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    Clinical Trial Results:
    Efficacy and Safety of sublingual immunotherapy with Allergoid LAIS®Birch-Alder tablets for patients with tree pollen-induced allergic rhinoconjunctivitis A Phase III study.

    Summary
    EudraCT number
    		 2013-002129-43
    Trial protocol
    		 DE  
    Global end of trial date
    17 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Oct 2021
    First version publication date
    17 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SMART_7
    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
    Coordinating investigator, Institut für Med. Statistik, Informatik u. Epidemiologie, +49 2214783456, informatik@imsie.de
    Scientific contact
    Coordinating investigator, Institut für Med. Statistik, Informatik u. Epidemiologie, +49 2214783456, informatik@imsie.de
    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
    17 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess the efficacy of sublingual immunotherapy with the allergoid LAIS® Birch-Alder tablets by the Total Combined Score (TCS) taking in account the Rhinoconjuncticitis Total Symptom Score (RTSS) of the six rhinoconjunctivitis symptoms (sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus and watery eyes and the Total Rescue Medication Score (TRMS) for the peak of the birch pollen season.
    Protection of trial subjects
    Moreover, the main procedures used to guarantee the subject’s anonymity especially during the analysis of their personal data were profoundly explained. The investigator also informed the patient of the possible risks linked to the administration of the product and the possible side effects which to his/her knowledge might occur. The patient was invited to ask questions which were answered by the responsible investigator until the patient was entirely satisfied. Before asking the patient to sign the consent form, the investigator ascertained that the patient had understood entirely and agreed to all information provided. Afterwards, a written Patient Informed Consent Form (ICF) and a Patient Information Form (which were previously approved by the leading ethics committee and notified to the local ethics committees) were handed over to the patient. Two copies of the ICF were to be dated and signed by the patient and the investigator, of which one copy was handed out to the patient. The second form was kept confidentially in the investigator’s file. The subject’s signature verified his/her agreement of participation in the trial. In agreement with the subject, the investigator informed the subject’s regular physician of his/her participation in the trial.
    Background therapy
    		 The intake of anti-symptomatic medication appropriate to an escalation scheme: Rescue medications : - Antihistamine (oral) - Additonal Levocabastine (eyedrops) - Additional Beclomethasone (nasal)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Nov 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 235
    Worldwide total number of subjects
    235
    EEA total number of subjects
    235
    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)
    235
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible subjects were assigned to one of the two treatment groups using a randomization list that was generated on the basis of subject identifiers by a randomization program. It was planned that each treatment group should consist of 120 patients.

    Pre-assignment
    Screening details
    		 Female or male patients aged 18 to 75 years with a history of at least two years of tree pollen induced allergic rhinitis and/or allergic rhinoconjunctivitis with or without seasonal controlled allergic asthma.

    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
    		 Investigator, Monitor, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Placebo and verum preparations were identical except of the active substances (carbamylated, monomeric allergoids of birch and alder).

    Arm title
    		 LAIS® Birch-Alder tablets
    Arm description
    		 LAIS® Birch-Alder tablets in a dosage of 1000 UA or placebo. Daily intake of one sublingual tablet.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LAIS® Birch-Alder tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Each patient was instructed to take one sublingual tablet per day, to place it under the tongue and to let it dissolve for two minutes before swallowing. During the treatment phase, the participant received either a daily dosage of 1,000 UA monomeric allergoid LAIS® Birch-Alder tablets or placebo according to the randomization-schedule. The study foresaw an intake of IMP over 12 weeks pre-seasonally (cumulative dose of 84,000 UA) and 8weeks co-seasonally. Delays in study approvals and patients’ recruitment moved forward the treatment. therefore the maximum pre-seasonally cumulative dose in the actively treated group amounted to 70,000 UA in only 25% of patients; 50% of the patients received a cumulative dose of only 63,000 UA and 25% of only 56,000 UA. Considering the early appearance of other cross reactive trees and the high number of subjects cosensitized, the pre-seasonal phase scheduled, important to switch on the therapeutic effect, can be considered absent for most subjects.

    Number of subjects in period 1 [1]
    		Placebo LAIS® Birch-Alder tablets
    Started
    96
    92
    Completed
    94
    88
    Not completed
    2
    4
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    1
    -
         lack of Compliance
    -
    1
         Missing at V4
    -
    1
         concomitant disease
    -
    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: Number of screened population is 235, while before randomization 47 subjects did not pass the screening procedures resulting as screening failure.

    Baseline characteristics

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

    Reporting group title
    LAIS® Birch-Alder tablets
    Reporting group description
    		 LAIS® Birch-Alder tablets in a dosage of 1000 UA or placebo. Daily intake of one sublingual tablet.

    Reporting group values
    		 Placebo LAIS® Birch-Alder tablets Total
    Number of subjects
    		 96 92 188
    Age categorical
    Units: Subjects
        Female or male adults (18 to 75) years
    		 96 92 188
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 46.36 (22 to 74) 46.25 (19 to 74) -
    Gender categorical
    Units: Subjects
        Female
    		 61 50 111
        Male
    		 35 42 77
    Subject analysis sets

    Subject analysis set title
    Safety set (S-set)/ Exposed Subjects
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all randomized subjects who have been exposed to the study medication at least once and consisted of 188 patients. Of these, 96 patients (51.1%) were assigned to the placebo-group and 92 patients (48.9%) received 1,000 UA/d

    Subject analysis set title
    Intention-To-Treat-set (ITT-set)/Evaluable Subjects
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT-set comprised all randomized subjects who met key eligibility and evaluability criteria according to the study protocol. Since the primary objective of this trial was the assessment of the efficacy of the sublingual therapy on the basis of the TCS during the peak pollen season, a complete set of diary data was the main criterion for inclusion into the ITT-set. In the case of missing data, the Last-Value-Carry-Forward-Option was applied.

    Subject analysis set title
    Per-Protocol-set (PP-set)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients who met all critera in the protocol and delivered a complete data set of measurements and evaluations of the primary efficacy variable were allocated to the PP-set.

    Subject analysis sets values
    		 Safety set (S-set)/ Exposed Subjects Intention-To-Treat-set (ITT-set)/Evaluable Subjects Per-Protocol-set (PP-set)
    Number of subjects
    188
    182
    126
    Age categorical
    Units: Subjects
        Female or male adults (18 to 75) years
    188
    182
    126
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
    111
    106
    70
        Male
    77
    76
    56

    End points

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

    Reporting group title
    LAIS® Birch-Alder tablets
    Reporting group description
    		 LAIS® Birch-Alder tablets in a dosage of 1000 UA or placebo. Daily intake of one sublingual tablet.

    Subject analysis set title
    Safety set (S-set)/ Exposed Subjects
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all randomized subjects who have been exposed to the study medication at least once and consisted of 188 patients. Of these, 96 patients (51.1%) were assigned to the placebo-group and 92 patients (48.9%) received 1,000 UA/d

    Subject analysis set title
    Intention-To-Treat-set (ITT-set)/Evaluable Subjects
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT-set comprised all randomized subjects who met key eligibility and evaluability criteria according to the study protocol. Since the primary objective of this trial was the assessment of the efficacy of the sublingual therapy on the basis of the TCS during the peak pollen season, a complete set of diary data was the main criterion for inclusion into the ITT-set. In the case of missing data, the Last-Value-Carry-Forward-Option was applied.

    Subject analysis set title
    Per-Protocol-set (PP-set)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients who met all critera in the protocol and delivered a complete data set of measurements and evaluations of the primary efficacy variable were allocated to the PP-set.

    Primary: TCS

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    End point title
    		 TCS
    End point description
    The primary objective is to assess the efficacy of sublingual immunotherapy with the allergoid LAIS® Birch-Alder tablets by the Total Combined Score (TCS) taking into account the Rhinoconjunctivitis Total Symptom Score (RTSS) of the six rhinoconjunctivitis symptoms (sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus and watery eyes) and the Total Rescue Medication Score (TRMS). As patients were screened only up to seven days before starting with drug intake, no baseline period exists.
    End point type
    Primary
    End point timeframe
    Evaluation will be done for the peak of the birch pollen season, defined by those 14 consecutive days per centre with the highest local tree pollen counts, starting with “high” pollen concentrations
    End point values
    		 Placebo LAIS® Birch-Alder tablets
    Number of subjects analysed
    94
    88
    Units: Score
        arithmetic mean (full range (min-max))
    11.75 (0.00 to 30.9)
    12.4 (0.00 to 30.1)
    Statistical analysis title
    		 daily TCS
    Comparison groups
    LAIS® Birch-Alder tablets v Placebo
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.594 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - the difference was statistically not significant (p=0.594)

    Secondary: TCS 30D

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    End point title
    		 TCS 30D
    End point description
    efficacy of a sublingual immunotherapy with the allergoid LAIS® Birch-Alder tablets related to the TCS for the birch pollen season of 30 days.
    End point type
    Secondary
    End point timeframe
    30 Days
    End point values
    		 Placebo LAIS® Birch-Alder tablets
    Number of subjects analysed
    94
    88
    Units: score
        arithmetic mean (full range (min-max))
    10.10 (0.2 to 30.0)
    10.29 (0.2 to 24.5)
    Statistical analysis title
    		 TCS 30D compare between groups
    Comparison groups
    Placebo v LAIS® Birch-Alder tablets
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.607
    Method
    		 Asymp. Sig. (2-tailed)
    Confidence interval

    Secondary: TCS 60 days

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    End point title
    		 TCS 60 days
    End point description
    In the experimental design used, the efficacy of the SLIT with the Lais Birch-Alder tablets was not confirmed in this trial. Multiple deviations occurred with heavy alteration of the clinical/methodological setting and a consequent adherence of the results to the expectations based on the original experimental model. Therefore, the conclusions of the study do not imply the product is basically ineffective when used and investigated in proper setting and experimental model. It is assumed that a sufficient pre-seasonal period before the onset of the pollen season is necessary to permit immunotherapy the consolidation of its therapeutic action, different from common drugs and based on a progressive immunostimulation redirecting the immune system toward tolerance, before the initiation of the natural pollen exposure. In this study, the pre-seasonal phase of the treatment schedule, important to switch on the therapeutic effect, can be considered absent for most subjects.
    End point type
    Secondary
    End point timeframe
    60 days. Assess the efficacy of a sublingual immunotherapy with the allergoid LAIS® Birch-Alder tablets related to the TCS) for the or the entire pollen season of 60 days (March and April).
    End point values
    		 Placebo LAIS® Birch-Alder tablets
    Number of subjects analysed
    94
    88
    Units: score
        arithmetic mean (full range (min-max))
    8.84 (0.1 to 26.7)
    9.13 (0.5 to 22.3)
    Statistical analysis title
    		 TCS 60D compare between groups
    Comparison groups
    Placebo v LAIS® Birch-Alder tablets
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.572
    Method
    		 Asymp. Sig. (2-tailed)
    Confidence interval

    Secondary: Rescue medication

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    End point title
    		 Rescue medication
    End point description
    The use of asthma rescue medication for the tree pollen season of 60 days was assessed for asthmatic patients as a secondary parameter. For the inhalation of corticosteroids with long-acting β2-agonists (twice daily by the patients) a score of maximum nine points was calculated.
    End point type
    Secondary
    End point timeframe
    60 days
    End point values
    		 Placebo LAIS® Birch-Alder tablets
    Number of subjects analysed
    94
    88
    Units: score
        arithmetic mean (full range (min-max))
    0.52 (0.00 to 8)
    0.88 (0.00 to 9)
    Statistical analysis title
    		 60D compare use of rescue medication.
    Comparison groups
    Placebo v LAIS® Birch-Alder tablets
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.567 [2]
    Method
    		 Asymp. Sig. (2-tailed)
    Confidence interval
    Notes
    [2] - The difference was statistically not significant (p=0.567)

    Secondary: Severity S

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    End point title
    		 Severity S
    End point description
    Improvement in the allergic severity S between baseline and visit V5 within the Conjunctival Provocation Test (CPT)
    End point type
    Secondary
    End point timeframe
    between baseline and post treatment final visit V5
    End point values
    		 Placebo LAIS® Birch-Alder tablets
    Number of subjects analysed
    94
    88
    Units: Score
        arithmetic mean (full range (min-max))
    0.12 (-1.8 to 2.00)
    0.16 (-1.5 to 1.9)
    Statistical analysis title
    		 Compare Severity S
    Statistical analysis description
    P-values comparing the allergic severity S between baseline and visit 5 betweent group (ITT-set)
    Comparison groups
    Placebo v LAIS® Birch-Alder tablets
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.497
    Method
    		 Asymp. Sig. (2-tailed)
    Confidence interval
    Notes
    [3] - 1)At baseline most of the patients exhibited low reactivity to the CPT with birch pollen extract, by reacting to highest concentrated provocation solution thus preventing a fine assessment of the subsequent improvement. 2) The change in the allergic severity S in the CPT between baseline and final visit was statistically significant within each of the both treatment groups, respectively.

    Secondary: CPT result score

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    End point title
    		 CPT result score
    End point description
    The changes of the threshold allergen concentration for a positive CPT between baseline and V5 were analyzed by means of the CPT result score. Regarding that a higher threshold for a positive CPT meant a lower allergic reactivity, a negative reaction to the CPT was rated as “0”. A positive reaction at the highest threshold of 10,000 SQ/ml was rated as “1”, a positive reaction at the threshold of 1,000 SQ/ml as “2” and positive reaction at the threshold of 100 SQ/ml as “3”. The changes of the threshold allergen concentration for a positive CPT were allocated to the following three categories: “improved”, “unchanged” or “worse” depending on wether a higher, the same or a lower allergen concentration was administered for a positive CPT at V5 compared to baseline, respectively.
    End point type
    Secondary
    End point timeframe
    between baseline and V5
    End point values
    		 Placebo LAIS® Birch-Alder tablets
    Number of subjects analysed
    94
    88
    Units: score
        arithmetic mean (full range (min-max))
    0.60 (-2 to 3)
    0.64 (-1 to 3)
    Statistical analysis title
    		 Delta CPT between the two treatment.
    Statistical analysis description
    comparing delta CPT between the two treatment
    Comparison groups
    Placebo v LAIS® Birch-Alder tablets
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.56 [5]
    Method
    		 Asymp. Sig. (2-tailed)
    Confidence interval
    Notes
    [4] - P-value comparing delta CPT between the two treatment groups
    [5] - IImprovement of the threshold allergen concentration in the CPT at V5 compared to baseline exhibited 59.1% of the patients in the 1,000 UA/d- group and 53.2% of the patients in the placebo group. However, difference was statistically not significant.

    Secondary: Well Days

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    End point title
    		 Well Days
    End point description
    The “well days” were defined as days of the entire tree pollen season with a maximum symptom score of 2 and no use of rescue medication according to Dahl (2006) and Durham (2006). The number of well days ranged between 0 and 59 days in both treatment groups.
    End point type
    Secondary
    End point timeframe
    60 Days
    End point values
    		 Placebo LAIS® Birch-Alder tablets
    Number of subjects analysed
    94
    88
    Units: days
        arithmetic mean (full range (min-max))
    17.7 (0.00 to 59)
    16.59 (0.00 to 59)
    Statistical analysis title
    		 Well Days Compare
    Statistical analysis description
    Well Days Compared between the two treatment groups
    Comparison groups
    LAIS® Birch-Alder tablets v Placebo
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 842 [6]
    Method
    		 Asymp. Sig. (2-tailed)
    Confidence interval
    Notes
    [6] - The difference between the two treatment groups was statistically not significant

    Secondary: IgG4

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    End point title
    		 IgG4
    End point description
    Delta birch pollen-specific IgG4 (mg/l) V0 – V5.
    End point type
    Secondary
    End point timeframe
    Blood sampling for the measurement of birch pollen specific IgG4 was performed at V0 and V5
    End point values
    		 Placebo LAIS® Birch-Alder tablets
    Number of subjects analysed
    94
    88
    Units: mg/ml
        arithmetic mean (full range (min-max))
    -0.11 (-6.11 to 4.44)
    -0.06 (-3.45 to 1.44)
    Statistical analysis title
    		 IgG4 between the two treatment groups
    Comparison groups
    Placebo v LAIS® Birch-Alder tablets
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.531 [8]
    Method
    		 Asymp. Sig. (2-tailed)
    Confidence interval
    Notes
    [7] - P-value comparing delta birch pollen specific IgG4 between the two treatment groups
    [8] - Comparing borh treatment groups, the difference in IgG4-concentration was statistically not significant (p=0.531)

    Secondary: RQLQ

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    End point title
    		 RQLQ
    End point description
    The patients were asked to fill in the RQLQ at V1 and V5. With this questionnaire, the problems that adults with rhinoconjunctivitis experienced during the study were measured. It had 28 questions in seven domains: activity limitations sleep impairment, non-nasal/eye symptoms, practical problems, nasal symptoms, eye symptoms and emotional problems. This was done by using a 7-point scale from 0 (not troubled) to 6 (extremely troubled).
    End point type
    Secondary
    End point timeframe
    RQLQ at V1 and V5
    End point values
    		 Placebo LAIS® Birch-Alder tablets
    Number of subjects analysed
    94
    88
    Units: score
        arithmetic mean (full range (min-max))
    -0.30 (-4 to 4)
    -0.52 (-3 to 2)
    Statistical analysis title
    		 global score RQLQ between the two treatment
    Comparison groups
    Placebo v LAIS® Birch-Alder tablets
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.484 [9]
    Method
    		 Asymp. Sig. (2-tailed)
    Confidence interval
    Notes
    [9] - There was no statistical significance between the both treatment groups (p=0.484)

    Secondary: Rhinitis Control Assessment Test (RCAT)

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    End point title
    		 Rhinitis Control Assessment Test (RCAT)
    End point description
    The rhinitis symptom control was compared between both treatment groups using the RCAT at V5. The RCAT encompassed 6 items (nasal congestion, sneezing, watery eyes, the sleep disruption, activity limitation caused by symptoms as well as a self-evaluation of the symptom control) and the responses were measured on a 5-point Likert-type scale. Thereby, the RCAT scores ranged from 6 to 30. Higher scores indicated better rhinitis control.
    End point type
    Secondary
    End point timeframe
    RCAT at V5.
    End point values
    		 Placebo LAIS® Birch-Alder tablets
    Number of subjects analysed
    94
    88
    Units: Score
        arithmetic mean (full range (min-max))
    14.32 (6 to 25)
    13.79 (6 to 25)
    Statistical analysis title
    		 RCAT score at V5 between the two treatment groups
    Comparison groups
    LAIS® Birch-Alder tablets v Placebo
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.545 [10]
    Method
    		 Asymp. Sig. (2-tailed)
    Confidence interval
    Notes
    [10] - The difference between the two treatment groups was statistically not significant (p=0.545)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    Of 188 patients in the safety analysis set, 65 patients reported a total number of 129 treatment emergent adverse events (TEAEs) which occured between V1 and V5 during the intake of study medication. No fatality or anaphylactic reaction occurred which would have required the use of epinephrine.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    nk
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    LAIS® Birch-Alder tablets
    Reporting group description
    		 LAIS® Birch-Alder tablets in a dosage of 1000 UA or placebo. Daily intake of one sublingual tablet.

    Serious adverse events
    		 Placebo LAIS® Birch-Alder tablets
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
    Additional description: The SAE was reported due to the intention of the patient to go to the hospital. At the hospital, the patient received an intraveneous infusion against pain but hospitalization was not neccessary. The investigator judged that there was no relation to
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (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
    		 Placebo LAIS® Birch-Alder tablets
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 96 (35.42%)
    31 / 92 (33.70%)
    Surgical and medical procedures
    Meniscus operation
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Local swelling
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Chest discomfort
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Discomfort
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Rhinitis atrophic
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Sneezing
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 92 (0.00%)
         occurrences all number
    2
    0
    Wheezing
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Nasal discomfort
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 92 (1.09%)
         occurrences all number
    1
    1
    Epistaxis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Nasal inflammation
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Asthma
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 92 (1.09%)
         occurrences all number
    1
    1
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Initial insomnia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    2 / 96 (2.08%)
    3 / 92 (3.26%)
         occurrences all number
    2
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 92 (0.00%)
         occurrences all number
    2
    0
    Peak expiratory flow rate decreased
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 96 (3.13%)
    4 / 92 (4.35%)
         occurrences all number
    3
    7
    Hypertonia
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 92 (0.00%)
         occurrences all number
    2
    0
    Eye pain
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Ocular discomfort
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Eye inflammation
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 96 (4.17%)
    2 / 92 (2.17%)
         occurrences all number
    4
    2
    Myosclerosis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Arthralgia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Muscle tightness
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 92 (1.09%)
         occurrences all number
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 96 (3.13%)
    2 / 92 (2.17%)
         occurrences all number
    3
    2
    Viral infection
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 96 (5.21%)
    9 / 92 (9.78%)
         occurrences all number
    5
    9
    Pharyngitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Vaginal infection
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 92 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 96 (0.00%)
    3 / 92 (3.26%)
         occurrences all number
    0
    3
    Tonsillitis bacterial
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Feb 2014
    Originally, the study was planned to last from November 2013 to the end of April 2014, consisting of the screening visit V0, five visits (V1-V5) during the treatment period, and one post-seasonal termination visit (V6). The intake of study medication (verum or placebo) was planned to last 20 weeks There was one substantial amendment of the study protocol version 3.0 prior to the start of the trial concerning the conduct of the study resulting in study protocol version 3.1. Due to a delay, the initiations of the investigator sites started in December instead of November 2013. Therefore the initially planned study duration of 20 weeks was shortened to 84 ± 14 days (12 ± 2 weeks). Visit 6 was cancelled and the intervals between V1 and V4 (56 ± 7 days) as well as V1 and V5 (84 ± 14 days) were newly determined. Diaries and rescue medication were handed out at visit V3 instead of visit V4. Visit 5 was defined as the termination visit at the end of the tree pollen season, containing all parameters to be checked from the former visit 6.
    28 Mar 2014
    A second substantial amendment of the study protocol was necessary due to the delayed start of the trial in combination with an expected early birch pollen season in 2014 based on the mild winter 2013/14. This amendment resulted in study protocol version 3.2. Instead of time intervals between V1 and V4 as well as V1 and V5, respectively, calendar weeks were determined for V4 (week 10 to 12, 10.03.2014 - 21.03.2014) and V5 (week 18 to 19, 28.04.2014 - 09.05.2014). Therefore, the study terminated at the latest in May 2014. Due to an unforeseen shortage of CPT-allergen solution announced in early January 2014 by the manufacturer ALK-Abello, the CPT at V3 was optional depending on sufficient allergen solution available
    03 Dec 2014
    In versions 3.0 to 3.2 of the study protocol it was planned to assess the TCS for the peak 30 days of the birch pollen season with a pollen count of at least “moderate” (stage 2 according to Deutscher Wetterdienst Medizin-Meteorologie). However, this 30 day peak was identical with the entire birch pollen season from end of March till end of April in Germany in 2014. Since the peak birch pollen season in 2014 lasted 14 days in all areas of Germany with a constant high pollen concentration (stage 3 according to Deutscher Wetterdienst Medizin-Meteorologie),it was decided in the blind review meeting to finally evaluate the primary efficacy variable for those 14 consecutive days at the centre with the highest local birch pollen counts (amendment 3 resulting in study protocol version 3.3). We specified the peak of the birch pollen season as 14 consecutive days with a “high” pollen count and used three analysis periods to distinguish between the peak of the birch pollen season and the entire season: Therefore, the TCS for the birch pollen season of 30 days as well as the RTSS, the six individual symptom scores of the RTSS and the TRMS for the peak birch pollen season of 14 days were evaluated as secondary parameters.

    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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