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Clinical Trial Results:
A multicentre randomised placebo-controlled double-blind clinical trial for evaluation of safety and efficacy of specific immunotherapy with an aluminium hydroxide-adsorbed Allergoid Preparation of house dust mite (Dermatophagoides pteronyssinus) in patients with allergic asthma bronchiale +/- rhinitis / rhinoconjunctivitis

Summary
EudraCT number	2004-003892-35
Trial protocol	DE
Global end of trial date	29 Mar 2011

Results information
Results version number	v1(current)
This version publication date	24 Jun 2018
First version publication date	24 Jun 2018
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

AL 0104 av

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

Clinical Trials Information, ALLERGOPHARMA GMBH & CO. KG., 0049 40427650,

Scientific contact

Clinical Trials Information, ALLERGOPHARMA GMBH & CO. KG., 0049 40427650,

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

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

Yes

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

Analysis stage

Final

Date of interim/final analysis

14 Sep 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Mar 2011

Was the trial ended prematurely?

Main objective of the trial

Evaluate efficacy and tolerability of specific immunotherapy (SIT) with an aluminium hydroxide-adsorbed allergoid preparation of the major allergens from Dermatophagoides pteronyssinus (D. pteronyssinus). This trial was random., double-blind, placebo-contr. phase III, in 2 parallel groups of patients over 18 y of age; children and adolesc less than 18 y in the control group received UC with study-specific pharmacotherapy, instead of placebo. Before randomisation to treatment, patient's minimal requirement of the inhaled corticosteroid dose to achieve asthma control was determined (patient diary, baseline). After randomisation to SIT, the study duration was 2 y for each patient (2 annual assessments). After the analysis of the 2 y results, a decision was made to complete a full 3 year course of SIT in all actively treated patients (as recommended by the World Health Organisation) and do an open-label 3 y follow-up in children. SIT=Specific Immunotheraphy UC=Usual Care

Protection of trial subjects

The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (ICH) guidance for Good Clinical Practice (GCP) and the applicable regulatory requirements. The study was conducted multinationally in accordance with the respective national legal requirements. Children and adolescents under 18 years in the control group did not receive placebo, but instead received usual care with study-specific pharmacotherapy; 'usual care' consisted of a reliever and controller asthma medication. Other than routine care, no specific measures were implemented for the protection of trial subjects.

Background therapy

Treatment of asthma in this study was by an inhaled corticosteroid: fluticasone propionate 100 – 1000 μg per day in adults (50 – 500 μg per day in children) dry powder inhalation from a disk device. The corticosteroid dose was adjusted during the baseline phase at the beginning of the study and during assessment phases (15 September to 15 February each study year) until one dose step below the threshold dose of asthma control criteria (according to GINA) was met. Acute symptomatic treatment of lower airways symptoms was with salbutamol metered dose inhaler (MDI; 100 μg per dose) used only as required. Other medication (including long acting-agonists, inhaled corticosteroids in the form of combination products was not permitted during the study. Treatment of allergic rhinitis / rhinoconjunctivitis and other concomitant diseases was on the investigators’ discretion. Long-term use of oral or other systemic corticosteroids (i.e. depot corticosteroids), immunoregulatory substances or medication that could influence the efficacy of SIT were exclusion criteria and their use was not permitted during the study. If further treatments (i.e. oral corticosteroids) were required for the treatment of asthma exacerbations, these could be used; the duration of those therapies was to be kept as short as possible and their use documented. DBP=Double Blind Phase FU=Follow up Phase GINA=Global Initiative for Asthma MDI=Metered Dose Inhaler OLP=Open Label Phase SIT=Specific Immunotheraphy

Evidence for comparator

Actual start date of recruitment

23 May 2005

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Poland: 107

Worldwide total number of subjects

130

EEA total number of subjects

130

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)

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

Overall, 235 subjects [111 children and adolescents (2-17 y); 124 adults (18-64 y)] were screened for eligibility. Of these, 130 subjects (66 children and adolescents; 64 adults ) were randomised to treatment, according to the exclusion and inclusion criteria.

Screening details

Screened and randomised to treatment according to the exclusion and inclusion criteria. Asthma was treated by inhaled Fluticasone propionate (FP); 100 - 1000 μg/day adults; 50 - 500 μg/day children, dry powder inhalation, disks. FP dose was adjusted during the baseline until 1 dose step below the threshold dose of asthma control criteria (GINA).

Period 1 title

1_Double blind phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Blinding implementation details

Following a baseline assessment, all patients received either placebo (usual care in patients under 18 y) or the treatment allergoid preparation from D. pteronyssinus allergens for 2 years. This represents the double-blind, placebo-controlled treatment phase. To minimise bias, different project leaders and monitors handled the 2 age groups of the study (adults and children), with a strict separation of information between these groups as well as between the participating centers

Are arms mutually exclusive

Yes

Children - Allergoid treatment (BDP)

Arm description

Children randomised to allergoid treatment during the double-blind phase of the study.

Arm type

Experimental

Investigational medicinal product name

D. pteronyssinus allergoid preparation

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

House dust mite allergens were extracted from purified mite bodies (D. pteronyssinus) with buffered saline, partially purified by diafiltration, characterised, chemically modified by treatment with aldehydes and adsorbed onto aluminium hydroxide. The concentration was specified in PNU. Two concentrations of the preparation were provided: strength A: 300 PNU/mL being a 1:10 dilution of strength B (3000 PNU/mL). The injections were administered slowly, strictly subcutaneously, under sterile precautionary measures, on the extensor side of the upper arm, a hand’s breadth above the elbow, using a short-ground cannula. After each administration at the trial center, the patient was kept under close supervision for at least 30 minutes. PNU=Protein nitrogen unit

Children - Usual care (BDP)

Arm description

Children randomised to usual care during the double-blind phase of the study.

Arm type

Usual care in children, instead of placebo

Investigational medicinal product name

Usual care

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

Patients under 18 years of age at the time of enrollment who were randomised to control group did not receive a placebo preparation. Pharmacotherapy according to the study specific medication was used instead in the control group (usual care). The 'usual care' consisted of a reliever and controller asthma medication.

Adults - Allergoid treatment (BDP)

Arm description

Adults randomised to Allergoid treatment during the double-blind phase of the study..

Arm type

Experimental

Investigational medicinal product name

D. pteronyssinus allergoid preparation

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Adults - Placebo (DBP)

Arm description

Adults randomised to placebo during the double-blind phase of the study.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

A placebo solution was supplied as comparator for patients over 18 years of age, containing histamine-dihydrochloride (0.0125 mg/mL corresponding to strength A and 0.125 mg/mL corresponding to strength B) and caramel as a colouring agent, to ensure blinding by the physician and patient. Placebo: solution containing aluminium hydroxide (Al(OH)3) in normal saline (9 g/L sodium chloride) was applied. For the injection volume and administration details of the placebo solution, please see the description above for the allergoid treatment arm.

Number of subjects in period 1	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Started	33	33	30	34
Completed	33	29	23	25
Not completed	0	4	7	9
Consent withdrawn by subject	-	3	5	3
Pregnancy	-	-	1	-
Lost to follow-up	-	1	1	5
Protocol deviation	-	-	-	1

Period 2 title

2_Open label phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Children - Allergoid treatment (OLP)

Arm description

Children randomised to Allergoid treatment during the double-blind phase entered into a 3rd year of open-label SIT.

Arm type

Experimental

Investigational medicinal product name

D. pteronyssinus allergoid preparation

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Adults - Allergoid treatment (OLP)

Arm description

Adults randomised to Allergoid treatment during the double-blind phase entered into a 3rd year of open-label SIT.

Arm type

Experimental

Investigational medicinal product name

D. pteronyssinus allergoid preparation

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 2 ^[1]	Children - Allergoid treatment (OLP)	Adults - Allergoid treatment (OLP)
Started	33	22
Completed	30	19
Not completed	3	3
Consent withdrawn by subject	-	1
Adverse event, non-fatal	1	-
Lost to follow-up	2	1
Decision by sponsor	-	1

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 subjects did not continue the study after the double blind phase in the active treatment, in the 'usual care', or the placebo treatment groups.

Period 3 title

3_Follow-up phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Children - Allergoid treatment (FU)

Arm description

Children from the control treatment group who were in the double-blind phase of the study and received the 'usual care' for 2 years were offered to enter an open-label SIT for 3 years, as a follow-up phase of the study.

Arm type

Experimental

Investigational medicinal product name

D. pteronyssinus allergoid preparation

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 3 ^[2]	Children - Allergoid treatment (FU)
Started	23
Completed	21
Not completed	2
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: Several trial subjects did not continue the study after the double blind phase in the active treatment, in the 'usual care', or the placebo treatment groups.

Baseline characteristics

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Reporting group title

Children - Allergoid treatment (BDP)

Reporting group description

Children randomised to allergoid treatment during the double-blind phase of the study.

Reporting group title

Children - Usual care (BDP)

Reporting group description

Children randomised to usual care during the double-blind phase of the study.

Reporting group title

Adults - Allergoid treatment (BDP)

Reporting group description

Adults randomised to Allergoid treatment during the double-blind phase of the study..

Reporting group title

Adults - Placebo (DBP)

Reporting group description

Adults randomised to placebo during the double-blind phase of the study.

Reporting group values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)	Total
Number of subjects	33	33	30	34	130
Age categorical
Units: Subjects
Children (2-11 years)	22	17	0	0	39
Adolescents (12-17 years)	11	16	0	0	27
Adults (18-64 years)	0	0	30	34	64
Gender categorical
Units: Subjects
Female	11	10	14	17	52
Male	22	23	16	17	78
Race
Units: Subjects
White	33	33	30	34	130

End points

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Reporting group title

Children - Allergoid treatment (BDP)

Reporting group description

Children randomised to allergoid treatment during the double-blind phase of the study.

Reporting group title

Children - Usual care (BDP)

Reporting group description

Children randomised to usual care during the double-blind phase of the study.

Reporting group title

Adults - Allergoid treatment (BDP)

Reporting group description

Adults randomised to Allergoid treatment during the double-blind phase of the study..

Reporting group title

Adults - Placebo (DBP)

Reporting group description

Adults randomised to placebo during the double-blind phase of the study.

Reporting group title

Children - Allergoid treatment (OLP)

Reporting group description

Children randomised to Allergoid treatment during the double-blind phase entered into a 3rd year of open-label SIT.

Reporting group title

Adults - Allergoid treatment (OLP)

Reporting group description

Adults randomised to Allergoid treatment during the double-blind phase entered into a 3rd year of open-label SIT.

Reporting group title

Children - Allergoid treatment (FU)

Reporting group description

Primary: 1_DBP_Minimum dose of inhaled corticosteroid to achieve asthma control, after 2 years of treatment

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End point title

1_DBP_Minimum dose of inhaled corticosteroid to achieve asthma control, after 2 years of treatment

End point description

The minimum FP dose for asthma control according to GINA, was assessed before SIT therapy (baseline) and after the 2nd year of treatment, using predefined dose steps. Asthma control assessment (based on the nature and severity of asthma symptoms and the use of rescue medication) was based on patient diary entries: night-time awakenings; morning peak flow; daytime asthma symptoms; use of salbutamol rescue medication; exacerbations of asthma; emergency visits/unscheduled visits to the investigator due to asthma. Good asthma control was achieved if all of the following were fulfilled in each of the last 2 weeks of the 4 week diary phase: no night-time awakenings; no exacerbations; no emergency visit. FP dose: Children=50 to 500 µg/day, Adults=100 to 1000 µg/day FP dose steps: 1=50μg; 2=100μg; 3=250μg; 4=500μg; 5=1000μg. Results represent the change in minimum asthma control dose of FP in children/adults, as dose steps; scale -4 to +3. FP=Fluticasone propionate

End point type

Primary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after 2 years of double-blind treatment.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	33 ^[1]	32	27	29
Units: subjects
Improvement (-4)	0	0	0	1
Improvement (-3)	10	5	4	4
Improvement (-2)	6	1	0	6
Improvement (-1)	9	12	5	2
No change (0)	3	9	9	7
Deterioration (+1)	2	3	6	5
Deterioration (+2)	3	1	2	3
Deterioration (+3)	0	1	1	1

Notes
[1] - Full Analysis Set for all treatment groups

1_Difference between treatment groups (children)

Statistical analysis description

Children: changes from baseline in FP dose steps after 2 years of treatment with SIT. FP=Fluticasone propionate SIT=Specific immunotherapy

Comparison groups

Children - Allergoid treatment (BDP) v Children - Usual care (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.0487

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[2] - This study was designed to demonstrate superiority of allergoid vs. placebo with regard to the inhalative dose of fluticasone propionate needed to ensure asthma control according to GINA recommendation.

2_Difference between treatment groups (adults)

Statistical analysis description

Adults: changes from baseline in fluticasone dose steps after 2 years of treatment with SIT. SIT=Specific immunotherapy

Comparison groups

Adults - Allergoid treatment (BDP) v Adults - Placebo (DBP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.4533

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[3] - This study was designed to demonstrate superiority of allergoid vs. placebo with regard to the inhalative dose of fluticasone propionate needed to ensure asthma control according to GINA recommendation.

Secondary: 2_DBP_Minimum dose of inhaled corticosteroid to achieve asthma control, after 1 year of treatment

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End point title

2_DBP_Minimum dose of inhaled corticosteroid to achieve asthma control, after 1 year of treatment

End point description

Please see the description provided for end point #1.

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after 1 year of double-blind treatment.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	33 ^[4]	32	27	29
Units: subjects
Improvement (-3)	3	2	4	5
Improvement (-2)	9	0	2	2
Improvement (-1)	11	8	4	3
No change (0)	6	11	10	9
Deterioration (+1)	4	8	5	7
Deterioration (+2)	0	2	2	3
Deterioration (+3)	0	1	0	0

Notes
[4] - Full Analysis Set for all treatment groups

1_Difference between treatment groups (children)

Statistical analysis description

Please see description provided for end point 1.

Comparison groups

Children - Usual care (BDP) v Children - Allergoid treatment (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.0006

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[5] - Please see description provided for end point 1.

2_Difference between treatment groups (adults)

Statistical analysis description

Please see description provided for end point 1.

Comparison groups

Adults - Allergoid treatment (BDP) v Adults - Placebo (DBP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.7051

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[6] - Please see description provided for end point 1.

Secondary: 3_DBP_Mean peak flow (L/min) during asthma control phases, after 2 year of treatment

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End point title

3_DBP_Mean peak flow (L/min) during asthma control phases, after 2 year of treatment

End point description

Mean peak flow values were assessed during the last 2 weeks of asthma control phases. Results show the changes from baseline in the pre-bronchodilator morning PEF [L/min] post treatment after 2 years of double-blind treatment. Results are based on the daily measurement of morning PEF documented in the diaries; the mean PEF during the last 2 weeks, when GINA ASTHMA CONTROL DOSE was determined. Evaluation was also performed after 1 year of treatment; results were similar to the 2 year assessment. PEF=Peak expiratory flow

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after 2 years of double-blind treatment.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	33 ^[7]	32	27	29
Units: L/min
median (full range (min-max))	50.70 (-38.5 to 155.7)	23.55 (-81.4 to 171.4)	13.20 (-42.8 to 138.6)	5.00 (-40.0 to 89.3)

Notes
[7] - Full Analysis Set for all treatment groups

1_Difference between treatment groups (children)

Statistical analysis description

Changes from baseline in peak flow (children) after 1 year of treatment with SIT. PEF=Peak expiratory flow SIT=Specific immunotherapy

Comparison groups

Children - Allergoid treatment (BDP) v Children - Usual care (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0315

Method

Wilcoxon (Mann-Whitney)

Confidence interval

2_Difference between treatment groups (adults)

Statistical analysis description

Changes from baseline in peak flow (children) after 1 year of treatment with SIT. PEF=Peak expiratory flow SIT=Specific immunotherapy

Comparison groups

Adults - Placebo (DBP) v Adults - Allergoid treatment (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4036

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: 4_DBP_Mean peak flow (% of predicted normal) during asthma control phases, after 2 years of treatment

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End point title

4_DBP_Mean peak flow (% of predicted normal) during asthma control phases, after 2 years of treatment

End point description

Please see the description provided for end point 3_DBP. Evaluation was also performed after 1 year of treatment; results were similar to the 2 year assessment.

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after 2 years of double-blind treatment.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	33 ^[8]	32	27	29
Units: % of predicted normal
median (full range (min-max))	4.00 (-27.8 to 44.2)	-4.10 (-27.9 to 32.0)	3.50 (-7.0 to 27.4)	1.0 (-7.7 to 15.8)

Notes
[8] - Full Analysis Set for all treatment groups

1_Difference between treatment groups (children)

Comparison groups

Children - Allergoid treatment (BDP) v Children - Usual care (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1584

Method

Wilcoxon (Mann-Whitney)

Confidence interval

2_Difference between treatment groups (adults)

Comparison groups

Adults - Allergoid treatment (BDP) v Adults - Placebo (DBP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2908

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: 5_DBP_Changes from baseline in the asthma control parameters, after 1 and 2 years of treatment

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End point title

5_DBP_Changes from baseline in the asthma control parameters, after 1 and 2 years of treatment

End point description

Changes from baseline in the asthma control parameters. The following items were documented daily for 4 to 5 periods of 4 weeks during each diary phase: 1) night-time awakenings; 2) morning PEF <80% of predicted normal; 3) daytime cough/dry cough; 4) daytime chest tightness; 5) daytime wheeze; 6) daytime dyspnoea; 7) asthma control phases with asthma summary score > 1; 8) use of salbutamol rescue medication; 9) exacerbations of asthma; 10) emergency visits/unscheduled visits to the investigator due to asthma. Note: No relevant differences were seen between allergoid preparation and comparator in any of the evaluated items or age group, after 1 year or 2 years of treatment. Thus, only a representative entry of data is made for the item: all asthma symptoms. Data are shown as the difference between the baseline and the end of treatment (after 2 years of double-blind treatment phase).

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after 1 and 2 years of double-blind treatment.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	33 ^[9]	32	27	29
Units: score
median (full range (min-max))	0.0 (-64 to 14)	-0.5 (-24 to 26)	-2.0 (-14 to 60)	-2.0 (-34 to 29)

Notes
[9] - Full Analysis Set for all treatment groups

1_Difference between treatment groups (children)

Comparison groups

Children - Allergoid treatment (BDP) v Children - Usual care (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4106

Method

Wilcoxon (Mann-Whitney)

Confidence interval

2_Difference between treatment groups (adults)

Comparison groups

Adults - Allergoid treatment (BDP) v Adults - Placebo (DBP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9967

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: 6_DBP_Changes from baseline in FEV1 after 1 and 2 years of treatment

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End point title

6_DBP_Changes from baseline in FEV1 after 1 and 2 years of treatment

End point description

Changes from baseline in the pre-bronchodilator morning FEV1 [L] post treatment, after 1 and 2 years of double-blind treatment. Determination of the Lung function tests FEV1 was performed by spirometry. For enrollment into the study the patients had to have a lung function of at least 80%. Note: No clinically relevant or statistically significant differences between allergoid and comparator were seen with regard to FEV1 in either of the 2 age groups, after 1 and 2 years of double-blind treatment. Thus, results are shown only for those obtained after 2 years of double-blind treatment. FEV1=forced expiratory volume in one second

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and at each visit during the diary assessment phases.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	33 ^[10]	31	25	27
Units: litre(s)
median (full range (min-max))	0.35 (-0.10 to 1.60)	0.41 (-0.01 to 1.10)	-0.08 (-1.46 to 0.46)	-0.16 (-1.40 to 0.16)

Notes
[10] - Full Analysis Set for all treatment groups

1_Difference between treatment groups (children)

Comparison groups

Children - Usual care (BDP) v Children - Allergoid treatment (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.311

Method

Wilcoxon (Mann-Whitney)

Confidence interval

2_Difference between treatment groups (adults)

Comparison groups

Adults - Allergoid treatment (BDP) v Adults - Placebo (DBP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1449

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: 7_DBP_Changes from baseline in maximal expiratory flow (MEF), after 1 and 2 years of treatment

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End point title

7_DBP_Changes from baseline in maximal expiratory flow (MEF), after 1 and 2 years of treatment

End point description

Determination of the lung function test MEF [Litres/sec] was performed by spirometry. Changes from baseline after 1 and 2 years of treatment were analysed for MEF25, MEF50, and MEF75. Note: Results are shown only for MEF75, obtained after 2 years of double-blind treatment. Results from MEF25 and MEF50 showed similar trend as the results for MEF75. MEF=Maximal expiratory flow at 25%, 50%, and 75% of vital capacity

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and at each visit during the diary assessment phases.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	33 ^[11]	31	18	20
Units: L/sec
median (full range (min-max))	0.50 (-1.04 to 2.02)	0.70 (-0.40 to 4.60)	0.15 (-1.50 to 2.09)	-0.55 (-2.51 to 0.90)

Notes
[11] - Full Analysis Set for all treatment groups

1_Difference between treatment groups (children)

Comparison groups

Children - Allergoid treatment (BDP) v Children - Usual care (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4563

Method

Wilcoxon (Mann-Whitney)

Confidence interval

2_Difference between treatment groups (adults)

Comparison groups

Adults - Allergoid treatment (BDP) v Adults - Placebo (DBP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0057

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: 8_DBP_Changes from baseline in the non-specific bronchial hyperactivity provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20FEV1), after 2 years of treatment

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End point title

8_DBP_Changes from baseline in the non-specific bronchial hyperactivity provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20FEV1), after 2 years of treatment

End point description

Changes from baseline in the non-specific bronchial hyperactivity provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20FEV1) after 2 years of treatment. The methacholine bronchial provocation test (MBPT) was performed to assess the bronchial hyperresponsiveness (BHR) during the course of study. The test was carried out according to the standardised and published 'short provocation protocol'. FEV1=Forced expiratory volume in one second PC20FEV1=Provocative concentration of methacholine required to produce a 20% fall in FEV1

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after 2 years of double-blind treatment.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	32 ^[12]	28	23	25
Units: ln(PC20FEV1)
median (full range (min-max))	0.708 (-4.27 to 4.74)	0.000 (-5.25 to 4.53)	0.000 (-2.19 to 2.96)	0.000 (-2.59 to 1.95)

Notes
[12] - Full Analysis Set for all treatment groups

1_Difference between treatment groups (children)

Comparison groups

Children - Allergoid treatment (BDP) v Children - Usual care (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5716

Method

Wilcoxon (Mann-Whitney)

Confidence interval

2_Difference between treatment groups (adults)

Comparison groups

Adults - Allergoid treatment (BDP) v Adults - Placebo (DBP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8923

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: 9_DBP_Changes from baseline in the immunological profile of sIgE, after 1 and 2 years of treatment

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End point title

9_DBP_Changes from baseline in the immunological profile of sIgE, after 1 and 2 years of treatment

End point description

Changes from baseline in the immunological profile of serum sIgE (mite-specific), after 1 and 2 years of treatment. Serum sIgE was determined using the RAST/CAP method. For inclusion in the study, patient had to have a positive RAST/CAP to D. pteronyssinus ≥ CAP class II (i.e. ≥ 0.70 kUIgE/L (kU = kilo-units). Results are presented in percent, as a change from baseline after treatment. Note: Results are presented only for data obtained after 2 years of treatment. Results obtained after 1 year of SIT were similar to those after 2 years of treatment. CAP=ImmunoCAP sIgE blood test sIgE=Specific immunoglobulin E RAST=Radio-allergo-sorbent test SIT=Specific immunotherapy

End point type

Secondary

End point timeframe

At baseline (before treatment), after 1 year and 2 years of double-blind of treatment.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	29 ^[13]	27	24	24
Units: percent
number (not applicable)	-22.9	2.0	-29.3	-11.3

Notes
[13] - Full Analysis Set for all treatment groups

1_Difference between treatment groups (children)

Comparison groups

Children - Allergoid treatment (BDP) v Children - Usual care (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0217

Method

Wilcoxon (Mann-Whitney)

Confidence interval

2_Difference between treatment groups (adults)

Comparison groups

Adults - Allergoid treatment (BDP) v Adults - Placebo (DBP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3278

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: 10_DBP_Changes from baseline in the immunological profile of sIgG1, after 1 and 2 years treatment

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End point title

10_DBP_Changes from baseline in the immunological profile of sIgG1, after 1 and 2 years treatment

End point description

Changes from baseline in the immunological profile of serum sIgG1 (specific for D. pteronyssinus-induced house dust mite), after 1 and 2 years SIT. Allergen specific ELISA was used to determine the sIgG1. Results are presented in percent, as a change from baseline after treatment. Results are presented here only for data obtained after 2 years of treatment; results obtained after after 2 years of SIT were similar to those after 1 year. sIgG1=specific immunoglobulin G1 (specific for D. pteronyssinus-induced house dust mite)

End point type

Secondary

End point timeframe

At baseline (before treatment), after 1 year, and 2 years of double-blind of treatment.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	29 ^[14]	27	24	24
Units: percent
number (not applicable)	85.2	-15.5	90.9	-11.6

Notes
[14] - Full Analysis Set for all treatment groups

1_Difference between treatment groups (children)

Comparison groups

Children - Allergoid treatment (BDP) v Children - Usual care (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

2_Difference between treatment groups (adults)

Comparison groups

Adults - Allergoid treatment (BDP) v Adults - Placebo (DBP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: 11_DBP_Changes from baseline in the immunological profile of sIgG4, after 1 and 2 years of treatment

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End point title

11_DBP_Changes from baseline in the immunological profile of sIgG4, after 1 and 2 years of treatment

End point description

Changes from baseline in the immunological profile of serum sIgG4 (specific for D. pteronyssinus-induced house dust mite), after 1 and 2 years of treatment. Allergen specific ELISA was used to determine the sIgG4. Results are presented in percent, as a change from baseline after treatment. Note: Results are presented here only for data obtained after 2 years of treatment; results obtained after after 2 years of SIT were similar to those after 1 year. sIgG4=specific immunoglobulin G4 (specific for D. pteronyssinus-induced house dust mite)

End point type

Secondary

End point timeframe

At baseline (before treatment), after 1 year and 2 years of double-blind treatment.

End point values	Children - Allergoid treatment (BDP)	Children - Usual care (BDP)	Adults - Allergoid treatment (BDP)	Adults - Placebo (DBP)
Number of subjects analysed	29	27	24	24
Units: percent
number (not applicable)	1146.9	3.8	541.5	-0.7

1_Difference between treatment groups (children)

Comparison groups

Children - Allergoid treatment (BDP) v Children - Usual care (BDP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

2_Difference between treatment groups (adults)

Comparison groups

Adults - Allergoid treatment (BDP) v Adults - Placebo (DBP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: 12_OLP_Minimum dose of inhaled corticosteroid to achieve asthma control, after the 3rd year of SIT

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End point title

12_OLP_Minimum dose of inhaled corticosteroid to achieve asthma control, after the 3rd year of SIT

End point description

During the 3rd year of the study, patients received SIT in an open-label manner. For further details, please refer to the description for the endpoint #1_BDP. Statistical evaluation was performed using Wilcoxon (Mann-Whitney) method; Analysis type: superiority 1_Change from baseline in PEF (children); p < 0.0001 2_Change from baseline in PEF (adults); p < 0.0001

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after the 3rd year of open-label SIT with allergoid preparation.

End point values	Children - Allergoid treatment (OLP)	Adults - Allergoid treatment (OLP)
Number of subjects analysed	33 ^[15]	21
Units: subjects
Improvement (-3)	10	1
Improvement (-2)	4	1
Improvement (-1)	13	6
No change (0)	1	6
Deterioration (+1)	5	5
Deterioration (+2)	0	1
Deterioration (+3)	0	1

Notes
[15] - Full Analysis Set for all treatment groups

No statistical analyses for this end point

Secondary: 13_OLP_Mean peak flow (L/min) during asthma control phases, after the 3rd year of SIT

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End point title

13_OLP_Mean peak flow (L/min) during asthma control phases, after the 3rd year of SIT

End point description

During the 3rd year of the study, patients received SIT in an open-label manner. For further details, please refer to the description for endpoint 3_DBP. Statistical evaluation was performed using Wilcoxon (Mann-Whitney) method; Analysis type: superiority 1_Change from baseline in PEF (children); p < 0.0001 2_Change from baseline in PEF (adults); p = 0.0094 SIT=Specific immunotherapy

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after the 3rd year of open-label SIT with allergoid preparation.

End point values	Children - Allergoid treatment (OLP)	Adults - Allergoid treatment (OLP)
Number of subjects analysed	33 ^[16]	21
Units: L/min
median (full range (min-max))	63.60 (5.8 to 163.6)	17.20 (-25.8 to 122.2)

Notes
[16] - Full Analysis Set for all treatment groups

No statistical analyses for this end point

Secondary: 14_OLP_Mean peak flow (% predicted) during asthma control phases, after the 3rd year of SIT

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End point title

14_OLP_Mean peak flow (% predicted) during asthma control phases, after the 3rd year of SIT

End point description

During the 3rd year of the study, patients received SIT in an open-label manner. For further details, please refer to the description for endpoint 3_DBP. Statistical evaluation was performed using Wilcoxon (Mann-Whitney) method; Analysis type: superiority 1_Change from baseline in PEF (children); p = 0.9096 2_Change from baseline in PEF (adults); p = 0.0024 SIT=Specific immunotherapy

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after the 3rd year of open-label SIT with allergoid preparation.

End point values	Children - Allergoid treatment (OLP)	Adults - Allergoid treatment (OLP)
Number of subjects analysed	33 ^[17]	21
Units: % of predicted normal
median (full range (min-max))	1.70 (-34.8 to 38.6)	4.40 (-3.6 to 28.9)

Notes
[17] - Full Analysis Set for all treatment groups

No statistical analyses for this end point

Secondary: 15_OLP_Changes from baseline in the asthma control parameters, after the 3rd year of SIT

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End point title

15_OLP_Changes from baseline in the asthma control parameters, after the 3rd year of SIT

End point description

During the 3rd year of the study, patients received SIT in an open-label manner. For further details, please refer to the description for endpoint #5_DBP. Note: No clinically relevant or statistically significant differences were seen between allergoid preparation and comparator in any of the evaluated items or age group, after the 3rd year of SIT. Thus, only a representative entry of data is made for the item: all asthma symptoms. Data are shown as the difference between the baseline and the end of treatment (after the 3rd year of double-blind treatment phase). Statistical evaluation was performed using Wilcoxon (Mann-Whitney) method; Analysis type: superiority 1_Change from baseline in PEF (children); p = 0.2987 2_Change from baseline in PEF (adults); p = 0.5048 SIT=Specific immunotherapy

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after the 3rd year of double-blind SIT with allergoid preparation.

End point values	Children - Allergoid treatment (OLP)	Adults - Allergoid treatment (OLP)
Number of subjects analysed	33 ^[18]	21
Units: score
median (full range (min-max))	-1.0 (-64 to 36)	3.0 (-15 to 60)

Notes
[18] - Full Analysis Set for all treatment groups

No statistical analyses for this end point

Secondary: 16_OLP_Changes from baseline in FEV1 after the 3rd year of SIT

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End point title

16_OLP_Changes from baseline in FEV1 after the 3rd year of SIT

End point description

During the 3rd year of the study, patients received SIT in an open-label manner. For further details, please refer to the description for endpoint #6_DBP. Statistical evaluation was performed using Wilcoxon (Mann-Whitney) method; Analysis type: superiority 1_Change from baseline in PEF (children); p < 0.0001 2_Change from baseline in PEF (adults); p < 0.0014 SIT=Specific immunotherapy

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after the 3rd year of open-label SIT with allergoid preparation. FEV1=forced expiratory volume in one second SIT=Specific immunotherapy

End point values	Children - Allergoid treatment (OLP)	Adults - Allergoid treatment (OLP)
Number of subjects analysed	33 ^[19]	21
Units: litre(s)
median (full range (min-max))	0.59 (-0.50 to 2.05)	-0.22 (-0.91 to 0.45)

Notes
[19] - Full Analysis Set for all treatment groups

No statistical analyses for this end point

Secondary: 17_OLP_Changes from baseline in maximal expiratory flow (MEF), after the 3rd year of SIT

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End point title

17_OLP_Changes from baseline in maximal expiratory flow (MEF), after the 3rd year of SIT

End point description

During the 3rd year of the study, patients received SIT in an open-label manner. For further details, please refer to the description for the endpoint #7_DBP. Note: Results are shown only for MEF75, obtained after the 3rd year of treatment. Results from MEF25 and MEF50 showed similar trend as the results for MEF75. Statistical evaluation was performed using Wilcoxon (Mann-Whitney) method; Analysis type: superiority 1_Change from baseline in PEF (children); p < 0.0001 2_Change from baseline in PEF (adults); p = 0.7917 MEF=Maximal expiratory flow at 25%, 50%, and 75% of vital capacity SIT=Specific immunotherapy

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after the 3rd year of open-label SIT with allergoid preparation.

End point values	Children - Allergoid treatment (OLP)	Adults - Allergoid treatment (OLP)
Number of subjects analysed	33 ^[20]	16
Units: L/sec
median (full range (min-max))	0.89 (-0.80 to 2.40)	-0.03 (-2.77 to 1.38)

Notes
[20] - Full Analysis Set for all treatment groups

No statistical analyses for this end point

Secondary: 18_OLP_Changes from baseline in the non-specific bronchial hyperactivity provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20FEV1), after the 3rd year of SIT

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End point title

18_OLP_Changes from baseline in the non-specific bronchial hyperactivity provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20FEV1), after the 3rd year of SIT

End point description

During the 3rd year of the study, patients received SIT in an open-label manner. For further details, please refer to the description for the endpoint #8_DBP. Statistical evaluation was performed using Wilcoxon (Mann-Whitney) method; Analysis type: superiority 1_Change from baseline in PEF (children); p = 0.0213 2_Change from baseline in PEF (adults); p = 0.0977 FEV1=Forced expiratory volume in one second PC20FEV1=Provocative concentration of methacholine required to produce a 20% fall in FEV1

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after the 3rd year of open-label SIT with allergoid preparation.

End point values	Children - Allergoid treatment (OLP)	Adults - Allergoid treatment (OLP)
Number of subjects analysed	31 ^[21]	16
Units: ln(PC20FEV1)
median (full range (min-max))	0.722 (-3.35 to 4.74)	0.413 (-2.25 to 4.83)

Notes
[21] - Full Analysis Set for all treatment groups

No statistical analyses for this end point

Secondary: 19_FU_Changes from baseline in FEV1 (L) after 3 years of SIT

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End point title

19_FU_Changes from baseline in FEV1 (L) after 3 years of SIT

End point description

During the follow-up 3 years of the study, patients received SIT in an open-label manner. For further details, please refer to the description for the endpoint #6_DBP. Statistical evaluation was performed using Wilcoxon (Mann-Whitney) method; Analysis type: superiority 1_Change from baseline in PEF (children); p = 0.0327 SIT=Specific immunotherapy

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after 3 years of open-label SIT with allergoid preparation.

End point values	Children - Allergoid treatment (FU)
Number of subjects analysed	22 ^[22]
Units: litre(s)
median (full range (min-max))	0.440 (-1.29 to 1.77)

Notes
[22] - Full Analysis Set

No statistical analyses for this end point

Secondary: 20_FU_Changes from baseline in maximal expiratory flow (MEF), after 3 years of SIT

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End point title

20_FU_Changes from baseline in maximal expiratory flow (MEF), after 3 years of SIT

End point description

During the follow-up 3 years of the study, patients received SIT in an open-label manner. For further details, please refer to the description for the endpoint #7_DBP. Note: Results are shown only for MEF75, obtained after 3 years of treatment with SIT. Results from MEF25 and MEF50 showed similar trend as the results for MEF75. Statistical evaluation was performed using Wilcoxon (Mann-Whitney) method; Analysis type: superiority 1_Change from baseline in PEF (children); p = 0.1019 MEF=Maximal expiratory flow at 25%, 50%, and 75% of vital capacity

End point type

Secondary

End point timeframe

Assessment period of approx. 6 months before treatment (baseline assessment) and after 3 years of open-label SIT with allergoid preparation.

End point values	Children - Allergoid treatment (FU)
Number of subjects analysed	22 ^[23]
Units: L/sec
median (full range (min-max))	0.53 (-3.19 to 2.57)

Notes
[23] - Full Analysis Set

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the start of the study (signing of the informed consent) until the end of the study (last study visit i.e. 2 years after study start for open-label phase, and 3 years for the follow-up phase.

Adverse event reporting additional description

Some AEs were reported during the 'bridging' phase of the study. This phase occurred between the 'blind-label' phase and 'open-label' phase, when no treatment was given. AEs that were reported during the 'bridging' phase were included in the 'blind-label' phase.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

8.0

Reporting group title

Screening/Baseline: Children - Allergoid treatment

Reporting group description

Children during the screening/baseline phase of the study, randomised to Allergoid treatment group.

Reporting group title

Screening/Baseline: Children - Usual care

Reporting group description

Children during the screening/baseline phase of the study, randomised to 'usual care' treatment group.

Reporting group title

Screening/Baseline: Adults - Allergoid treatment

Reporting group description

Adults during the screening/baseline phase of the study, randomised to Allergoid treatment group.

Reporting group title

Screening/Baseline: Adults - Placebo

Reporting group description

Adults during the screening/baseline phase of the study, randomised to placebo treatment group.

Reporting group title

DBP: Children - Allergoid treatment

Reporting group description

Children randomised to allergoid treatment, during the double-blind treatment phase.

Reporting group title

DBP: Children - Usual care

Reporting group description

Children randomised to usual care, during the double-blind treatment phase..

Reporting group title

DBP: Adults - Allergoid treatment

Reporting group description

Adults randomised to Allergoid treatment, during the double-blind treatment phase.

Reporting group title

DBP: Adults - Placebo

Reporting group description

Adults randomised to placebo, during the double-blind treatment phase.

Reporting group title

OLP: Children - Allergoid treatment

Reporting group description

Children receiving Allergoid treatment during the open-label phase (OLP).

Reporting group title

OLP: Adults - Allergoid treatment

Reporting group description

Adults receiving Allergoid treatment during the open-label phase (OLP).

Reporting group title

FU: Children - Allergoid treatment

Reporting group description

Children receiving Allergoid treatment during the follow-up phase (FU).

Serious adverse events	Screening/Baseline: Children - Allergoid treatment	Screening/Baseline: Children - Usual care	Screening/Baseline: Adults - Allergoid treatment	Screening/Baseline: Adults - Placebo	DBP: Children - Allergoid treatment	DBP: Children - Usual care	DBP: Adults - Allergoid treatment	DBP: Adults - Placebo	OLP: Children - Allergoid treatment	OLP: Adults - Allergoid treatment	FU: Children - Allergoid treatment
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	4 / 32 (12.50%)	0 / 28 (0.00%)	3 / 31 (9.68%)	5 / 33 (15.15%)	0 / 21 (0.00%)	9 / 23 (39.13%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Lumbar vertebral fracture
Additional description: One occurrence of this AE was during the 'bridging' phase (adults, placebo group).
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	1 / 31 (3.23%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Vascular disorders
Orthostatic dysregulation
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Tonsillectomy
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (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	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	0 / 0	0 / 0	0 / 0
Rehabilitation therapy
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cyanosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Anorexia
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	1 / 31 (3.23%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Eye disorders
Conjunctivitis allergic
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (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	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	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma exacerbation
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (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	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	0 / 0	0 / 0	0 / 0
Bronchitis acute
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	1 / 31 (3.23%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Wheezing
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal septum deviation
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Urticaria generalised
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acne pustular
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eczema
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pruritus
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Acute appendicitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (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	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	0 / 0	0 / 0	0 / 0
Superinfection
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess
Additional description: This SAE occurred during the 'bridging' phase of the study.
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (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	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	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Screening/Baseline: Children - Allergoid treatment	Screening/Baseline: Children - Usual care	Screening/Baseline: Adults - Allergoid treatment	Screening/Baseline: Adults - Placebo	DBP: Children - Allergoid treatment	DBP: Children - Usual care	DBP: Adults - Allergoid treatment	DBP: Adults - Placebo	OLP: Children - Allergoid treatment	OLP: Adults - Allergoid treatment	FU: Children - Allergoid treatment
Total subjects affected by non serious adverse events
subjects affected / exposed	25 / 33 (75.76%)	23 / 32 (71.88%)	5 / 28 (17.86%)	7 / 31 (22.58%)	32 / 33 (96.97%)	31 / 32 (96.88%)	15 / 28 (53.57%)	18 / 31 (58.06%)	25 / 33 (75.76%)	4 / 21 (19.05%)	17 / 23 (73.91%)
Injury, poisoning and procedural complications
Meniscus lesion
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	1 / 28 (3.57%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 28 (0.00%)	1 / 31 (3.23%)	0 / 33 (0.00%)	0 / 32 (0.00%)	1 / 28 (3.57%)	1 / 31 (3.23%)	0 / 33 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1	0	1	0	0	1	1	0	0	1
General disorders and administration site conditions
Injection site pain
Additional description: One occurrence of this AE was during the 'bridging' phase (adults, placebo group).
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	4 / 33 (12.12%)	0 / 32 (0.00%)	3 / 28 (10.71%)	2 / 31 (6.45%)	2 / 33 (6.06%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	4	0	3	2	2	0	0
Injection site pruritus
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	5 / 33 (15.15%)	0 / 32 (0.00%)	3 / 28 (10.71%)	1 / 31 (3.23%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	5	0	3	1	1	0	0
Injection site swelling
Additional description: One occurrence of this AE was during the 'bridging' phase (adults, placebo group).
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	9 / 33 (27.27%)	0 / 32 (0.00%)	6 / 28 (21.43%)	5 / 31 (16.13%)	1 / 33 (3.03%)	1 / 21 (4.76%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	9	0	6	5	1	1	0
Pyrexia
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	2 / 32 (6.25%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0
Social circumstances
Family stress
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	2 / 31 (6.45%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0
Eye disorders
Conjunctivitis allergic
subjects affected / exposed	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	1 / 32 (3.13%)	1 / 28 (3.57%)	1 / 31 (3.23%)	2 / 33 (6.06%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1	0	0	1	1	1	1	2	0	1
Conjunctivitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	2 / 32 (6.25%)	0 / 28 (0.00%)	1 / 31 (3.23%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	0	2	0	1	0	0	0
Gastrointestinal disorders
Dyspepsia
subjects affected / exposed	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 28 (0.00%)	0 / 31 (0.00%)	2 / 33 (6.06%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1	0	0	2	0	0	0	0	0	1
Vomiting
subjects affected / exposed	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	2 / 33 (6.06%)	0 / 32 (0.00%)	1 / 28 (3.57%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	1	0	0	0	2	0	1	0	0	0	0
Nausea
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	1 / 28 (3.57%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0	0
Abdominal pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	2 / 32 (6.25%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
Additional description: Three occurrences of this AE were during the 'bridging' phase (children, usual care treatment group).
subjects affected / exposed	7 / 33 (21.21%)	9 / 32 (28.13%)	0 / 28 (0.00%)	0 / 31 (0.00%)	15 / 33 (45.45%)	14 / 32 (43.75%)	3 / 28 (10.71%)	0 / 31 (0.00%)	7 / 33 (21.21%)	0 / 21 (0.00%)	2 / 23 (8.70%)
occurrences all number	7	9	0	0	15	17	3	0	7	0	2
Rhinitis allergic
subjects affected / exposed	2 / 33 (6.06%)	2 / 32 (6.25%)	0 / 28 (0.00%)	0 / 31 (0.00%)	4 / 33 (12.12%)	4 / 32 (12.50%)	1 / 28 (3.57%)	2 / 31 (6.45%)	5 / 33 (15.15%)	0 / 21 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	2	0	0	4	4	1	2	5	0	2
Cough
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	1 / 31 (3.23%)	2 / 33 (6.06%)	4 / 32 (12.50%)	2 / 28 (7.14%)	4 / 31 (12.90%)	2 / 33 (6.06%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	1	2	4	2	4	2	0	0
Wheezing
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 28 (0.00%)	1 / 31 (3.23%)	2 / 33 (6.06%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	0	0	0	0	1	0	1	2	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	2 / 23 (8.70%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2
Dyspnoea
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	2 / 32 (6.25%)	1 / 28 (3.57%)	2 / 31 (6.45%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	0	2	1	2	0	0	0
Skin and subcutaneous tissue disorders
Urticaria generalised
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	1 / 28 (3.57%)	0 / 31 (0.00%)	2 / 33 (6.06%)	0 / 21 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	0	0	0	1	0	1	0	2	0	1
Musculoskeletal and connective tissue disorders
Tenosynovitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	1 / 31 (3.23%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 33 (6.06%)	2 / 32 (6.25%)	0 / 28 (0.00%)	0 / 31 (0.00%)	3 / 33 (9.09%)	2 / 32 (6.25%)	2 / 28 (7.14%)	0 / 31 (0.00%)	2 / 33 (6.06%)	0 / 21 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	2	0	0	3	2	2	0	2	0	2
Bronchitis acute
Additional description: One occurrence of this AE was during the 'bridging' phase (children, usual care treatment group)
subjects affected / exposed	6 / 33 (18.18%)	3 / 32 (9.38%)	0 / 28 (0.00%)	0 / 31 (0.00%)	11 / 33 (33.33%)	10 / 32 (31.25%)	0 / 28 (0.00%)	1 / 31 (3.23%)	5 / 33 (15.15%)	2 / 21 (9.52%)	3 / 23 (13.04%)
occurrences all number	6	3	0	0	11	10	0	1	5	2	3
Gastroenteritis
subjects affected / exposed	1 / 33 (3.03%)	2 / 32 (6.25%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	1	2	0	0	1	0	0	0	0	0	0
Nasopharyngitis
Additional description: One occurrence of this AE was during the 'bridging' phase (children, usual care treatment group). One occurrence of this AE was during the 'bridging' phase (adults, placebo group).
subjects affected / exposed	11 / 33 (33.33%)	13 / 32 (40.63%)	4 / 28 (14.29%)	3 / 31 (9.68%)	20 / 33 (60.61%)	15 / 32 (46.88%)	6 / 28 (21.43%)	6 / 31 (19.35%)	6 / 33 (18.18%)	1 / 21 (4.76%)	10 / 23 (43.48%)
occurrences all number	11	13	4	3	20	16	6	6	6	1	10
Pharyngitis
subjects affected / exposed	3 / 33 (9.09%)	6 / 32 (18.75%)	1 / 28 (3.57%)	0 / 31 (0.00%)	18 / 33 (54.55%)	11 / 32 (34.38%)	6 / 28 (21.43%)	9 / 31 (29.03%)	4 / 33 (12.12%)	0 / 21 (0.00%)	6 / 23 (26.09%)
occurrences all number	3	6	1	0	18	11	6	9	4	0	6
Rhinitis
Additional description: One occurrence of this AE was during the 'bridging' phase (children, usual care treatment group).
subjects affected / exposed	6 / 33 (18.18%)	4 / 32 (12.50%)	0 / 28 (0.00%)	2 / 31 (6.45%)	4 / 33 (12.12%)	7 / 32 (21.88%)	2 / 28 (7.14%)	1 / 31 (3.23%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	6	4	0	2	4	7	2	1	1	0	0
Sinusitis
subjects affected / exposed	3 / 33 (9.09%)	0 / 32 (0.00%)	1 / 28 (3.57%)	1 / 31 (3.23%)	1 / 33 (3.03%)	0 / 32 (0.00%)	2 / 28 (7.14%)	0 / 31 (0.00%)	1 / 33 (3.03%)	1 / 21 (4.76%)	0 / 23 (0.00%)
occurrences all number	3	0	1	1	1	0	2	0	1	1	0
Smallpox
subjects affected / exposed	2 / 33 (6.06%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	2	0	0	0	1	0	0	0	0	0	0
Tonsillitis
subjects affected / exposed	1 / 33 (3.03%)	1 / 32 (3.13%)	1 / 28 (3.57%)	0 / 31 (0.00%)	3 / 33 (9.09%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	1	1	1	0	3	0	0	0	1	0	0
Acute tonsillitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	2 / 33 (6.06%)	3 / 32 (9.38%)	0 / 28 (0.00%)	1 / 31 (3.23%)	1 / 33 (3.03%)	0 / 21 (0.00%)	2 / 23 (8.70%)
occurrences all number	0	0	0	0	2	3	0	1	1	0	2
Ear infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	2 / 32 (6.25%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	1	0	0
Laryngitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	2 / 33 (6.06%)	0 / 32 (0.00%)	2 / 28 (7.14%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	2	0	2	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	2 / 33 (6.06%)	2 / 32 (6.25%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	2	2	0	0	1	0	0
Viral infection
Additional description: One occurrence of this AE was during the 'bridging' phase (children, usual care treatment group).
subjects affected / exposed	1 / 33 (3.03%)	1 / 32 (3.13%)	0 / 28 (0.00%)	0 / 31 (0.00%)	4 / 33 (12.12%)	1 / 32 (3.13%)	0 / 28 (0.00%)	0 / 31 (0.00%)	1 / 33 (3.03%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	1	1	0	0	4	1	0	0	1	0	0
Herpes simplex
Additional description: One occurrence of this AE was during the 'bridging' phase (children, usual care treatment group)
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	3 / 23 (13.04%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	3
Influenza
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	2 / 28 (7.14%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0
Tracheitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	4 / 28 (14.29%)	1 / 31 (3.23%)	0 / 33 (0.00%)	1 / 21 (4.76%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	0	0	4	1	0	1	0
Oral candidiasis
Additional description: Two occurrences of this AE were during the 'bridging' phase (children, usual care treatment group).
subjects affected / exposed	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	2 / 32 (6.25%)	0 / 28 (0.00%)	0 / 31 (0.00%)	0 / 33 (0.00%)	0 / 21 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

25 Feb 2005

Non-substantial amendment: Administrative and operative amendments. • A second project manager responsible for the open investigation in patients < 18 years of age was appointed, and a Blind Data Review Board was established. • To ensure confidentiality of information gained in the open part of this study from the double-blind investigation in adults, regulations pertaining to the separation of both study parts were established. • The randomisation procedure and the number of (randomised) patients per center were clarified. • For patients who received other than the permitted asthma medication, the assessment of medication for efficacy analysis was defined. • Two repeats of house dust sampling for the determination of house dust mite allergens were made obligatory. • The method (chi-squared test) of group comparison in case of only few steps of changes from baseline was added. • For the assessment of the primary endpoint (asthma control), the data from the last two weeks of every 4-week diary had to be available. The randomisation procedure and the number of (randomised) patients per center had to available.

04 May 2005

Non-substantial amendment: Administrative and operative amendment. Adjust study administrative items.

30 Aug 2005

Substantial amendment Adjust study procedures in the study protocol: • Omit the determination of unspecific bronchial provocation testing and nitric oxide determination in exhaled air at screening. • While recording the lung function data during the assessment phases of the study, also include the assessment of MEF25, 50, and 75 (MEF25, MEF50, MEF75=maximal expiratory flow at 25% – 50% – 75% of vital capacity).

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_DBP_Minimum dose of inhaled corticosteroid to achieve asthma control, after 2 years of treatment

Primary: 1_DBP_Minimum dose of inhaled corticosteroid to achieve asthma control, after 2 years of treatment

Secondary: 2_DBP_Minimum dose of inhaled corticosteroid to achieve asthma control, after 1 year of treatment

Secondary: 2_DBP_Minimum dose of inhaled corticosteroid to achieve asthma control, after 1 year of treatment

Secondary: 3_DBP_Mean peak flow (L/min) during asthma control phases, after 2 year of treatment

Secondary: 3_DBP_Mean peak flow (L/min) during asthma control phases, after 2 year of treatment

Secondary: 4_DBP_Mean peak flow (% of predicted normal) during asthma control phases, after 2 years of treatment

Secondary: 4_DBP_Mean peak flow (% of predicted normal) during asthma control phases, after 2 years of treatment

Secondary: 5_DBP_Changes from baseline in the asthma control parameters, after 1 and 2 years of treatment

Secondary: 5_DBP_Changes from baseline in the asthma control parameters, after 1 and 2 years of treatment

Secondary: 6_DBP_Changes from baseline in FEV1 after 1 and 2 years of treatment

Secondary: 6_DBP_Changes from baseline in FEV1 after 1 and 2 years of treatment

Secondary: 7_DBP_Changes from baseline in maximal expiratory flow (MEF), after 1 and 2 years of treatment

Secondary: 7_DBP_Changes from baseline in maximal expiratory flow (MEF), after 1 and 2 years of treatment

Secondary: 8_DBP_Changes from baseline in the non-specific bronchial hyperactivity provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20FEV1), after 2 years of treatment

Secondary: 8_DBP_Changes from baseline in the non-specific bronchial hyperactivity provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20FEV1), after 2 years of treatment

Secondary: 9_DBP_Changes from baseline in the immunological profile of sIgE, after 1 and 2 years of treatment

Secondary: 9_DBP_Changes from baseline in the immunological profile of sIgE, after 1 and 2 years of treatment

Secondary: 10_DBP_Changes from baseline in the immunological profile of sIgG1, after 1 and 2 years treatment

Secondary: 10_DBP_Changes from baseline in the immunological profile of sIgG1, after 1 and 2 years treatment

Secondary: 11_DBP_Changes from baseline in the immunological profile of sIgG4, after 1 and 2 years of treatment

Secondary: 11_DBP_Changes from baseline in the immunological profile of sIgG4, after 1 and 2 years of treatment

Secondary: 12_OLP_Minimum dose of inhaled corticosteroid to achieve asthma control, after the 3rd year of SIT

Secondary: 12_OLP_Minimum dose of inhaled corticosteroid to achieve asthma control, after the 3rd year of SIT

Secondary: 13_OLP_Mean peak flow (L/min) during asthma control phases, after the 3rd year of SIT

Secondary: 13_OLP_Mean peak flow (L/min) during asthma control phases, after the 3rd year of SIT

Secondary: 14_OLP_Mean peak flow (% predicted) during asthma control phases, after the 3rd year of SIT

Secondary: 14_OLP_Mean peak flow (% predicted) during asthma control phases, after the 3rd year of SIT

Secondary: 15_OLP_Changes from baseline in the asthma control parameters, after the 3rd year of SIT

Secondary: 15_OLP_Changes from baseline in the asthma control parameters, after the 3rd year of SIT

Secondary: 16_OLP_Changes from baseline in FEV1 after the 3rd year of SIT

Secondary: 16_OLP_Changes from baseline in FEV1 after the 3rd year of SIT

Secondary: 17_OLP_Changes from baseline in maximal expiratory flow (MEF), after the 3rd year of SIT

Secondary: 17_OLP_Changes from baseline in maximal expiratory flow (MEF), after the 3rd year of SIT

Secondary: 18_OLP_Changes from baseline in the non-specific bronchial hyperactivity provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20FEV1), after the 3rd year of SIT

Secondary: 18_OLP_Changes from baseline in the non-specific bronchial hyperactivity provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20FEV1), after the 3rd year of SIT

Secondary: 19_FU_Changes from baseline in FEV1 (L) after 3 years of SIT

Secondary: 19_FU_Changes from baseline in FEV1 (L) after 3 years of SIT

Secondary: 20_FU_Changes from baseline in maximal expiratory flow (MEF), after 3 years of SIT

Secondary: 20_FU_Changes from baseline in maximal expiratory flow (MEF), after 3 years of SIT

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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