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Clinical Trial Results:
A multicenter, placebo-controlled, double-blind study to evaluate efficacy and safety of a perennial sublingual specific immunotherapy with a solution of grass pollen allergen extract in children with clinically relevant grass pollen sensitivity in comparison to a symptomatic standard treatment with add on placebo.

Summary
EudraCT number	2006-005911-82
Trial protocol	DE PL
Global end of trial date	17 Aug 2015

Results information
Results version number	v1(current)
This version publication date	28 Jun 2017
First version publication date	28 Jun 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AL0506st

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

ALLERGOPHARMA GMBH & CO. KG.

Sponsor organisation address

Hermann-Körner-Straße 52, Reinbek, Germany, 21465

Public contact

Department of Clinical Trials, Allergopharma GmbH & Co. KG, 0049 040427650,

Scientific contact

Department of Clinical Trials, Allergopharma GmbH & Co. KG, 0049 040427650,

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000337-PIP01-08

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Feb 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Aug 2015

Was the trial ended prematurely?

Main objective of the trial

1) Obtain evidence for the safety and efficacy of sublingual immunotherapy with grass pollen allergens formulated as solution in comparison with a symptomatic standard treatment with add on placebo in a representative number of grass pollen-allergic children, suffering from allergic rhinitis/rhinoconjunctivitis with or without bronchial asthma (Global Initiative for Asthma [GINA] I and II). 2) Assess immunologic parameters during the course of the study, to obtain evidence of immunologic effects of the therapeutic vaccine. Note: Study participants were patients with IgE-mediated allergic disease manifested as symptoms of allergic rhinitis/rhinoconjunctivitis with or without allergic bronchial asthma (GINA I and II), triggered by grass pollen allergens. To take into account the pollen seasons, this study took place in DE and PL between March 2008 to August 2015. The study design consisted of 3 phases: double-blind (active or placebo), open label (active) , follow-up (none).

Protection of trial subjects

The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices guidelines, and local legal requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Feb 2008

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 133

Country: Number of subjects enrolled

Germany: 74

Worldwide total number of subjects

207

EEA total number of subjects

207

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

182

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patients were recruited in study centers in Germany and Poland. The screening phase was performed in two subsequent years. Phase 1 was performed from 02/2008 to 06/2008 with baseline assessment during the grass pollen season 2008 and phase 2 from 08/2008 to 05/2009 with baseline assessment during the grass pollen season of the year 2009.

Screening details

The screening was performed according to the inclusion and exclusion criteria. In total, 573 patients were screened and 207 patients were randomised into the study. Patient screening was performed in two subsequent years.

Period 1 title

Double blind phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Data analyst, Carer, Assessor, Subject

Blinding implementation details

The packing material of the study preparations (active treatment and placebo) was of uniform and neutral design. Each package was marked as study medication, stating the study number, the year of treatment as well as name and address of the manufacturer. Labelling was in accordance with the respective national requirements for clinical study preparations. All packages were clearly labelled "For use in clinical trials".

Are arms mutually exclusive

Yes

Active treatment SLIT

Arm description

Subjects received sublingual specific immunotherapy (SLIT) with grass pollen allergen extract.

Arm type

Experimental

Investigational medicinal product name

Grass pollen allergen extract

Investigational medicinal product code

Other name

Sublingual specific immunotherapy (SLIT)

Pharmaceutical forms

Oral solution

Routes of administration

Sublingual use

Dosage and administration details

Sublingual Specific Immunotherapy (SLIT) Solution of grass pollen allergen extract in a water/glycerol in phosphate buffered saline. The study medication was a mixture of grass pollen allergens in a water/glycerol solution with phosphate buffered saline and was filled into polyethylene single-dose containers. The liquid was standardised to contain a major allergen content of 40μg grasses group 5 (in house assay). The allergen extracts consisted of Dactylis glomerata, Festuca pratensis, Holcus lanatus, Lolium perenne, Phleum pratense and Poa pratensis. Patients dispensed the liquid drop wise under the tongue, kept it there for 3 minutes and swallowed afterwards. In total up to 4 drops could be removed from the container (100% dose). Patients were treated perennially.

Placebo

Arm description

Subjects received placebo.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Sublingual use

Dosage and administration details

Sublingual Specific Immunotherapy (SLIT) Solution of water/glycerol in phosphate buffered saline. Patients dispensed the liquid drop-wise under the tongue, kept it there for 3 minutes and swallowed afterwards. In total up to 4 drops could be removed from the container (100% dose). Patients were treated perennially.

Number of subjects in period 1	Active treatment SLIT	Placebo
Started	158	49
Completed	132	47
Not completed	26	2
Consent withdrawn by subject	9	1
Moved to another town	1	-
Adverse event, non-fatal	8	-
Non-compliant	3	1
In-Exclusion criteria	2	-
Drug intolerance	2	-
Lost to follow-up	1	-

Period 2 title

Open label phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

'Active-Active' treatment

Arm description

The open-label phase (OLP) included 3 years of open label active treatment for patients randomised to placebo and 2 years of open label active treatment for patients randomised to active treatment. In all analyses of the OLP the previously active treated patients are named ‘Active - Active’ and the previously placebo treated patients ‘Placebo - Active’.

Arm type

Experimental

Investigational medicinal product name

Grass pollen allergen extract

Investigational medicinal product code

Other name

Sublingual specific immunotherapy (SLIT)

Pharmaceutical forms

Concentrate for oral solution

Routes of administration

Sublingual use

Dosage and administration details

'Placebo-Active' treatment

Arm description

Arm type

Experimental

Investigational medicinal product name

Grass pollen allergen extract

Investigational medicinal product code

Other name

Sublingual specific immunotherapy (SLIT)

Pharmaceutical forms

Concentrate for oral solution

Routes of administration

Sublingual use

Dosage and administration details

Number of subjects in period 2 ^[1]	'Active-Active' treatment	'Placebo-Active' treatment
Started	131	46
Completed	119	33
Not completed	12	13
Consent withdrawn by subject	2	6
Physician decision	1	-
Adverse event, non-fatal	1	4
Non-compliant	1	1
Other	4	2
Lost to follow-up	3	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Several trial subject did not continue the study after the double blind phase, in the active treatment as well as in the placebo treatment groups.

Period 3 title

Follow-up phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

'Active-Active' treatment

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

'Placebo-Active' treatment

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3 ^[2]	'Active-Active' treatment	'Placebo-Active' treatment
Started	85	23
Completed	76	20
Not completed	9	3
In-/Exclusion criteria	1	-
Consent withdrawn by subject	6	-
Physician decision	-	1
Non-compliant	-	1
Other	-	1
Lost to follow-up	2	-

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Patients entering the follow-up phase was not the same as the number completing the preceding period. The reasons for this were: Several trial subject did not continue the study after the open label phase, in the active-active treatment as well as in the placebo-active treatment groups.

Baseline characteristics

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Reporting group title

Active treatment SLIT

Reporting group description

Subjects received sublingual specific immunotherapy (SLIT) with grass pollen allergen extract.

Reporting group title

Placebo

Reporting group description

Subjects received placebo.

Reporting group values	Active treatment SLIT	Placebo	Total
Number of subjects	158	49	207
Age categorical
Units: Subjects
Children (2-11 years)	139	43	182
Adolescents (12-17 years)	19	6	25
Age continuous
Units: years
arithmetic mean (standard deviation)	8.74 ( 2.27 )	8.67 ( 2.32 )	-
Gender categorical
Units: Subjects
Female	47	14	61
Male	111	35	146
Race
Units: Subjects
African descent	0	1	1
Asian descent	0	1	1
Caucasian	157	47	204
Caucasian, African descent	1	0	1
Smoking status
Units: Subjects
Smoking	0	0	0
Non-smoking	158	49	207
Household pets
Units: Subjects
None	103	25	128
Pet(s)	55	24	79
Weight
Units: kg
arithmetic mean (standard deviation)	31.56 ( 10.44 )	29.64 ( 8.85 )	-
Height
Units: cm
arithmetic mean (standard deviation)	134 ( 14.82 )	133.16 ( 13.98 )	-

End points

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Reporting group title

Active treatment SLIT

Reporting group description

Subjects received sublingual specific immunotherapy (SLIT) with grass pollen allergen extract.

Reporting group title

Placebo

Reporting group description

Subjects received placebo.

Reporting group title

'Active-Active' treatment

Reporting group description

Reporting group title

'Placebo-Active' treatment

Reporting group description

Reporting group title

'Active-Active' treatment

Reporting group description

Reporting group title

'Placebo-Active' treatment

Reporting group description

Primary: 1_01_Change of the area under the curve (AUC) of symptom and medication score (SMS) after 1 year of treatment; DBP

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End point title

1_01_Change of the area under the curve (AUC) of symptom and medication score (SMS) after 1 year of treatment; DBP

End point description

The primary endpoint of this study was the change of the AUC of the SMS from the baseline season to the season after one year of treatment. SMS was calculated by the daily sum of symptoms and the use of anti-allergic medication documented in patients diaries during the grass pollen seasons. The grass pollen season for data analysis - was the time window of 6 weeks (42 days) with the highest pollen counts. Symptoms to be considered were: • Eyes (itching, tear flow, redness) • Nose (sneezing, itching, running, blocking) • Chest (cough, wheezing, dyspnoea) Score (according to intensity) 0 = absent symptoms (no sign/symptom evident) 1 = mild symptoms, minimal inconvenience 2 = moderate, bothersome but tolerable symptoms 3 = severe symptoms that interfered with activities of daily living and/or sleeping Daily medication scores were assigned as in the AMS Scoring Conventions for Allergopharma clinical studies. AUC=Area under the curve SMS=symptom and medication score

End point type

Primary

End point timeframe

Baseline to 1 year after treatment.

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	124 ^[1]	42 ^[2]
Units: score
arithmetic mean (standard deviation)	-212.5 ( 211.8 )	-97.8 ( 196.8 )

Notes
[1] - Full analysis set; Change to baseline
[2] - Full analysis set; Change to baseline

Change to baseline (after 1 year of treatment)

Statistical analysis description

Change to baseline (after 1 year of treatment).

Comparison groups

Active treatment SLIT v Placebo

Number of subjects included in analysis

166

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.004 ^[4]

Method

ANOVA

Parameter type

Mean difference (final values)

Point estimate

-109.56

Confidence interval

level

95%

sides

2-sided

lower limit

-183.53

upper limit

-35.59

Variability estimate

Standard error of the mean

Dispersion value

37.39

Notes
[3] - The statistical null-hypothesis of no difference between the mean changes of AUC of SMS between treatment groups was tested in a confirmatory sense with an ANOVA model adjusted by gender and year of baseline.
[4] - Superiority of active treatment over placebo after one year of SLIT was demonstrated.

Secondary: 1_03a & 03b_AUC of symptom score and AUC of medication score; DBP

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End point title

1_03a & 03b_AUC of symptom score and AUC of medication score; DBP

End point description

Change in the AUC of the score, evaluated separately by symptom score and by medication score. Criteria for the symptom score and by medication score are summarized under the endpoint 1_01. When the symptom score was evaluated by gender, the results were similar to the results of the FAS. AUC=Area under the curve FAS=Full analysis set SMS=Symptom and medication score

End point type

Secondary

End point timeframe

Baseline to 1 year of treatment.

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	124 ^[5]	42 ^[6]
Units: score
arithmetic mean (standard deviation)
Symptom score	-126.6 ( 130.7 )	-55.2 ( 144.2 )
Medication score	-85.9 ( 121.1 )	-42.6 ( 106.5 )

Notes
[5] - Full analysis set; Change to baseline
[6] - Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 1_04_AUC of rhinoconjunctivitis (RC)-SMS; DBP

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End point title

1_04_AUC of rhinoconjunctivitis (RC)-SMS; DBP

End point description

AUC of rhinoconjunctivitis (RC)-SMS The AUC of RC-SMS (which scored only symptoms and medication related to nose and eyes) was evaluated as a secondary endpoint after one year of treatment. Criteria for the symptom score and by medication score are summarized under the endpoint 1_01. AUC=Area under the curve FAS=Full analysis set RC=Rhinoconjunctivitis SMS=Symptom and medication score

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment.

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	124 ^[7]	42 ^[8]
Units: score
arithmetic mean (standard deviation)	-199.7 ( 206.1 )	-83.6 ( 186 )

Notes
[7] - Full analysis set; Change to baseline
[8] - Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 1_05_Number of well days overall; DBP

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End point title

1_05_Number of well days overall; DBP

End point description

The number of well days was defined as the number of days with symptom score ≤ 4 and medication score of 0. When the number of well days was evaluated by subgroups gender, the results were similar to those observed for the overall number of well days.

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment.

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	124 ^[9]	42 ^[10]
Units: day
arithmetic mean (standard deviation)	9.3 ( 12.4 )	5.1 ( 11.1 )

Notes
[9] - Full analysis set; Change to baseline
[10] - Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 1_06_Rhinoconjunctivitis (RC) well days; DBP

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End point title

1_06_Rhinoconjunctivitis (RC) well days; DBP

End point description

The number of RC well days was defined as the number of days with RC symptom score ≤ 3 and medication score of 0. RC=Rhinoconjunctivitis

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment.

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	124 ^[11]	42 ^[12]
Units: day
arithmetic mean (standard deviation)	8.6 ( 12.1 )	4.3 ( 10.6 )

Notes
[11] - Full analysis set; Change to baseline
[12] - Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 1_07_Responder analysis overall; DBP

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End point title

1_07_Responder analysis overall; DBP

End point description

Patient’s response to the study medication defined as an improvement of at least 40% in the AUC of the SMS in the season after the 1st year of treatment compared to the AUC of the SMS in the baseline season. Shown are patients who were responders. The number of patients 'Missing' are shown under the results table. There were no substantial differences observed when analysing the response by gender, as compared with the FAS. AUC=Area under the curve FAS=Full analysis set SMS=Symptom and medication score

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment.

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	124 ^[13]	42 ^[14]
Units: patient	63	14

Notes
[13] - Full analysis set
[14] - Full analysis set

No statistical analyses for this end point

Secondary: 1_08_Conjunctival provocation test (CPT); DBP

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End point title

1_08_Conjunctival provocation test (CPT); DBP

End point description

CPT reproduces the events occurring by instilling an allergen on the ocular surface. A lyophilized grass pollen allergen extract with a standardised activity wasreconstituted and diluted for the provocation test. The initial concentration was 5 SBU/mL. Titration was performed with increasing concentrations and the highest concentration was 5,000 SBU/mL. Changes in specific CPT results (threshold concentration) at baseline to the end of one treatment year were evaluated in the FAS. The evaluation of the CPT results (threshold concentration) by gender was difficult to interpret due to the small sample size in the single subgroups. CPT=Conjunctival provocation test FAS=Full analysis set SBU=Standard biological units per millilitre

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment.

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	132 ^[15]	47 ^[16]
Units: patient
Missing	1	1
Improved	71	19
Unchanged	47	20
Worsened	13	7

Notes
[15] - FAS=Full analysis set
[16] - FAS=Full analysis set

No statistical analyses for this end point

Secondary: 1_09_Immunological profile: IgE; DBP

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End point title

1_09_Immunological profile: IgE; DBP

End point description

Immunological profile: IgE Specific IgE, IgG1, and IgG4 values were evaluated at screening visit V I/-1, after grass pollen season in baseline year at V I/6, after three months of treatment at V I/10 and V II/12 and every study year before (V II/1 and V III/1) and at the end of the grass pollen season (V II/7 and V III/6) as well as the absolute change from screening. Median values are presented because of the wide variation of the measurements and the small sample size of the placebo population. Immunologic changes in IgE, IgG1, and IgG4 antibody levels were also evaluated by gender. The immunologic results in the subgroup analyses were similar to the results from the FAS.

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment. V I/6 Baseline V I/10 After 3 months of treatment V II/1 Before grass pollen season V II/7 At end of grass pollen season

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	132 ^[17]	47 ^[18]
Units: kUA/L
median (full range (min-max))
V I/6 Baseline	6.4 (-24.2 to 47.1)	7.6 (-5.4 to 41.7)
V I/10 After three months of treatment	2 (-41.8 to 47.5)	0.6 (-14 to 24.2)
V II/1 Before grass pollen season	1.3 (-30.4 to 37.7)	0 (-19 to 24.2)
V II/7 At end of grass pollen season	1.8 (-32 to 37.7)	10.2 (-1.9 to 46.6)

Notes
[17] - Full analysis set; Change to baseline V I/6 N=129 V I/10 N=129 V II/1 N=126 V II/7 N=130
[18] - Full analysis set; Change to baseline V I/6 N=45 V I/10 N=46 V II/1 N=43 V II/7 N=46

No statistical analyses for this end point

Secondary: 1_10_Immunological profile: IgG1; DBP

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End point title

1_10_Immunological profile: IgG1; DBP

End point description

Immunological profile: IgG1 Specific IgE, IgG1, and IgG4 values were evaluated at screening visit V I/-1, after grass pollen season in baseline year at V I/6, after three months of treatment at V I/10 and V II/12 and every study year before (V II/1 and V III/1) and at the end of the grass pollen season (V II/7 and V III/6) as well as the absolute change from screening. Median values are presented because of the wide variation of the measurements and the small sample size of the placebo population. Immunologic changes in IgE, IgG1, and IgG4 antibody levels were also evaluated by gender. The immunologic results in the subgroup analyses were similar to the results from the FAS.

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment. V I/6 Baseline V I/10 After three months of treatment V II/1 Before grass pollen season V II/7 At end of grass pollen season

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	132 ^[19]	47 ^[20]
Units: μg/L
median (full range (min-max))
V I/6 Baseline	210 (-9387 to 9706)	188 (-740 to 6126)
V I/10 After three months of treatment	898 (-9522 to 64821)	-18.5 (-1134 to 1792)
V II/1 Before grass pollen season	1046 (-9522 to 84545)	-49 (-1134 to 391)
V II/7 At end of grass pollen season	895.5 (-8762 to 105313)	107 (-718 to 4924)

Notes
[19] - Full analysis set; Change to baseline V I/6 N=129 V I/10 N=129 V II/1 N=126 V II/7 N=130
[20] - Full analysis set; Change to baseline V I/6 N=45 V I/10 N=46 V II/1 N=43 V II/7 N=46

No statistical analyses for this end point

Secondary: 1_11_Immunological profile: IgG4; DBP

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End point title

1_11_Immunological profile: IgG4; DBP

End point description

Immunological profile: IgG4 Specific IgE, IgG1, and IgG4 values were evaluated at screening visit V I/-1, after grass pollen season in baseline year at V I/6, after three months of treatment at V I/10 and V II/12 and every study year before (V II/1 and V III/1) and at the end of the grass pollen season (V II/7 and V III/6) as well as the absolute change from screening. Median values are presented because of the wide variation of the measurements and the small sample size of the placebo population. Immunologic changes in IgE, IgG1, and IgG4 antibody levels were also evaluated by gender. The immunologic results in the subgroup analyses were similar to the results from the FAS.

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment. V I/6 Baseline V I/10 After three months of treatment V II/1 Before grass pollen season V II/7 At end of grass pollen season

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	132 ^[21]	47 ^[22]
Units: μg/L
median (full range (min-max))
V I/6 Baseline	162 (-544 to 24673)	141 (-118 to 7206)
V I/10 After three months of treatment	1264 (-15531 to 86331)	0 (-487 to 763)
V II/1 Before grass pollen season	1234 (-15531 to 278808)	-1 (-1702 to 232)
V II/7 At end of grass pollen season	1204.5 (-10799 to 187812)	96 (-1246 to 2265)

Notes
[21] - Full analysis set; Change to baseline V I/6 N=129 V I/10 N=129 V II/1 N=126 V II/7 N=130
[22] - Full analysis set; Change to baseline V I/6 N=45 V I/10 N=46 V II/1 N=43 V II/7 N=46

No statistical analyses for this end point

Secondary: 1_12a & 1_12 b_Vital signs: Diastolic blood pressure; Systolic blood pressure; DBP

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End point title

1_12a & 1_12 b_Vital signs: Diastolic blood pressure; Systolic blood pressure; DBP

End point description

Diastolic blood pressure [mmHg]; Systolic blood pressure [mmHg]; Diastolic blood pressure, Systolic blood pressure: Change to baseline Changes in vital signs from baseline visit (V I/-1) to last visit in first treatment year (V II/7).

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment. From baseline visit (V I/-1) to last visit treatment year (V II/7).

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	131 ^[23]	46 ^[24]
Units: mmHg
median (full range (min-max))
Diastolic blood pressure	0 (-30 to 35)	0 (-22 to 25)
Systolic blood pressure	0 (-23 to 43)	-1 (-20 to 24)

Notes
[23] - Safety analysis set
[24] - Safety analysis set

No statistical analyses for this end point

Secondary: 1_13_Vital signs: Heart rate; DBP

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End point title

1_13_Vital signs: Heart rate; DBP

End point description

Vital signs: Heart rate (Beats per minute) Heart rate: Change to baseline Changes in vital signs from baseline visit (V I/-1) to last visit in first treatment year (V II/7). bpm=Beats per minute

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment. From baseline visit (V I/-1) to last visit treatment year (V II/7).

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	130 ^[25]	46 ^[26]
Units: bpm
median (full range (min-max))	-2 (-36 to 53)	2 (-30 to 48)

Notes
[25] - Safety analysis set
[26] - Safety analysis set

No statistical analyses for this end point

Secondary: 1_14_Vital signs: Respiratory rate; DBP

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End point title

1_14_Vital signs: Respiratory rate; DBP

End point description

Vital signs: Respiratory rate (breaths per min) Changes in vital signs from baseline visit (V I/-1) to last visit in first treatment year (V II/7).

End point type

Secondary

End point timeframe

Baseline to 1 year after treatment. From baseline visit (V I/-1) to last visit treatment year (V II/7).

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	128 ^[27]	46 ^[28]
Units: breaths per min
median (full range (min-max))	0 (-22 to 24)	0 (-17 to 12)

Notes
[27] - Safety analysis set
[28] - Safety analysis set

No statistical analyses for this end point

Secondary: 2_01_Change of the area under the curve (AUC) of symptom and medication score (SMS) after treatment; OLP

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End point title

2_01_Change of the area under the curve (AUC) of symptom and medication score (SMS) after treatment; OLP

End point description

AUC of SMS over all treatment years for the FAS population during the OLP, by treatment group. Treatment groups: • 'Active-Active' represents patients who received active treatment during the double-blind phase and active treatment during the open-label phase. • 'Placebo-Active' represents patients who received placebo during the double-blind phase and active treatment during the open-label phase. Criteria for the symptom score and by medication score are summarized under the endpoint 1_01. The number of patients available at each time point is shown under the results table. AUC=Area under the curve FAS=Full analysis set OLP=Open label phase SMS=Symptom and medication score

End point type

Secondary

End point timeframe

Baseline to 1st, 2nd, 3rd, 4th year after treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[29]	36 ^[30]
Units: score
arithmetic mean (standard deviation)
1st year	-213.3 ( 209.4 )	-132 ( 183.7 )
2nd year	-288.5 ( 251 )	-232.1 ( 202.8 )
3rd year	-350.8 ( 276.2 )	-328.2 ( 207.4 )
4th year	0 ( 0 )	-312.8 ( 240.5 )

Notes
[29] - Full analysis set; Change to baseline 1st year N=118 2nd year N=115 3rd year N=110 4th year N=NA
[30] - Full analysis set; Change to baseline 1st year N=34 2nd year N=36 3rd year N=35 4th year N=26

No statistical analyses for this end point

Secondary: 2_03a_AUC of symptom score; OLP

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End point title

2_03a_AUC of symptom score; OLP

End point description

Criteria for the symptom score and medication score are summarized under the endpoint 1_01. The number of patients available at each time point is shown under the results table. For the treatment group 'Active-Active', 4th year, the AUC of symptom score was not performed; because the EudraCT database requires a value in the Table, this is indicated as 0 (±0).

End point type

Secondary

End point timeframe

Baseline to 1st, 2nd, 3rd, 4th year after treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[31]	36 ^[32]
Units: score
arithmetic mean (standard deviation)
1st year	-126.2 ( 132.1 )	-78.6 ( 130.6 )
2nd year	-166.6 ( 168.4 )	-136.3 ( 139.4 )
3rd year	-199.6 ( 170 )	-185.2 ( 152.6 )
4th year	0 ( 0 )	-183.1 ( 140.6 )

Notes
[31] - Full analysis set; Change to baseline 1st year N=118 2nd year N=115 3rd year N=110 4th year N=NA
[32] - Full analysis set; Change to baseline 1st year N=34 2nd year N=36 3rd year N=35 4th year N=26

No statistical analyses for this end point

Secondary: 2_03b_AUC of medication score; OLP

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End point title

2_03b_AUC of medication score; OLP

End point description

Criteria for the symptom score and medication score are summarized under the endpoint 1_01. The number of patients available at each time point is shown under the results table. For the treatment group 'Active-Active', 4th year, the AUC of medication score was not performed; because the EudraCT database requires a value in the Table, this is indicated as 0 (±0).

End point type

Secondary

End point timeframe

Baseline to 1st, 2nd, 3rd, 4th year after treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[33]	36 ^[34]
Units: score
arithmetic mean (standard deviation)
1st year	-87.1 ( 118.3 )	-53.4 ( 112.1 )
2nd year	-121.8 ( 124.3 )	-95.8 ( 127.4 )
3rd year	-151.2 ( 153.2 )	-143.1 ( 113.4 )
4th year	0 ( 0 )	-129.7 ( 127.2 )

Notes
[33] - Full analysis set; Change to baseline 1st year N=118 2nd year N=115 3rd year N=110 4th year N=NA
[34] - Full analysis set; Change to baseline 1st year N=34 2nd year N=36 3rd year N=35 4th year N=26

No statistical analyses for this end point

Secondary: 2_04_AUC of rhinoconjunctivitis (RC)-SMS; OLP

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End point title

2_04_AUC of rhinoconjunctivitis (RC)-SMS; OLP

End point description

AUC of rhinoconjunctivitis (RC)-SMS. For further details please see the description for endpoint 1-04.

End point type

Secondary

End point timeframe

Baseline to 1st, 2nd, 3rd, 4th year after treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[35]	36 ^[36]
Units: score
arithmetic mean (standard deviation)
1st year	-200.3 ( 204 )	-114.7 ( 179 )
2nd year	-263.3 ( 243.6 )	-220.7 ( 193.8 )
3rd year	-334.3 ( 268.9 )	-297 ( 207.3 )
4th year	0 ( 0 )	-266.5 ( 216.8 )

Notes
[35] - Full analysis set; Change to baseline 1st year N=118 2nd year N=115 3rd year N=110 4th year N=NA
[36] - Full analysis set; Change to baseline 1st year N=34 2nd year N=36 3rd year N=35 4th year N=26

No statistical analyses for this end point

Secondary: 2_05_Number of well days overall; OLP

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End point title

2_05_Number of well days overall; OLP

End point description

The number of well days was defined as the number of days with symptom score ≤ 4 and medication score of 0.

End point type

Secondary

End point timeframe

Baseline to 1st, 2nd, 3rd, 4th year after treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[37]	36 ^[38]
Units: day
arithmetic mean (standard deviation)
1st year	8.8 ( 12.1 )	6.1 ( 11.6 )
2nd year	14.1 ( 13.9 )	11.3 ( 15.3 )
3rd year	19.8 ( 16.2 )	19.5 ( 15.3 )
4th year	0 ( 0 )	22.7 ( 14.7 )

Notes
[37] - Full analysis set; Change to baseline 1st year N=118 2nd year N=115 3rd year N=110 4th year N=NA
[38] - Full analysis set; Change to baseline 1st year N=34 2nd year N=36 3rd year N=35 4th year N=26

No statistical analyses for this end point

Secondary: 2_06_Rhinoconjunctivitis (RC) well days; OLP

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End point title

2_06_Rhinoconjunctivitis (RC) well days; OLP

End point description

The number of RC well days was defined as the number of days with RC symptom score ≤ 3 and medication score of 0. RC=Rhinoconjunctivitis

End point type

Secondary

End point timeframe

Baseline to 1st, 2nd, 3rd, 4th year after treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[39]	36 ^[40]
Units: day
arithmetic mean (standard deviation)
1st year	8.2 ( 11.8 )	5 ( 11.3 )
2nd year	13.2 ( 13.8 )	9.9 ( 15 )
3rd year	18.5 ( 16 )	17.9 ( 15.9 )
4th year	0 ( 0 )	20.3 ( 15.2 )

Notes
[39] - Full analysis set; Change to baseline 1st year N=118 2nd year N=115 3rd year N=110 4th year N=NA
[40] - Full analysis set; Change to baseline 1st year N=34 2nd year N=36 3rd year N=35 4th year N=26

No statistical analyses for this end point

Secondary: 2_07_Responder analysis overall; OLP

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End point title

2_07_Responder analysis overall; OLP

End point description

A positive response to study medication was defined as at least 40% improvement of AUC of SMS from baseline to the end of treatment year. Shown are patients who were responders by treatment year. The number of patients 'Missing' for a particular time point evaluation are shown under the results table. For the treatment group 'Active-Active', 4th year, the responder analysis overall was not performed; because the EudraCT database requires a value in the Table, this is indicated as 0 (±0).

End point type

Secondary

End point timeframe

Baseline to 1st, 2nd, 3rd, 4th year after treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[41]	36 ^[42]
Units: patient
1st year	59	13
2nd year	79	24
3rd year	81	30
4th year	0	21

Notes
[41] - Full analysis set Missing 1st y N=7 2nd y N=10 3rd y N=15 4th y N=NA
[42] - Full analysis set Missing 1st y N=2 2nd y N=0 3rd y N=1 4th y N=10

No statistical analyses for this end point

Secondary: 2_08_Conjunctival provocation test (CPT); OLP

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End point title

2_08_Conjunctival provocation test (CPT); OLP

End point description

For details please see the description for endpoint 1-09.

End point type

Secondary

End point timeframe

Baseline to end of 3rd year after treatment.

End point values	'Active-Active' treatment
Number of subjects analysed	125 ^[43]
Units: patient
Missing	6
Improved	105
Unchanged	8
Worsened	6

Notes
[43] - Full analysis set

No statistical analyses for this end point

Secondary: 2_09_Immunological profile: IgE; OLP

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End point title

2_09_Immunological profile: IgE; OLP

End point description

Number of patients in the study groups Active-Active V I/6 N=122 V I/10 N=122 V II/1 N=119 V II/7 N=123 V II/12 N=46 V III/1 N=40 V III/6 N=48 Placebo-Active V I/6 N=34 V I/10 N=35 V II/1 N=33 V II/7 N=36 V II/12 N=15 V III/1 N=14 V III/6 N=17

End point type

Secondary

End point timeframe

Baseline to visit: V I/6 Baseline V I/10 After 3 months of treatm V II/1 Before grass pollen season V II/7 At end of grass pollen season V II/12 After 3 months of treatm V III/1 Before grass pollen season V III/6 At end of grass pollen season

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[44]	36 ^[45]
Units: kUA/L
median (full range (min-max))
V I/6	6.43 (-24.2 to 47.1)	10.94 (-5.4 to 41.7)
V I/10	1.98 (-41.8 to 47.5)	1.23 (-14 to 24.2)
V II/1	1.25 (-30.4 to 37.7)	0 (-14 to 24.2)
V II/7	1.54 (-32 to 37.7)	11.09 (-1.6 to 46.6)
V II/12	-1.82 (-34.8 to 26)	13.5 (-7.9 to 37.7)
V III/1	-3.67 (-41.4 to 20.7)	2.53 (-5.9 to 35.6)
V III/6	-0.2 (-41.4 to 31.6)	3.81 (-9.3 to 35.6)

Notes
[44] - Full analysis set; Change to baseline
[45] - Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 2_10_Immunological profile: IgG1; OLP

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End point title

2_10_Immunological profile: IgG1; OLP

End point description

End point type

Secondary

End point timeframe

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[46]	36 ^[47]
Units: μg/L
median (full range (min-max))
V I/6	215 (-9387 to 9706)	181 (-740 to 6126)
V I/10	911 (-9522 to 64821)	0 (-740 to 1792)
V II/1	1054 (-9522 to 84545)	-12 (-780 to 391)
V II/7	887 (-8762 to 105313)	128.5 (-718 to 4924)
V II/12	850.5 (-258 to 86801)	553 (-197 to 9102)
V III/1	598 (-242 to 56380)	549 (-62 to 13123)
V III/6	725.5 (-4067 to 67302)	420 (-1379 to 9209)

Notes
[46] - Full analysis set; Change to baseline
[47] - Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 2_11_Immunological profile: IgG4; OLP

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End point title

2_11_Immunological profile: IgG4; OLP

End point description

End point type

Secondary

End point timeframe

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[48]	36 ^[49]
Units: μg/L
median (full range (min-max))
V I/6	164 (-544 to 24673)	148 (-118 to 7206)
V I/10	1352 (-15531 to 86331)	0 (-283 to 763)
V II/1	1293 (-15531 to 278808)	-1 (-1702 to 232)
V II/7	1435 (-10799 to 187812)	119.5 (-1246 to 2265)
V II/12	1381.5 (-53 to 158729)	195 (-181 to 9993)
V III/1	657.5 (-47 to 117410)	492.5 (-19 to 11489)
V III/6	1138 (-16 to 150727)	416 (-12 to 8454)

Notes
[48] - Full analysis set; Change to baseline
[49] - Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 2_12a_Vital signs: Diastolic blood pressure; OLP

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End point title

2_12a_Vital signs: Diastolic blood pressure; OLP

End point description

Diastolic blood pressure: change to baseline from the indicated study visits, during OLP. OLP=Open-label phase

End point type

Secondary

End point timeframe

Baseline to visit: V II/7 At end of grass pollen season V III/6 V IV/6 V V/6

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	130 ^[50]	46 ^[51]
Units: mmHg
median (full range (min-max))
V II/7	0 (-30 to 35)	0 (-22 to 25)
V III/6	2 (-36 to 30)	0 (-16 to 20)
V IV/6	4.5 (-23 to 37)	3.5 (-18 to 25)
V V/6	0 (0 to 0)	1 (-25 to 20)

Notes
[50] - Safety analysis set; change to baseline V II/7 N=129 V III/6 N=127 V IV/6 N=122 V V/6 N=NA
[51] - Safety analysis set; change to baseline V II/7 N=46 V III/6 N=37 V IV/6 N=36 V V/6 N=34

No statistical analyses for this end point

Secondary: 2_12b_Vital signs: Systolic blood pressure; OLP

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End point title

2_12b_Vital signs: Systolic blood pressure; OLP

End point description

Systolic blood pressure: change to baseline from the indicated study visits, during OLP. OLP=Open-label phase

End point type

Secondary

End point timeframe

Baseline to visit: V II/7 At end of grass pollen season V III/6 V IV/6 V V/6

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	130 ^[52]	46 ^[53]
Units: mmHg
median (full range (min-max))
V II/7	0 (-23 to 43)	-1 (-20 to 24)
V III/6	0 (-39 to 28)	0 (-23 to 25)
V IV/6	5 (-39 to 37)	0.5 (-20 to 25)
V V/6	0 (0 to 0)	5 (-15 to 21)

Notes
[52] - Safety analysis set; change to baseline V II/7 N=129 V III/6 N=127 V IV/6 N=122 V V/6 N=NA
[53] - Safety analysis set; change to baseline V II/7 N=46 V III/6 N=37 V IV/6 N=36 V V/6 N=34

No statistical analyses for this end point

Secondary: 2_13_Vital signs: Heart rate; OLP

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End point title

2_13_Vital signs: Heart rate; OLP

End point description

Vital signs: Heart rate (Beats per minute) Change to baseline from the indicated study visits, during OLP. bpm=Beats per minute OLP=Open-label phase

End point type

Secondary

End point timeframe

Baseline to visit: V II/7 At end of grass pollen season V III/6 V IV/6 V V/6

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	130 ^[54]	46 ^[55]
Units: bpm
median (full range (min-max))
V II/7	-2 (-36 to 53)	2 (-30 to 48)
V III/6	-2 (-36 to 35)	0 (-52 to 42)
V IV/6	-6 (-40 to 28)	-2 (-40 to 32)
V V/6	0 (0 to 0)	-2.5 (-40 to 28)

Notes
[54] - Safety analysis set; change to baseline V II/7 N=128 V III/6 N=127 V IV/6 N=122 V V/6 N=NA
[55] - Safety analysis set; change to baseline V II/7 N=46 V III/6 N=37 V IV/6 N=36 V V/6 N=34

No statistical analyses for this end point

Secondary: 2_14_Vital signs: Respiratory rate; OLP

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End point title

2_14_Vital signs: Respiratory rate; OLP

End point description

Vital signs: Respiratory rate (breaths per min) Change to baseline from the indicated study visits, during OLP. bpm=Beats per minute OLP=Open-label phase

End point type

Secondary

End point timeframe

Baseline to visit: V II/7 At end of grass pollen season V III/6 V IV/6 V V/6

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	130 ^[56]	46 ^[57]
Units: breaths per min
median (full range (min-max))
V II/7	0 (-22 to 24)	0 (-17 to 12)
V III/6	0 (-18 to 18)	0 (-16 to 6)
V IV/6	-1 (-23 to 18)	0 (-18 to 10)
V V/6	0 (0 to 0)	0 (-17 to 18)

Notes
[56] - Safety analysis set; change to baseline V II/7 N=126 V III/6 N=126 V IV/6 N=122 V V/6 N=NA
[57] - Safety analysis set; change to baseline V II/7 N=46 V III/6 N=37 V IV/6 N=36 V V/6 N=34

No statistical analyses for this end point

Secondary: 3_01_Change of the area under the curve (AUC) of symptom and medication score (SMS); FU

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End point title

3_01_Change of the area under the curve (AUC) of symptom and medication score (SMS); FU

End point description

This prospective follow-up (FU) phase included patients who had previously received active treatment in the course of the clinical study. During the FU phase, no study treatments were administered to the patients (treatment-free). For the FU phase of the study, the FU2 Full analysis set (FAS), which was a subset of the FU ALL patients, was used for the efficacy assessments and included 77 patients (Active - Active) and 23 patients (Placebo - Active) with AUC diary data available for at least 1 season during the FU. Criteria for the symptom score and by medication score are summarized under the endpoint 1-01. Data show results for patients in the subset FU2 Full analysis set, over the entire study years (y). FU2 Full analysis set Active- Active reporting group Pbo N=0 Act y1 N=71 Act y2 N=70 Act y3 N=71 FU y1 N=34 FU y2 N=65 Placebo- Active reporting group Pbo N=21 Act y1 N=22 Act y2 N=22 Act y3 N=18 FU y1 N=20 FU y2 N=19

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[58]	23 ^[59]
Units: score
arithmetic mean (standard deviation)
Placebo	0 ( 0 )	-161.6 ( 189.1 )
Active year 1	-226.7 ( 213.6 )	-231.5 ( 163.6 )
Active year 2	-285.5 ( 265.1 )	-292.8 ( 193.5 )
Active year 3	-346 ( 256.3 )	-296 ( 261.4 )
FU year 1	-286.8 ( 218.9 )	-331.7 ( 298.4 )
FU year 2	-340.7 ( 258.3 )	-288.8 ( 209.6 )

Notes
[58] - FU2 Full Analysis Set; Change to baseline
[59] - FU2 Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 3_03a_AUC of symptom score; FU

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End point title

3_03a_AUC of symptom score; FU

End point description

Criteria for the symptom score score are summarized under the endpoint 1_01. The FU2 Full analysis set (FAS), which was a subset of the FU ALL patients, was used for the efficacy assessments is described in endpoint 3_01. The number of patients available at each time point is shown below. FU2 Full analysis set Active- Active reporting group Pbo=0 Act y1 N=71 Act y2 N=70 Act y3 N=71 FU y1 N=34 FU y2 N=65 Placebo- Active reporting group Pbo N=21 Act y1 N=22 Act y2 N=22 Act y3 N=18 FU y1 N=20 FU y2 N=19

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[60]	23 ^[61]
Units: score
arithmetic mean (standard deviation)
Placebo	0 ( 0 )	-81.1 ( 142.5 )
Active year 1	-138.9 ( 146.1 )	-133.6 ( 134.4 )
Active year 2	-174.6 ( 179.4 )	-178.2 ( 156.6 )
Active year 3	-210.9 ( 162.1 )	-178.4 ( 162.8 )
FU year 1	-194.7 ( 132.3 )	-180.6 ( 209 )
FU year 2	-208.7 ( 169.1 )	-181.4 ( 142.5 )

Notes
[60] - FU2 Full analysis set; Change to baseline
[61] - FU2 Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 3_03b_AUC of medication score; FU

Top of page

End point title

3_03b_AUC of medication score; FU

End point description

Criteria for the medication score are summarized under the endpoint 1_01. The FU2 Full analysis set (FAS), which was a subset of the FU ALL patients, was used for the efficacy assessments is described in endpoint 3_01. The number of patients available at each time point is shown below. FU2 Full analysis set Active- Active reporting group Pbo=0 Act y1 N=71 Act y2 N=70 Act y3 N=71 FU y1 N=34 FU y2 N=65 Placebo- Active reporting group Pbo N=21 Act y1 N=22 Act y2 N=22 Act y3 N=18 FU y1 N=20 FU y2 N=19

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[62]	23 ^[63]
Units: score
arithmetic mean (standard deviation)
Placebo	0 ( 0 )	-80.6 ( 98.2 )
Active year 1	-87.8 ( 113.5 )	-97.9 ( 86.9 )
Active year 2	-110.9 ( 121.5 )	-114.6 ( 104.4 )
Active year 3	-135.1 ( 144.6 )	-117.6 ( 130.5 )
FU year 1	-92 ( 130.8 )	-151.2 ( 135.2 )
FU year 2	-132 ( 140.7 )	-107.4 ( 125.2 )

Notes
[62] - FU2 Full analysis set; Change to baseline
[63] - FU2 Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 3_04_AUC of rhinoconjunctivitis (RC)-SMS; FU

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End point title

3_04_AUC of rhinoconjunctivitis (RC)-SMS; FU

End point description

AUC of rhinoconjunctivitis (RC)-SMS. For further details please see the description for endpoint 1_04. The FU2 Full analysis set (FAS), which was a subset of the FU ALL patients, was used for the efficacy assessments is described in endpoint 3_01. Criteria for the symptom score and by medication score are summarized under the endpoint 1_01. Data show results for patients in the subset FU2 Full analysis set, over the entire study years (y). FU2 Full analysis set Active- Active reporting group Pbo=0 Act y1 N=71 Act y2 N=70 Act y3 N=71 FU y1 N=34 FU y2 N=65 Placebo- Active reporting group Pbo N=21 Act y1 N=22 Act y2 N=22 Act y3 N=18 FU y1 N=20 FU y2 N=19

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[64]	23 ^[65]
Units: score
arithmetic mean (standard deviation)
Placebo	0 ( 0 )	-132 ( 182 )
Active year 1	-214.9 ( 210.3 )	-202 ( 169 )
Active year 2	-265.5 ( 258 )	-257.5 ( 189 )
Active year 3	-333.5 ( 250.8 )	-253.7 ( 237 )
FU year 1	-263.9 ( 219.6 )	-282.2 ( 287.4 )
FU year 2	-320.4 ( 256.2 )	-242.5 ( 192.3 )

Notes
[64] - FU2 Full analysis set; Change to baseline
[65] - FU2 Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 3_05_Number of well days, overall; FU

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End point title

3_05_Number of well days, overall; FU

End point description

The number of well days was defined as the number of days with symptom score ≤ 4 and medication score of 0. Criteria for the symptom score and by medication score are summarized under the endpoint 1_01. Data show results for patients in the subset FU2 Full analysis set, over the entire study years (y). FU2 Full analysis set Active- Active reporting group Pbo=0 Act y1 N=71 Act y2 N=70 Act y3 N=71 FU y1 N=34 FU y2 N=65 Placebo- Active reporting group Pbo N=21 Act y1 N=22 Act y2 N=22 Act y3 N=18 FU y1 N=20 FU y2 N=19

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[66]	23 ^[67]
Units: day
arithmetic mean (standard deviation)
Placebo	0 ( 0 )	7.2 ( 13.6 )
Active year 1	10.3 ( 12.1 )	10 ( 14.2 )
Active year 2	13.2 ( 14.5 )	15.3 ( 14.4 )
Active year 3	19.9 ( 16.1 )	20.2 ( 16.5 )
FU year 1	18.7 ( 15.4 )	19.2 ( 17.5 )
FU year 2	18.7 ( 15 )	15.7 ( 12 )

Notes
[66] - FU2 Full analysis set; Change to baseline
[67] - FU2 Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 3_06_Rhinoconjunctivitis (RC) well days overall; FU

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End point title

3_06_Rhinoconjunctivitis (RC) well days overall; FU

End point description

The number of RC well days was defined as the number of days with RC symptom score ≤ 3 and medication score of 0. Criteria for the medication score are summarized under the endpoint 1_01. The FU2 Full analysis set (FAS), which was a subset of the FU ALL patients, was used for the efficacy assessments is described under the endpoint xx. The number of patients available at each time point is shown below. FU2 Full analysis set Active- Active reporting group Pbo=0 Act y1 N=71 Act y2 N=70 Act y3 N=71 FU y1 N=34 FU y2 N=65 Placebo- Active reporting group Pbo N=21 Act y1 N=22 Act y2 N=22 Act y3 N=18 FU y1 N=20 FU y2 N=19 RC=Rhinoconjunctivitis

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[68]	23 ^[69]
Units: day
arithmetic mean (standard deviation)
Placebo	0 ( 0 )	5.6 ( 13 )
Active year 1	9.6 ( 11.7 )	8 ( 14 )
Active year 2	12.6 ( 14.2 )	14 ( 15 )
Active year 3	19 ( 15.9 )	16.9 ( 16.4 )
FU year 1	17.4 ( 15.6 )	17.6 ( 17.7 )
FU year 2	17.8 ( 15.3 )	13.5 ( 11.6 )

Notes
[68] - FU2 Full analysis set; Change to baseline
[69] - FU2 Full analysis set; Change to baseline

No statistical analyses for this end point

Secondary: 3_07_Responder analysis overall; FU

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End point title

3_07_Responder analysis overall; FU

End point description

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[70]	23 ^[71]
Units: patient
Placebo	0	9
Active year 1	40	14
Active year 2	46	18
Active year 3	52	14
FU year 1	26	16
FU year 2	50	15

Notes
[70] - FU2 Full analysis set Missing Pbo N=Not appl A y1 N=6 A y2 N=7 A y3 N=6 FU y1 N=43 FU y2 N=12
[71] - FU2 Full analysis set Missing Pbo N=2 A y1 N=1 A y2 N=1 A y3 N=5 FU y1 N=3 FU y2 N=4

No statistical analyses for this end point

Secondary: 3_08_Responder analysis (AUC of RC-SMS)

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End point title

3_08_Responder analysis (AUC of RC-SMS)

End point description

A positive response to study medication for the AUC of RC-SMS was defined as an at least 40% decrease of AUC of RC-SMS from baseline to the end of 1 treatment year. Shown are patients who were responders by treatment year. The number of patients 'Missing' for a particular time point evaluation are shown under the results table.

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[72]	23 ^[73]
Units: patient
Placebo	0	9
Active year 1	39	15
Active year 2	43	16
Active year 3	57	14
FU year 1	25	14
FU year 2	51	15

Notes
[72] - FU2 Full analysis set Missing Pbo N=Not appl A y1 N=6 A y2 N=7 A y3 N=6 FU y1 N=43 FU y2 N=12
[73] - FU2 Full analysis set Missing Pbo N=2 A y1 N=1 A y2 N=1 A y3 N=5 FU y1 N=3 FU y2 N=4

No statistical analyses for this end point

Secondary: 3_09 _Cured allergy rate according to SMS; FU

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End point title

3_09 _Cured allergy rate according to SMS; FU

End point description

The number of patients with cured allergy was calculated according to Tribanek et al. (refr. below). A patient was defined to be cured from his allergy if at most 1 mild symptom (or respective medication) per day in mean was present during the 42 days of the evaluation period. The analysis was performed based on the SMS as well as the RC-SMS. Shown are patients who were responders by treatment year. The number of patients 'Missing' for a particular time point evaluation are below. Patients 'Missing' at the evaluation time point Active - Active treatment group Act y1 N=1 Act y2 N=2 Act y3 N=2 FU y1 N=42 FU y2 N=7 Pbo - Active treatment group Act y1 N=0 Act y2 N=0 Act y3 N=4 FU y1 N=2 FU y2 N=3 #) Tribanek M; Narkus A; Haefner D; Meyer H. How to define ‘curing allergy’? Results from a subcutaneous specific immunotherapy study using a high-dose hypoallergenic grass pollen preparation. Allergy 2012;67[S96]:526).

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[74]	23 ^[75]
Units: patient
Active year 1	6	2
Active year 2	9	3
Active year 3	20	4
FU year 1	5	4
FU year 2	13	1

Notes
[74] - FU2 Full analysis set
[75] - FU2 Full analysis set

No statistical analyses for this end point

Secondary: 3_10_Cured allergy according to RC-SMS

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End point title

3_10_Cured allergy according to RC-SMS

End point description

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[76]	23 ^[77]
Units: patient
Active year 1	6	3
Active year 2	9	3
Active year 3	24	4
FU year 1	5	4
FU year 2	16	1

Notes
[76] - FU2 Full analysis set
[77] - FU2 Full analysis set

No statistical analyses for this end point

Secondary: 3_11a_Vital signs: Diastolic blood pressure; FU

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End point title

3_11a_Vital signs: Diastolic blood pressure; FU

End point description

Changes in vital signs from baseline visit (V I/-1) to last visit in the FU phase were evaluated. The number of patients who contributed result to a particular time points is shown below. Active - Active treatment group Active year 1 N=85 Active year 2 N=85 Active year 3v N=85 FU year 1 FUV1 N=49 FU year 1 FUV6 N=49 FU year 2 FUV1-2 N=76 FU year 2 FUV6-2 N=74 Placebo - Active treatment group Placebo N=23 Active year 1 N=23 Active year 2 N=23 Active year 3 N=23 FU year 1 FUV1 N=22 FU year 1 FUV6 N=21 FU year 2 FUV1-2 N=21 FU year 2 FUV6-2 N=20

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	85 ^[78]	23 ^[79]
Units: mmHg
median (full range (min-max))
Placebo	0 (0 to 0)	2 (-20 to 25)
Active year 1	0 (-24 to 30)	2 (-12 to 20)
Active year 2	2 (-36 to 30)	7 (-7 to 25)
Active year 3	5 (-20 to 32)	2 (-14 to 20)
FU year 1 FUV1	5 (-20 to 32)	9.5 (-14 to 30)
FU year 1 FUV6	5 (-20 to 39)	5 (-10 to 20)
FU year 2 FUV1-2	5 (-25 to 32)	5 (-10 to 20)
FU year 2 FUV6-2	6 (-20 to 32)	5.5 (-10 to 20)

Notes
[78] - FU All patients set; Change to baseline Placebo result is not applicable for this treatment group
[79] - FU All patients set; Change to baseline

No statistical analyses for this end point

Secondary: 3_11b_Vital signs: Systolic blood pressure; FU

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End point title

3_11b_Vital signs: Systolic blood pressure; FU

End point description

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	85 ^[80]	23 ^[81]
Units: mmHg
median (full range (min-max))
Placebo	0 (0 to 0)	0 (-15 to 22)
Active year 1	1 (-20 to 25)	1 (-15 to 25)
Active year 2	1 (-20 to 28)	6 (-13 to 25)
Active year 3	5 (-15 to 37)	5 (-15 to 21)
FU year 1 FUV1	5 (-35 to 35)	5.5 (-5 to 25)
FU year 1 FUV6	9 (-25 to 35)	10 (-3 to 30)
FU year 2 FUV1-2	10 (-20 to 44)	10 (-9 to 34)
FU year 2 FUV6-2	10 (-25 to 33)	10 (-7 to 32)

Notes
[80] - FU All patients set; Change to baseline Placebo result is not applicable for this treatment group
[81] - FU All patients set; Change to baseline

No statistical analyses for this end point

Secondary: 3_12_Vital signs: Heart rate; FU

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End point title

3_12_Vital signs: Heart rate; FU

End point description

Changes in vital signs from baseline visit (V I/-1) to last visit in the FU phase were evaluated. The number of patients who contributed results to a particular time points is shown below. Active - Active treatment group Active year 1 N=84 Active year 2 N=85 Active year 3v N=85 FU year 1 FUV1 N=49 FU year 1 FUV6 N=49 FU year 2 FUV1-2 N=76 FU year 2 FUV6-2 N=74 Placebo - Active treatment group Placebo N=23 Active year 1 N=23 Active year 2 N=23 Active year 3 N=23 FU year 1 FUV1 N=22 FU year 1 FUV6 N=22 FU year 2 FUV1-2 N=21 FU year 2 FUV6-2 N=20 bpm=beats per minute FU=Follow-up

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	85 ^[82]	23 ^[83]
Units: bpm
median (full range (min-max))
Placebo	0 (0 to 0)	4 (-20 to 24)
Active year 1	-2 (-36 to 53)	1 (-23 to 42)
Active year 2	0 (-36 to 32)	-5 (-18 to 32)
Active year 3	-7 (-40 to 28)	-3 (-28 to 28)
FU year 1 FUV1	-6 (-31 to 28)	-5 (-22 to 38)
FU year 1 FUV6	-4 (-36 to 33)	-2 (-22 to 30)
FU year 2 FUV1-2	-4 (-36 to 56)	-5 (-25 to 30)
FU year 2 FUV6-2	-4 (-54 to 34)	-2.5 (-25 to 26)

Notes
[82] - FU All patients set; Change to baseline Placebo result is not applicable for this treatment group
[83] - FU All patients set; Change to baseline

No statistical analyses for this end point

Secondary: 3_13_Vital signs: Respiratory rate; FU

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End point title

3_13_Vital signs: Respiratory rate; FU

End point description

Vital signs: Respiratory rate (breaths per min) Changes in vital signs from baseline visit (V I/-1) to last visit in the FU phase were evaluated. The number of patients who contributed results to a particular time points is shown below. Active - Active treatment group Active year 1 N=84 Active year 2 N=85 Active year 3v N=85 FU year 1 FUV1 N=49 FU year 1 FUV6 N=49 FU year 2 FUV1-2 N=76 FU year 2 FUV6-2 N=74 Placebo - Active treatment group Placebo N=23 Active year 1 N=23 Active year 2 N=23 Active year 3 N=23 FU year 1 FUV1 N=22 FU year 1 FUV6 N=22 FU year 2 FUV1-2 N=21 FU year 2 FUV6-2 N=20

End point type

Secondary

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	85 ^[84]	23 ^[85]
Units: breaths per min
median (full range (min-max))
Placebo	0 (0 to 0)	0 (-17 to 7)
Active year 1	0 (-22 to 24)	0 (-16 to 6)
Active year 2	0 (-18 to 8)	0 (-18 to 10)
Active year 3	-1 (-23 to 14)	0 (-17 to 18)
FU year 1 FUV1	-2 (-21 to 9)	0 (-17 to 12)
FU year 1 FUV6	-2 (-19 to 8)	0 (-17 to 10)
FU year 2 FUV1-2	-2 (-22 to 14)	0 (-6 to 10)
FU year 2 FUV6-2	-2 (-23 to 11)	0 (-4 to 12)

Notes
[84] - FU All patients set; Change to baseline Placebo result is not applicable for this treatment group
[85] - FU All patients set; Change to baseline

No statistical analyses for this end point

Post-hoc: 1_02_Change of the AUC of SMS after 1 year of treatment: sensitivity analysis; DBP

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End point title

1_02_Change of the AUC of SMS after 1 year of treatment: sensitivity analysis; DBP

End point description

For sensitivity analyses, the missing SMS values were replaced by the patient’s highest value of the defined time period (if not more than 25% of the values were missing). This SMS was referred to as the 'worst case' SMS and was analysed using the FAS. Criteria for the symptom score and by medication score are summarized under the endpoint 1_01. AUC=Area under the curve SMS=Symptom and medication score FAS=Full analysis set

End point type

Post-hoc

End point timeframe

Baseline to 1 year after treatment.

End point values	Active treatment SLIT	Placebo
Number of subjects analysed	124 ^[86]	42 ^[87]
Units: score
arithmetic mean (standard deviation)	-222 ( 212.1 )	-96.7 ( 198.9 )

Notes
[86] - Full analysis set; Change to baseline
[87] - Full analysis set; Change to baseline

Change to baseline (after 1 year of treatment)

Statistical analysis description

The sensitivity analysis of the AUC of the worst case SMS was repeated with the FAS.

Comparison groups

Active treatment SLIT v Placebo

Number of subjects included in analysis

166

Analysis specification

Pre-specified

Analysis type

other ^[88]

P-value

= 0.0018

Method

ANOVA

Parameter type

Mean difference (final values)

Point estimate

-119.72

Confidence interval

level

95%

sides

2-sided

lower limit

-194.01

upper limit

-45.43

Variability estimate

Standard error of the mean

Dispersion value

37.5517

Notes
[88] - Because differences between treatment groups were observed for the mean baseline AUC of the SMS, further post-hoc sensitivity analyses were conducted to adjust for these unexpected baseline differences. These analyses tested the difference between the mean changes of AUC of SMS between treatment groups with an analysis of covariance (ANCOVA) model adjusted for gender, year of baseline, centre and AUC of the SMS at baseline.

Post-hoc: 2_02_Change of the area under the curve (AUC) of symptom and medication score (SMS): sensitivity analysis; OLP

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End point title

2_02_Change of the area under the curve (AUC) of symptom and medication score (SMS): sensitivity analysis; OLP

End point description

AUC of SMS over all treatment years for the FAS population during the OLP, by treatment group; sensitivity analysis. For sensitivity analyses, missing SMS values were replaced by the patient’s highest value of the defined time period (if not more than 25% of the values were missing). This SMS was referred to as the 'worst case' SMS and was analysed in the FAS. Treatment groups: • 'Active-Active' represents patients who received active treatment during the double-blind phase and active treatment during the open-label phase. • 'Placebo-Active' represents patients who received placebo during the double-blind phase and active treatment during the open-label phase. Criteria for the symptom score and by medication score are summarized under the endpoint 1_01. The number of patients available at each time point is shown under the results table. AUC=Area under the curve FAS=Full analysis set OLP=Open label phase SMS=Symptom and medication score

End point type

Post-hoc

End point timeframe

Baseline to 1st, 2nd, 3rd, 4th year after treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	125 ^[89]	36 ^[90]
Units: score
arithmetic mean (standard deviation)
1st year	-223.9 ( 209.7 )	-136.8 ( 180.2 )
2nd year	-300.9 ( 251.9 )	-230.7 ( 205.3 )
3rd year	-360.6 ( 281.3 )	-332.9 ( 209 )
4th year	0 ( 0 )	-322.1 ( 236.4 )

Notes
[89] - Full analysis set; Change to baseline 1st year N=118 2nd year N=115 3rd year N=110 4th year N=NA
[90] - Full analysis set; Change to baseline 1st year N=34 2nd year N=36 3rd year N=35 4th year N=26

No statistical analyses for this end point

Post-hoc: 3_02_Change of the AUC of SMS: sensitivity analysis; FU

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End point title

3_02_Change of the AUC of SMS: sensitivity analysis; FU

End point description

This prospective follow-up (FU) phase included patients who had previously received active treatment in the course of the clinical study; sensitivity analysis. For a description of the the 'sensitivity analysis', see endpoint 1_02. The FU2 Full analysis set (FAS), which was a subset of the FU ALL patients, was used for the efficacy assessments is described in endpoint 3_01. Criteria for the symptom score and by medication score are summarized under the endpoint 1_01. Data show results for patients in the subset FU2 Full analysis set, over the entire study years (y). FU2 Full analysis set Active- Active reporting group Pbo=0 Act y1 N=71 Act y2 N=70 Act y3 N=71 FU y1 N=34 FU y2 N=65 Placebo- Active reporting group Pbo N=21 Act y1 N=22 Act y2 N=22 Act y3 N=18 FU y1 N=20 FU y2 N=19

End point type

Post-hoc

End point timeframe

Baseline to 1st and 2nd pollen season, after 3 years of active treatment.

End point values	'Active-Active' treatment	'Placebo-Active' treatment
Number of subjects analysed	77 ^[91]	23 ^[92]
Units: score
arithmetic mean (standard deviation)
Placebo	0 ( 0 )	-166.5 ( 185.5 )
Active year 1	-239.6 ( 214.6 )	-231.9 ( 163.8 )
Active year 2	-298.9 ( 267 )	-288.8 ( 190.7 )
Active year 3	-359.5 ( 260.7 )	-300.1 ( 250.5 )
FU year 1	-286.5 ( 227.1 )	-323.3 ( 296 )
FU year 2	-345.8 ( 261.8 )	-281.9 ( 211.4 )

Notes
[91] - FU2 Full analysis set; Change to baseline
[92] - FU2 Full analysis set; Change to baseline

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 3 years from the start of the study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

13.1

Reporting group title

Double-blind phase: Active treatment 1st year

Reporting group description

Reporting group title

Double-blind phase: Placebo 1st year

Reporting group description

Reporting group title

Double-blind phase: Active treatment 2nd year

Reporting group description

Reporting group title

Double-blind phase: Placebo 2nd year

Reporting group description

Reporting group title

Open label phase: Active - Active treatment

Reporting group description

Reporting group title

Open label phase: Placebo - Active treatment

Reporting group description

Reporting group title

Follow-up phase: Active - Active treatment

Reporting group description

Reporting group title

Follow-up phase: Placebo - Active treatment

Reporting group description

Serious adverse events	Double-blind phase: Active treatment 1st year	Double-blind phase: Placebo 1st year	Double-blind phase: Active treatment 2nd year	Double-blind phase: Placebo 2nd year	Open label phase: Active - Active treatment	Open label phase: Placebo - Active treatment	Follow-up phase: Active - Active treatment	Follow-up phase: Placebo - Active treatment
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 158 (3.16%)	0 / 49 (0.00%)	1 / 52 (1.92%)	2 / 22 (9.09%)	10 / 158 (6.33%)	5 / 46 (10.87%)	0 / 85 (0.00%)	0 / 23 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0
Injury, poisoning and procedural complications
Spinal column injury
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dysarthria
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	3 / 158 (1.90%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	0 / 158 (0.00%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Visual impairment
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	1 / 22 (4.55%)	0 / 158 (0.00%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	1 / 22 (4.55%)	0 / 158 (0.00%)	2 / 46 (4.35%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Hypoaesthesia facial
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neurodermatitis
subjects affected / exposed	1 / 158 (0.63%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Abnormal behaviour
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	0 / 158 (0.00%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anger
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	0 / 158 (0.00%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Scoliosis
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 158 (0.63%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 158 (0.63%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia chlamydial
subjects affected / exposed	1 / 158 (0.63%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	2 / 158 (1.27%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	2 / 158 (1.27%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	1 / 52 (1.92%)	0 / 22 (0.00%)	1 / 158 (0.63%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	0 / 52 (0.00%)	0 / 22 (0.00%)	0 / 158 (0.00%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Double-blind phase: Active treatment 1st year	Double-blind phase: Placebo 1st year	Double-blind phase: Active treatment 2nd year	Double-blind phase: Placebo 2nd year	Open label phase: Active - Active treatment	Open label phase: Placebo - Active treatment	Follow-up phase: Active - Active treatment	Follow-up phase: Placebo - Active treatment
Total subjects affected by non serious adverse events
subjects affected / exposed	139 / 158 (87.97%)	39 / 49 (79.59%)	47 / 52 (90.38%)	21 / 22 (95.45%)	146 / 158 (92.41%)	37 / 46 (80.43%)	37 / 85 (43.53%)	8 / 23 (34.78%)
Investigations
Peak expiratory flow rate decreased
subjects affected / exposed	9 / 158 (5.70%)	4 / 49 (8.16%)	3 / 52 (5.77%)	1 / 22 (4.55%)	11 / 158 (6.96%)	3 / 46 (6.52%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	10	5	5	1	22	4	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	5 / 158 (3.16%)	1 / 49 (2.04%)	2 / 52 (3.85%)	2 / 22 (9.09%)	8 / 158 (5.06%)	3 / 46 (6.52%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	5	1	2	2	8	3	1	0
Injury, poisoning and procedural complications
Arthropod sting
subjects affected / exposed	4 / 158 (2.53%)	0 / 49 (0.00%)	2 / 52 (3.85%)	0 / 22 (0.00%)	9 / 158 (5.70%)	0 / 46 (0.00%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	4	0	2	0	11	0	1	0
Nervous system disorders
Headache
subjects affected / exposed	28 / 158 (17.72%)	9 / 49 (18.37%)	8 / 52 (15.38%)	3 / 22 (13.64%)	35 / 158 (22.15%)	14 / 46 (30.43%)	7 / 85 (8.24%)	1 / 23 (4.35%)
occurrences all number	42	13	14	3	99	26	10	1
General disorders and administration site conditions
Oral administration complication
subjects affected / exposed	28 / 158 (17.72%)	1 / 49 (2.04%)	5 / 52 (9.62%)	8 / 22 (36.36%)	31 / 158 (19.62%)	10 / 46 (21.74%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	35	1	5	8	37	11	0	0
Pyrexia
subjects affected / exposed	14 / 158 (8.86%)	3 / 49 (6.12%)	2 / 52 (3.85%)	1 / 22 (4.55%)	24 / 158 (15.19%)	2 / 46 (4.35%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	16	5	3	1	31	5	1	0
Influenza like illness
subjects affected / exposed	3 / 158 (1.90%)	1 / 49 (2.04%)	3 / 52 (5.77%)	1 / 22 (4.55%)	8 / 158 (5.06%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	4	1	3	1	12	1	0	0
Malaise
subjects affected / exposed	5 / 158 (3.16%)	1 / 49 (2.04%)	1 / 52 (1.92%)	2 / 22 (9.09%)	10 / 158 (6.33%)	3 / 46 (6.52%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	6	1	2	4	14	5	0	0
Ear and labyrinth disorders
Ear pruritus
subjects affected / exposed	16 / 158 (10.13%)	0 / 49 (0.00%)	1 / 52 (1.92%)	0 / 22 (0.00%)	16 / 158 (10.13%)	2 / 46 (4.35%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	24	0	1	0	25	6	0	0
Ear pain
subjects affected / exposed	5 / 158 (3.16%)	0 / 49 (0.00%)	2 / 52 (3.85%)	0 / 22 (0.00%)	8 / 158 (5.06%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	5	0	2	0	13	1	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	4 / 158 (2.53%)	5 / 49 (10.20%)	1 / 52 (1.92%)	1 / 22 (4.55%)	10 / 158 (6.33%)	4 / 46 (8.70%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	5	8	1	1	11	4	0	0
Eye disorders
Conjunctivitis
subjects affected / exposed	5 / 158 (3.16%)	2 / 49 (4.08%)	0 / 52 (0.00%)	0 / 22 (0.00%)	8 / 158 (5.06%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	6	2	0	0	10	0	0	0
Conjunctivitis allergic
subjects affected / exposed	9 / 158 (5.70%)	5 / 49 (10.20%)	4 / 52 (7.69%)	3 / 22 (13.64%)	18 / 158 (11.39%)	6 / 46 (13.04%)	0 / 85 (0.00%)	1 / 23 (4.35%)
occurrences all number	12	8	4	3	22	8	0	1
Eye pruritus
subjects affected / exposed	22 / 158 (13.92%)	5 / 49 (10.20%)	4 / 52 (7.69%)	4 / 22 (18.18%)	25 / 158 (15.82%)	6 / 46 (13.04%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	26	7	4	4	35	7	0	0
Eye allergy
subjects affected / exposed	3 / 158 (1.90%)	0 / 49 (0.00%)	1 / 52 (1.92%)	1 / 22 (4.55%)	5 / 158 (3.16%)	3 / 46 (6.52%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	3	0	1	1	6	4	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	10 / 158 (6.33%)	4 / 49 (8.16%)	2 / 52 (3.85%)	2 / 22 (9.09%)	15 / 158 (9.49%)	5 / 46 (10.87%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	12	9	3	2	20	6	1	0
Abdominal pain upper
subjects affected / exposed	17 / 158 (10.76%)	3 / 49 (6.12%)	4 / 52 (7.69%)	3 / 22 (13.64%)	27 / 158 (17.09%)	6 / 46 (13.04%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	19	4	5	3	41	6	0	0
Diarrhoea
subjects affected / exposed	13 / 158 (8.23%)	5 / 49 (10.20%)	6 / 52 (11.54%)	0 / 22 (0.00%)	18 / 158 (11.39%)	4 / 46 (8.70%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	18	7	6	0	33	6	1	0
Nausea
subjects affected / exposed	20 / 158 (12.66%)	4 / 49 (8.16%)	5 / 52 (9.62%)	1 / 22 (4.55%)	25 / 158 (15.82%)	3 / 46 (6.52%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	23	4	6	1	33	9	0	0
Vomiting
subjects affected / exposed	23 / 158 (14.56%)	4 / 49 (8.16%)	5 / 52 (9.62%)	2 / 22 (9.09%)	31 / 158 (19.62%)	6 / 46 (13.04%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	27	6	5	2	40	6	1	0
Enteritis
subjects affected / exposed	2 / 158 (1.27%)	1 / 49 (2.04%)	1 / 52 (1.92%)	2 / 22 (9.09%)	5 / 158 (3.16%)	3 / 46 (6.52%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	2	1	1	2	5	4	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	30 / 158 (18.99%)	7 / 49 (14.29%)	11 / 52 (21.15%)	5 / 22 (22.73%)	50 / 158 (31.65%)	11 / 46 (23.91%)	3 / 85 (3.53%)	1 / 23 (4.35%)
occurrences all number	45	7	15	7	92	27	3	1
Dyspnoea
subjects affected / exposed	12 / 158 (7.59%)	1 / 49 (2.04%)	1 / 52 (1.92%)	2 / 22 (9.09%)	14 / 158 (8.86%)	3 / 46 (6.52%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	15	1	4	3	30	3	2	0
Epistaxis
subjects affected / exposed	14 / 158 (8.86%)	4 / 49 (8.16%)	4 / 52 (7.69%)	0 / 22 (0.00%)	15 / 158 (9.49%)	2 / 46 (4.35%)	4 / 85 (4.71%)	0 / 23 (0.00%)
occurrences all number	24	7	4	0	36	2	6	0
Oropharyngeal pain
subjects affected / exposed	7 / 158 (4.43%)	2 / 49 (4.08%)	7 / 52 (13.46%)	0 / 22 (0.00%)	17 / 158 (10.76%)	3 / 46 (6.52%)	2 / 85 (2.35%)	1 / 23 (4.35%)
occurrences all number	10	2	7	0	30	5	2	1
Sneezing
subjects affected / exposed	4 / 158 (2.53%)	3 / 49 (6.12%)	1 / 52 (1.92%)	2 / 22 (9.09%)	7 / 158 (4.43%)	3 / 46 (6.52%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	7	3	1	2	11	3	0	0
Throat irritation
subjects affected / exposed	17 / 158 (10.76%)	0 / 49 (0.00%)	0 / 52 (0.00%)	3 / 22 (13.64%)	18 / 158 (11.39%)	4 / 46 (8.70%)	0 / 85 (0.00%)	1 / 23 (4.35%)
occurrences all number	30	0	0	3	32	5	0	1
Asthma
subjects affected / exposed	3 / 158 (1.90%)	1 / 49 (2.04%)	2 / 52 (3.85%)	1 / 22 (4.55%)	8 / 158 (5.06%)	4 / 46 (8.70%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	3	1	2	2	9	8	1	0
Rhinitis allergic
subjects affected / exposed	3 / 158 (1.90%)	1 / 49 (2.04%)	2 / 52 (3.85%)	0 / 22 (0.00%)	11 / 158 (6.96%)	5 / 46 (10.87%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	3	1	2	0	12	6	0	0
Nasal discomfort
subjects affected / exposed	7 / 158 (4.43%)	0 / 49 (0.00%)	1 / 52 (1.92%)	0 / 22 (0.00%)	8 / 158 (5.06%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	7	0	1	0	8	1	0	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	7 / 158 (4.43%)	2 / 49 (4.08%)	0 / 52 (0.00%)	1 / 22 (4.55%)	10 / 158 (6.33%)	2 / 46 (4.35%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	10	2	0	1	16	3	0	0
Rash
subjects affected / exposed	7 / 158 (4.43%)	3 / 49 (6.12%)	1 / 52 (1.92%)	0 / 22 (0.00%)	9 / 158 (5.70%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	8	4	1	0	10	0	0	0
Urticaria
subjects affected / exposed	2 / 158 (1.27%)	1 / 49 (2.04%)	1 / 52 (1.92%)	1 / 22 (4.55%)	4 / 158 (2.53%)	3 / 46 (6.52%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	2	1	1	1	4	3	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	14 / 158 (8.86%)	1 / 49 (2.04%)	4 / 52 (7.69%)	0 / 22 (0.00%)	20 / 158 (12.66%)	4 / 46 (8.70%)	2 / 85 (2.35%)	0 / 23 (0.00%)
occurrences all number	15	1	4	0	26	4	2	0
Gastroenteritis
subjects affected / exposed	10 / 158 (6.33%)	1 / 49 (2.04%)	4 / 52 (7.69%)	1 / 22 (4.55%)	21 / 158 (13.29%)	2 / 46 (4.35%)	2 / 85 (2.35%)	0 / 23 (0.00%)
occurrences all number	12	1	5	1	26	2	2	0
Nasopharyngitis
subjects affected / exposed	46 / 158 (29.11%)	13 / 49 (26.53%)	26 / 52 (50.00%)	9 / 22 (40.91%)	74 / 158 (46.84%)	23 / 46 (50.00%)	14 / 85 (16.47%)	3 / 23 (13.04%)
occurrences all number	72	22	41	14	200	47	20	6
Pharyngitis
subjects affected / exposed	18 / 158 (11.39%)	4 / 49 (8.16%)	1 / 52 (1.92%)	2 / 22 (9.09%)	32 / 158 (20.25%)	8 / 46 (17.39%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	21	4	1	2	40	11	0	0
Respiratory tract infection viral
subjects affected / exposed	7 / 158 (4.43%)	2 / 49 (4.08%)	1 / 52 (1.92%)	0 / 22 (0.00%)	8 / 158 (5.06%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	9	2	1	0	10	1	0	0
Rhinitis
subjects affected / exposed	9 / 158 (5.70%)	4 / 49 (8.16%)	0 / 52 (0.00%)	0 / 22 (0.00%)	19 / 158 (12.03%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	9	4	0	0	24	1	0	0
Tonsillitis
subjects affected / exposed	5 / 158 (3.16%)	6 / 49 (12.24%)	1 / 52 (1.92%)	1 / 22 (4.55%)	11 / 158 (6.96%)	2 / 46 (4.35%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	7	6	1	1	17	3	1	0
Upper respiratory tract infection
subjects affected / exposed	8 / 158 (5.06%)	4 / 49 (8.16%)	2 / 52 (3.85%)	1 / 22 (4.55%)	13 / 158 (8.23%)	5 / 46 (10.87%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	10	5	2	1	19	6	0	0
Viral infection
subjects affected / exposed	11 / 158 (6.96%)	8 / 49 (16.33%)	4 / 52 (7.69%)	1 / 22 (4.55%)	21 / 158 (13.29%)	2 / 46 (4.35%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	11	8	5	1	25	4	1	0
Viral rhinitis
subjects affected / exposed	8 / 158 (5.06%)	1 / 49 (2.04%)	2 / 52 (3.85%)	0 / 22 (0.00%)	12 / 158 (7.59%)	1 / 46 (2.17%)	1 / 85 (1.18%)	0 / 23 (0.00%)
occurrences all number	10	1	3	0	17	1	1	0
Gastrointestinal infection
subjects affected / exposed	0 / 158 (0.00%)	0 / 49 (0.00%)	2 / 52 (3.85%)	0 / 22 (0.00%)	8 / 158 (5.06%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	3	0	9	1	0	0
H1N1 influenza
subjects affected / exposed	1 / 158 (0.63%)	0 / 49 (0.00%)	3 / 52 (5.77%)	0 / 22 (0.00%)	4 / 158 (2.53%)	0 / 46 (0.00%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	1	0	3	0	4	0	0	0
Influenza
subjects affected / exposed	1 / 158 (0.63%)	0 / 49 (0.00%)	4 / 52 (7.69%)	0 / 22 (0.00%)	5 / 158 (3.16%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	1	0	4	0	5	1	0	0
Otitis media
subjects affected / exposed	5 / 158 (3.16%)	1 / 49 (2.04%)	2 / 52 (3.85%)	0 / 22 (0.00%)	8 / 158 (5.06%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	5	1	2	0	8	1	0	0
Pseudocroup
subjects affected / exposed	1 / 158 (0.63%)	0 / 49 (0.00%)	0 / 52 (0.00%)	1 / 22 (4.55%)	1 / 158 (0.63%)	1 / 46 (2.17%)	0 / 85 (0.00%)	0 / 23 (0.00%)
occurrences all number	1	0	0	1	3	1	0	0

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1_01_Change of the area under the curve (AUC) of symptom and medication score (SMS) after 1 year of treatment; DBP

Primary: 1_01_Change of the area under the curve (AUC) of symptom and medication score (SMS) after 1 year of treatment; DBP

Secondary: 1_03a & 03b_AUC of symptom score and AUC of medication score; DBP

Secondary: 1_03a & 03b_AUC of symptom score and AUC of medication score; DBP

Secondary: 1_04_AUC of rhinoconjunctivitis (RC)-SMS; DBP

Secondary: 1_04_AUC of rhinoconjunctivitis (RC)-SMS; DBP

Secondary: 1_05_Number of well days overall; DBP

Secondary: 1_05_Number of well days overall; DBP

Secondary: 1_06_Rhinoconjunctivitis (RC) well days; DBP

Secondary: 1_06_Rhinoconjunctivitis (RC) well days; DBP

Secondary: 1_07_Responder analysis overall; DBP

Secondary: 1_07_Responder analysis overall; DBP

Secondary: 1_08_Conjunctival provocation test (CPT); DBP

Secondary: 1_08_Conjunctival provocation test (CPT); DBP

Secondary: 1_09_Immunological profile: IgE; DBP

Secondary: 1_09_Immunological profile: IgE; DBP

Secondary: 1_10_Immunological profile: IgG1; DBP

Secondary: 1_10_Immunological profile: IgG1; DBP

Secondary: 1_11_Immunological profile: IgG4; DBP

Secondary: 1_11_Immunological profile: IgG4; DBP

Secondary: 1_12a & 1_12 b_Vital signs: Diastolic blood pressure; Systolic blood pressure; DBP

Secondary: 1_12a & 1_12 b_Vital signs: Diastolic blood pressure; Systolic blood pressure; DBP

Secondary: 1_13_Vital signs: Heart rate; DBP

Secondary: 1_13_Vital signs: Heart rate; DBP

Secondary: 1_14_Vital signs: Respiratory rate; DBP

Secondary: 1_14_Vital signs: Respiratory rate; DBP

Secondary: 2_01_Change of the area under the curve (AUC) of symptom and medication score (SMS) after treatment; OLP

Secondary: 2_01_Change of the area under the curve (AUC) of symptom and medication score (SMS) after treatment; OLP

Secondary: 2_03a_AUC of symptom score; OLP

Secondary: 2_03a_AUC of symptom score; OLP

Secondary: 2_03b_AUC of medication score; OLP

Secondary: 2_03b_AUC of medication score; OLP

Secondary: 2_04_AUC of rhinoconjunctivitis (RC)-SMS; OLP

Secondary: 2_04_AUC of rhinoconjunctivitis (RC)-SMS; OLP

Secondary: 2_05_Number of well days overall; OLP

Secondary: 2_05_Number of well days overall; OLP

Secondary: 2_06_Rhinoconjunctivitis (RC) well days; OLP

Secondary: 2_06_Rhinoconjunctivitis (RC) well days; OLP

Secondary: 2_07_Responder analysis overall; OLP

Secondary: 2_07_Responder analysis overall; OLP

Secondary: 2_08_Conjunctival provocation test (CPT); OLP

Secondary: 2_08_Conjunctival provocation test (CPT); OLP

Secondary: 2_09_Immunological profile: IgE; OLP

Secondary: 2_09_Immunological profile: IgE; OLP

Secondary: 2_10_Immunological profile: IgG1; OLP

Secondary: 2_10_Immunological profile: IgG1; OLP

Secondary: 2_11_Immunological profile: IgG4; OLP

Secondary: 2_11_Immunological profile: IgG4; OLP

Secondary: 2_12a_Vital signs: Diastolic blood pressure; OLP

Secondary: 2_12a_Vital signs: Diastolic blood pressure; OLP

Secondary: 2_12b_Vital signs: Systolic blood pressure; OLP

Secondary: 2_12b_Vital signs: Systolic blood pressure; OLP

Secondary: 2_13_Vital signs: Heart rate; OLP

Secondary: 2_13_Vital signs: Heart rate; OLP

Secondary: 2_14_Vital signs: Respiratory rate; OLP

Secondary: 2_14_Vital signs: Respiratory rate; OLP

Secondary: 3_01_Change of the area under the curve (AUC) of symptom and medication score (SMS); FU

Secondary: 3_01_Change of the area under the curve (AUC) of symptom and medication score (SMS); FU

Secondary: 3_03a_AUC of symptom score; FU

Secondary: 3_03a_AUC of symptom score; FU

Secondary: 3_03b_AUC of medication score; FU

Secondary: 3_03b_AUC of medication score; FU

Secondary: 3_04_AUC of rhinoconjunctivitis (RC)-SMS; FU

Secondary: 3_04_AUC of rhinoconjunctivitis (RC)-SMS; FU

Secondary: 3_05_Number of well days, overall; FU

Secondary: 3_05_Number of well days, overall; FU

Secondary: 3_06_Rhinoconjunctivitis (RC) well days overall; FU

Secondary: 3_06_Rhinoconjunctivitis (RC) well days overall; FU

Secondary: 3_07_Responder analysis overall; FU

Secondary: 3_07_Responder analysis overall; FU

Secondary: 3_08_Responder analysis (AUC of RC-SMS)