End point description
    In this study a subpopulation analysis on the primary endpoint was carried out by excluding from the overall patients those belonging to the Genoa hospital. The analyzes was motivated by virtue of the fact that Liguria, like Southern Italy and the islands macro area, never reached the peak pollen (from 15 to 22 maximum level reached for 7 consecutive days. The endpoints evaluated was the TCS.
    End point type
    Primary
    End point timeframe
    consecutive 14-days of maximum pollen load within the peak of the birch pollen season
    End point values
    		 LAIS® Birch/Alder Placebo
    Number of subjects analysed
    31
    34
    Units: Score
        arithmetic mean (confidence interval 95%)
    1.0180 (0.8015 to 1.2345)
    1.7375 (1.5621 to 1.8989)
    Statistical analysis title
    		 TCS 14D Difference (LAIS – Placebo) between means
    Statistical analysis description
    In this study a subpopulation analysis on the primary endpoint was carried out by excluding from the overall patients those belonging to the Genoa hospital. The analyzes was motivated by virtue of the fact that Liguria, like Southern Italy and the islands macro area, never reached the peak pollen (from 15 to 22 maximum level reached for 7 consecutive days. The endpoints evaluated were the TCS, the RTSS and the TRMS.
    Comparison groups
    LAIS® Birch/Alder v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [2] - Compared to placebo, the treatment group had lower symptom score RTSS (P<0.0001) and made less use of rescue medication (P=0.0027). TCS values were significantly lower in the treatment group compared to placebo (P<0.0001)

    Primary: TCS 30D Efficacy

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    End point title
    		 TCS 30D Efficacy
    End point description
    Total Combined Score (TCS) both at 30-day peak in birch pollen season The analysis on modified ITT (FAS) was based on all investigational centers.
    End point type
    Primary
    End point timeframe
    30-day peak in birch pollen season.
    End point values
    		 LAIS® Birch/Alder Placebo FAS
    Number of subjects analysed
    36
    40
    76
    Units: Score
        arithmetic mean (confidence interval 95%)
    0.9109 (0.7430 to 1.0788)
    1.5121 (1.3629 to 1.6614)
    -0.60 (-0.83 to -0.38)
    Statistical analysis title
    		 TCS 30D compare between groups
    Comparison groups
    LAIS® Birch/Alder v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [3] - As to TCS for the birch pollen peak at 30 days, these values were significantly lower in the treatment group compared to placebo (difference in mean -0.60; L95%CI, U95%CI: -0.83 to -0.38. P<0.0001)

    Secondary: TCS 60D efficacy

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    End point title
    		 TCS 60D efficacy
    End point description
    Total Combined Score (TCS) for the overall 60-day birch pollen season of (March to April). The analysis on ITT was based on all investigational centers.
    End point type
    Secondary
    End point timeframe
    overall 60-day birch pollen season (March to April)
    End point values
    		 LAIS® Birch/Alder Placebo FAS
    Number of subjects analysed
    36
    40
    76
    Units: Score
        arithmetic mean (confidence interval 95%)
    0.9486 (0.8803 to 1.0168)
    1.1936 (1.1373 to 1.2499)
    -0.25 (-0.33 to -0.16)
    Statistical analysis title
    		 TCS 60D compare between groups
    Comparison groups
    LAIS® Birch/Alder v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [4] - TCS values referring to the overall 60-day birch pollen season (March to April) were significantly lower in the treatment group compared to the placebo group (difference in mean -0.25; L95%CI, U95%CI: -0.33 to -0.16. P<0.0001)

    Secondary: Well Days 60D

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    End point title
    		 Well Days 60D
    End point description
    The “well days”, being defined as days of the entire tree pollen season with a maximum symptom score of 2 and no rescue medication use according to Dahl (2006) and Durham (2006). The number of “well days” will be compared between arms fitting a generalized linear model as defined by Nelder and Wedderburn. To this aim, a Poisson distribution for the related variable will be assumed as well as the default natural logarithm link function. The two-sided 95% confidence interval will be calculated according the Poisson distribution assumed for the statistical test;
    End point type
    Secondary
    End point timeframe
    60 days of the entire birch pollen season
    End point values
    		 LAIS® Birch/Alder Placebo
    Number of subjects analysed
    38
    40
    Units: Score
        arithmetic mean (confidence interval 95%)
    39.0000 (37.0641 to 41.0370)
    34.4500 (32.6783 to 36.3178)
    Statistical analysis title
    		 Wll Days60D between group means
    Comparison groups
    LAIS® Birch/Alder v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0009
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [5] - The “well days”, being defined as “days of the entire birch pollen season with a maximum symptom score of 2 and no rescue medication”, were significantly higher than the placebo.(difference in mean 4.55; L95%CI, U95%CI:; 2.52 to 6.58. P=0.0009).

    Secondary: Global Evaluation

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    End point title
    		 Global Evaluation
    End point description
    A global evaluation carried out by the patient for the total tree pollen season The following scale will be used: 0 = worsening 1 = no change 2 = slight to moderate improvement 3 = good to excellent improvement the global evaluation was processed as described for the individual symptom scores.
    End point type
    Secondary
    End point timeframe
    total tree pollen season
    End point values
    		 LAIS® Birch/Alder Placebo FAS
    Number of subjects analysed
    29
    35
    Units: Score
        arithmetic mean (confidence interval 95%)
    2.7241 (2.4187 to 3.0296)
    2.6857 (2.4077 to 2.9638)
    0.04 (-0.37 to 0.45)
    Statistical analysis title
    		 Global Evaluation Difference Between Group means
    Comparison groups
    LAIS® Birch/Alder v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.8531
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [6] - The Treatment Satisfaction was significantly higher in the treatment group compared to placebo (difference in mean 0.04; L95%CI, U95%CI: -0.37 to 0.45. P=0.8531)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    To document the safety of the treatment by the physical examinations, the safety laboratory data and the description of the adverse events (frequency, intensity, severity and duration of adverse events) during the treatment with LAIS® Birch/Alder tablets
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Lais birch alder
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Lais birch alder Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 46 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Myocarditis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
    Additional description: symptoms of pulmonary embolism with severe intensity, no change of therapy has been done, patient was hospitalized, the event was resolved
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (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: 0%
    Non-serious adverse events
    		 Lais birch alder Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 42 (50.00%)
    16 / 46 (34.78%)
    Vascular disorders
    Essential hypertension
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Oedema mucosal
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 46 (4.35%)
         occurrences all number
    1
    2
    Immune system disorders
    Oral allergy syndrome
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Throat irritation
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 46 (0.00%)
         occurrences all number
    6
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Cough
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 46 (2.17%)
         occurrences all number
    2
    1
    Dysphonia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Nasal discomfort
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 46 (2.17%)
         occurrences all number
    1
    2
    Nasal inflammation
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 46 (4.35%)
         occurrences all number
    0
    2
    Asthma
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    4
    nasal obstruction
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    4
    Status asthmaticus
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Cardiac disorders
    Myocarditis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    Aphonia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Epilepsy
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 46 (4.35%)
         occurrences all number
    2
    2
    Migraine with aura
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Eye pruritus
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal mass
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 46 (4.35%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 46 (2.17%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Pancreatitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    Rash erythematous
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Rash pruritic
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Rosacea
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 46 (4.35%)
         occurrences all number
    1
    2
    Neck pain
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Rheumatic fever
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Gingival abscess
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Hordeolum
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Influenza
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 46 (2.17%)
         occurrences all number
    4
    1
    Otitis externa
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Viral pharyngitis
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 46 (2.17%)
         occurrences all number
    1
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 46 (4.35%)
         occurrences all number
    0
    3
    Tooth abscess
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 46 (4.35%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2018
    Version 2.00: Is based on Version 1.00 and was created as part of the response to the “Letter of Content-Related Deficiencies” by the AIFA (28 SEP 2018)
    15 Mar 2019
    Version 3.00: Changes due to recovery of the trial and its execution in the 2019/2020 pollinic season.

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

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

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