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Clinical Trial Results:
Multicenter, placebo-controlled, long-term study of Depigoid Birch 5000 in adults and adolescents with allergic rhinitis and/or rhinoconjunctivitis with or without intermittent asthma

Summary
EudraCT number	2012-000414-11
Trial protocol	DE LT CZ FI PL LV
Global end of trial date	30 Jul 2018

Results information
Results version number	v1(current)
This version publication date	02 Jan 2020
First version publication date	02 Jan 2020
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

603-PG-PSC-191

ISRCTN number

US NCT number

NCT01694836

WHO universal trial number (UTN)

Sponsor organisation name

LETI Pharma GmbH

Sponsor organisation address

Stockumer Str. 28, Witten, Germany, 58453

Public contact

Medical Department, LETI Pharma GmbH, 0049 2302202860, info@leti.de

Scientific contact

Medical Department, LETI Pharma GmbH, 0049 2302202860, info@leti.de

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000630-PIP02-09

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?

Yes

Analysis stage

Final

Date of interim/final analysis

30 Jul 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Jul 2018

Global end of trial reached?

Yes

Global end of trial date

30 Jul 2018

Was the trial ended prematurely?

Main objective of the trial

To investigate the long-term efficacy and safety of depigmented and glutaraldehyde polymerized allergenic extract of 100% birch pollen (Depigoid Birch) at a concentration of 5000 DPP/mL applied according to the perennial treatment regimen in comparison to placebo in adult and adolescent patients with birch pollen-induced allergic rhinitis and/or rhinoconjunctivitis.

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 protocol, all amendments, informed consent forms (ICF) were approved by an independent ethics committee (IEC) and health authorities; ICF was explained to and consent obtained from each patient before participation. To minimize risks, stopping criteria were defined and an independent Data Monitoring Committee (DMC) was created to assess the progress, safety and critical efficacy endpoints of the study. Three interim analyses were planned to assess efficacy of the treatment and the study futility. In addition, patients were permitted to use rescue medication (RM) to alleviate allergic symptoms; these medications are also used as symptomatic RM in daily clinical routine for allergic rhino-conjunctivitis and allergic intermittent asthma; after the study ended, the placebo-treated patients were also offered a 3-year perennial specific immunotherapy (SIT) with Depigoid Birch as a follow-up treatment in countries where legally possible. The sponsor issued a global protocol amendment requiring the withdrawal of all co-sensitized patients and continuing only with patients mono-sensitized to birch (according to the skin prick test at screening), because statistically significant differences in favor of Depigoid Birch 5000 over placebo for the treatment of allergic rhinitis and/or rhino-conjunctivitis, with or without intermittent asthma, could only be shown in mono-sensitized patients (demonstrated by results of planned 2nd-year interim analysis, the additional analyses of 3rd-year data and the post-hoc analyses of 2nd and 3rd year data performed by the DMC).

Background therapy

Country-specific RMs were used in the study for treatment of potentially occurring characteristic symptoms related to the underlying disease (allergic rhinitis/rhinoconjunctivitis with or without asthma due to birch pollen).

Evidence for comparator

Placebo control was used in this study. It was appropriate as the European Medicines Agency (EMA) guideline on clinical development of products for SIT for the treatment of allergic diseases (CHMP/EWP/18504/2006) recommends that Phase III studies in immunotherapy should show superiority of test drugs to placebo.

Actual start date of recruitment

17 Sep 2012

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?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 215

Country: Number of subjects enrolled

Czech Republic: 50

Country: Number of subjects enrolled

Finland: 48

Country: Number of subjects enrolled

Germany: 217

Country: Number of subjects enrolled

Latvia: 30

Country: Number of subjects enrolled

Lithuania: 55

Country: Number of subjects enrolled

Russian Federation: 34

Worldwide total number of subjects

649

EEA total number of subjects

615

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)

592

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patients (12-70 y) from 7 countries were enrolled and screened over 2 recruitment periods (started Sep-2012, ended Jan-2014). 649 of 973 (66.7%) enrolled patients were randomized to treatment (434 to Depigoid Birch; 215 to placebo).

Screening details

Subjects were included if they had immunoglobulin E (IgE)-mediated seasonal allergic rhinitis and/or rhinoconjunctivitis with or without intermittent asthma due to birch pollen allergy verified by specific IgE reactivity (CAP-RAST ≥2) and positive Skin Prick Test (SPT) (wheal diameter of at least 3.0 mm) within one month prior to screening (SCR).

Period 1 title

Treatment phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

The matching placebo had similar appearance to Depigoid Birch 5000. The Sponsor remained blinded to the study treatment during the study. Sealed emergency cards (containing the study code, the randomization number and the information about the therapy regimen) were available at the study site and could be opened if knowledge of the study therapy regimen was necessary to provide optimal treatment to the patient in case of an emergency.

Are arms mutually exclusive

Yes

Mono-sensitized Year 1-3/Depigoid Birch

Arm description

Treatment arms are defined here according to the evaluation of the data in the final analysis. Patients in this arm were mono-sensitized according to the Skin Prick Test results at screening. They were randomized to treatment with Depigoid Birch 5000 and completed all 3 years of treatment phase.

Arm type

Experimental

Investigational medicinal product name

Depigoid Birch 5000

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

The initial rush build-up treatment phase (V1-1) comprised subcutaneous administration of 2 injections of Depigoid Birch 5000, a 0.2 mL injection followed by a 0.3 mL injection 30 minutes later in the upper left arm and upper right arm, respectively. The maintenance treatment phase comprised subcutaneous administration of 0.5 mL injection of Depigoid Birch in 4- to 6-week intervals over 3 pollen seasons. In total, 29 subcutaneous injections were administered for the maintenance phase of approximately 3 years including 3 pollen seasons. The total volume of 0.5 mL of injection was administered in the upper arm, preferably alternating between left and right arm from visit to visit. Patient were observed at the site for at least 30 minutes after the injections.

Co-sensitized Year 1-3/Depigoid Birch

Arm description

Treatment arms are defined here according to the evaluation of the data in the final analysis. Patients in this arm were co-sensitized according to the Skin Prick Test results at screening (against grass and/or weed pollen and/or perennial allergens). They were randomized to treatment with Depigoid Birch 5000 and completed all 3 years of treatment phase.

Arm type

Experimental

Investigational medicinal product name

Depigoid Birch 5000

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Mono-sensitized Year 1-3/Placebo

Arm description

Treatment arms are defined here according to the evaluation of the data in the final analysis. Patients in this arm were mono-sensitized according to the Skin Prick Test results at screening. They were randomized to treatment with placebo and completed all 3 years of treatment phase.

Arm type

Experimental

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

The initial rush build-up treatment phase (V1-1) comprised subcutaneous administration of 2 injections of placebo, a 0.2 mL injection followed by a 0.3 mL injection 30 minutes later in the upper left arm and upper right arm, respectively. The maintenance treatment phase comprised subcutaneous administration of 0.5 mL injection of placebo in 4- to 6-week intervals over 3 pollen seasons. In total, 29 subcutaneous injections were administered for the maintenance phase of approximately 3 years including 3 pollen seasons. The total volume of 0.5 mL of injection was administered in the upper arm, preferably alternating between left and right arm from visit to visit. Patient were observed at the site for at least 30 minutes after the injections.

Co-sensitized Year 1-3/Placebo

Arm description

Treatment arms are defined here according to the evaluation of the data in the final analysis. Patients in this arm were co-sensitized according to the Skin Prick Test results at screening (against grass and/or weed pollen and/or perennial allergens). They were randomized to treatment with placebo and completed all 3 years of treatment phase.

Arm type

Experimental

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

Number of subjects in period 1	Mono-sensitized Year 1-3/Depigoid Birch	Co-sensitized Year 1-3/Depigoid Birch	Mono-sensitized Year 1-3/Placebo	Co-sensitized Year 1-3/Placebo
Started	174	260	85	130
Completed	134	212	66	103
Not completed	40	48	19	27
Consent withdrawn by subject	13	16	5	8
Adverse event, non-fatal	6	8	1	3
Discontinued treatment but remained in the study	4	2	-	4
Pregnancy	-	2	-	1
Other reason	12	8	7	5
Lack of compliance	1	1	-	2
Lost to follow-up	2	4	4	2
Lack of efficacy	2	2	1	1
Protocol deviation	-	5	1	1

Period 2 title

Treatment-free follow-up phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

Only Mono-sensitized patients completed the follow-up phase in the study. No treatment was administered in this phase. The Sponsor remained blinded to the study treatment. Sealed emergency cards (containing the study code, the randomization number and the information about the therapy regimen) were available at the study site and could be opened if knowledge of the study therapy regimen was necessary to provide optimal treatment to the patient in an emergency.

Are arms mutually exclusive

Yes

Mono-sensitized Year 1-5/Depigoid Birch

Arm description

Arm type

Follow-up

Investigational medicinal product name

Depigoid Birch 5000

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

The patients in the Mono-sensitized Year 1-3/Depigoid Birch 5000 group were followed up for 2 years post-treatment. No treatment was administered during the follow-up period.

Mono-sensitized Year 1-5/Placebo

Arm description

Treatment arms are defined here according to the evaluation of the data in the final analysis. Patients in this arm were mono-sensitized according to the Skin Prick Test results at screening. They were randomized to treatment with placebo and completed all 5 years of study duration (3 years treatment and 2 years treatment-free follow-up).

Arm type

Follow-up

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

The patients in the Mono-sensitized Year 1-3/Placebo group were followed up for 2 years post-treatment. No treatment was administered during the follow-up period.

Number of subjects in period 2 ^[1]	Mono-sensitized Year 1-5/Depigoid Birch	Mono-sensitized Year 1-5/Placebo
Started	174	85
Completed	128	64
Not completed	46	21
Consent withdrawn by subject	18	7
Adverse event, non-fatal	7	1
Other reason	12	7
Lack of compliance	1	-
Lost to follow-up	5	4
Lack of efficacy	2	1
Protocol deviation	1	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: Data analysis for Mono-sensitized patients were conducted for periods Year 1-3 (treatment phase; Period 1) and Year 1-5 (treatment + follow-up phase; Period 2). No separate analysis was conducted for the follow-up phase (Year 4-5). Therefore, the number of subjects starting the follow-up phase (Period 2) is derived from the number of subjects starting the treatment phase (Year 1 in the treatment phase).

Baseline characteristics

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Reporting group title

Mono-sensitized Year 1-3/Depigoid Birch

Reporting group description

Reporting group title

Co-sensitized Year 1-3/Depigoid Birch

Reporting group description

Reporting group title

Mono-sensitized Year 1-3/Placebo

Reporting group description

Treatment arms are defined here according to the evaluation of the data in the final analysis. Patients in this arm were mono-sensitized according to the Skin Prick Test results at screening. They were randomized to treatment with placebo and completed all 3 years of treatment phase.

Reporting group title

Co-sensitized Year 1-3/Placebo

Reporting group description

Treatment arms are defined here according to the evaluation of the data in the final analysis. Patients in this arm were co-sensitized according to the Skin Prick Test results at screening (against grass and/or weed pollen and/or perennial allergens). They were randomized to treatment with placebo and completed all 3 years of treatment phase.

Reporting group values	Mono-sensitized Year 1-3/Depigoid Birch	Co-sensitized Year 1-3/Depigoid Birch	Mono-sensitized Year 1-3/Placebo	Co-sensitized Year 1-3/Placebo	Total
Number of subjects	174	260	85	130	649
Age categorical
Units: Subjects
Adolescents (12-17 years)	11	24	3	11	49
Adults (18-70 years)	163	236	82	119	600
Age continuous
Units: years
arithmetic mean (standard deviation)	38.8 ± 12.96	37.3 ± 13.60	41.0 ± 12.84	35.9 ± 13.25	-
Gender categorical
Units: Subjects
Female	98	138	48	73	357
Male	76	122	37	57	292
Race
Units: Subjects
White	174	259	84	129	646
Other	0	1	1	1	3
Asthmatic reaction to birch pollen in the past
Units: Subjects
Yes	50	69	28	38	185
No	124	191	57	92	464
Asthmatic status at baseline
Units: Subjects
Yes	59	88	31	46	224
No	115	172	54	84	425
Patients with nasal/ocular symptoms with at least moderate intensity
Units: Subjects
Yes	174	260	85	130	649
No	0	0	0	0	0
Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	73.5 ± 17.77	74.8 ± 16.03	73.1 ± 13.99	73.3 ± 15.91	-
Height
Units: centimeter(s)
arithmetic mean (standard deviation)	171.7 ± 9.50	172.3 ± 10.18	169.2 ± 8.75	171.8 ± 9.91	-
BMI
Units: kilogram(s)/square meter
arithmetic mean (standard deviation)	24.7 ± 4.59	25.1 ± 4.34	25.5 ± 4.24	24.6 ± 3.99	-
Time (years) since the first allergic reaction to birch pollen
Units: Years
arithmetic mean (standard deviation)	12.1 ± 9.45	12.7 ± 9.60	10.8 ± 8.02	13.7 ± 10.48	-

Subject analysis set title

Mono-sensitized FAS/Depigoid Birch 5000

Subject analysis set type

Full analysis

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Full Analysis Set (FAS)/Depigoid Birch 5000 contained all randomized mono-sensitized patients who received Depigoid Birch 5000 and provide at least one primary efficacy assessment after start of treatment. This was equivalent to a modified intention-to-treat (mITT) population.

Subject analysis set title

Mono-sensitized SAF/Depigoid Birch 5000

Subject analysis set type

Safety analysis

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Safety Analysis Set (SAF)/Depigoid Birch 5000 contained all randomized mono-sensitized patients who received at least one dose of Depigoid Birch 5000. Patients were assigned to treatment groups as treated.

Subject analysis set title

Mono-sensitized PP Year 3/Depigoid Birch 5000

Subject analysis set type

Per protocol

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Per Protocol (PP) Year 3/Depigoid Birch 5000 contained all mono-sensitized patients of the FAS in Year 3 who received Depigoid Birch 5000 without major protocol deviations relevant for the statistical evaluation.

Subject analysis set title

Mono-sensitized PP Year 5/Depigoid Birch 5000

Subject analysis set type

Per protocol

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Per Protocol (PP) Year 5/Depigoid Birch 5000 contained all mono-sensitized patients of the FAS in Year 5 who received Depigoid Birch 5000 without major protocol deviations relevant for the statistical evaluation.

Subject analysis set title

Mono-sensitized Al PK set/Depigoid Birch 5000

Subject analysis set type

Sub-group analysis

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Aluminium Pharmacokinetic (Al PK) set/Depigoid Birch 5000 contained randomized mono-sensitized patients who received Depigoid Birch 5000 and enrolled in the PK sub-study with post-baseline Al(OH)3 plasma and/or urine measurements.

Subject analysis set title

Co-sensitized FAS/Depigoid Birch 5000

Subject analysis set type

Full analysis

Subject analysis set description

Co-sensitized patients were those who were with co-allergies through a positive skin prick test (SPT) at screening, and were subsequently enrolled in the study by signing the ICF. The Co-sensitized Full Analysis Set (FAS)/Depigoid Birch 5000 contained all randomized co-sensitized patients who received Depigoid Birch 5000 and provide at least one primary efficacy assessment after start of treatment. This was equivalent to a modified intention-to-treat (mITT) population.

Subject analysis set title

Co-sensitized SAF/Depigoid Birch 5000

Subject analysis set type

Safety analysis

Subject analysis set description

Co-sensitized patients were those who were with co-allergies through a positive skin prick test (SPT) at screening. The Co-sensitized Safety Analysis Set (SAF)/Depigoid Birch 5000 contained all randomized co-sensitized patients who received at least one dose of Depigoid Birch 5000. Patients were assigned to treatment groups as treated.

Subject analysis set title

Co-sensitized PP Year 3/Depigoid Birch 5000

Subject analysis set type

Per protocol

Subject analysis set description

Co-sensitized patients were those who were with co-allergies through a positive skin prick test (SPT) at screening. The Co-sensitized Per Protocol (PP) Year 3/Depigoid Birch 5000 contained all co-sensitized patients of the FAS in Year 3 who received Depigoid Birch 5000 without major protocol deviations relevant for the statistical evaluation.

Subject analysis set title

Co-sensitized Al PK set/Depigoid Birch 5000

Subject analysis set type

Sub-group analysis

Subject analysis set description

Co-sensitized patients were those who were with co-allergies through a positive skin prick test (SPT) at screening. The Co-sensitized Aluminium Pharmacokinetic (Al PK) set/Depigoid Birch 5000 contained all randomized co-sensitized patients who received Depigoid Birch 5000 and enrolled in the PK sub-study with post-baseline Al(OH)3 plasma and/or urine measurements.

Subject analysis set title

Mono-sensitized FAS/Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Full Analysis Set (FAS)/Placebo contained all randomized mono-sensitized patients who received placebo and provide at least one primary efficacy assessment after start of treatment. This was equivalent to a modified intention-to-treat (mITT) population.

Subject analysis set title

Mono-sensitized SAF/Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Safety Analysis Set (SAF)/Placebo contained all randomized mono-sensitized patients who received at least one dose of placebo. Patients were assigned to treatment groups as treated.

Subject analysis set title

Mono-sensitized PP Year 3/Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Per Protocol (PP) Year 3/Placebo contained all mono-sensitized patients of the FAS in Year 3 who received placebo without major protocol deviations relevant for the statistical evaluation.

Subject analysis set title

Mono-sensitized PP Year 5/Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Per Protocol (PP) Year 5/Placebo contained all mono-sensitized patients of the FAS in Year 5 who received placebo without major protocol deviations relevant for the statistical evaluation.

Subject analysis set title

Mono-sensitized Al PK set/Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Aluminium Pharmacokinetic (Al PK) set/Placebo contained randomized mono-sensitized patients who received placebo and enrolled in the PK sub-study with post-baseline Al(OH)3 plasma and/or urine measurements.

Subject analysis set title

Co-sensitized FAS/Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Co-sensitized patients were those who were with co-allergies through a positive skin prick test (SPT) at screening, and were subsequently enrolled in the study by signing the ICF. The Co-sensitized Full Analysis Set (FAS)/Placebo contained all randomized co-sensitized patients who received placebo and provide at least one primary efficacy assessment after start of treatment. This was equivalent to a modified intention-to-treat (mITT) population.

Subject analysis set title

Co-sensitized SAF/Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Co-sensitized patients were those who were with co-allergies through a positive skin prick test (SPT) at screening. The Co-sensitized Safety Analysis Set (SAF)/Placebo contained all randomized co-sensitized patients who received at least one dose of placebo. Patients were assigned to treatment groups as treated.

Subject analysis set title

Co-sensitized PP Year 3/Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Co-sensitized patients were those who were with co-allergies through a positive skin prick test (SPT) at screening. The Co-sensitized Per Protocol (PP) Year 3/Placebo contained all co-sensitized patients of the FAS in Year 3 who received placebo without major protocol deviations relevant for the statistical evaluation.

Subject analysis set title

Co-sensitized Al PK set/Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Co-sensitized patients were those who were with co-allergies through a positive skin prick test (SPT) at screening. The Co-sensitized Aluminium Pharmacokinetic (Al PK) set/Placebo contained all randomized co-sensitized patients who received placebo and enrolled in the PK sub-study with post-baseline Al(OH)3 plasma and/or urine measurements.

Subject analysis set title

Mono- and Co-sensitized Al PK set/Depigoid Birch

Subject analysis set type

Sub-group analysis

Subject analysis set description

The Mono- and Co-sensitized Aluminium Pharmacokinetic (Al PK) set/Depigoid Birch contained all randomized mono- and co-sensitized patients who received Depigoid Birch and enrolled in the PK sub-study with post-baseline Al(OH)3 plasma and/or urine measurements.

Subject analysis set title

Mono- and Co-sensitized Al PK set/Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

The Mono- and Co-sensitized Aluminium Pharmacokinetic (Al PK) set/Placebo contained all randomized mono- and co-sensitized patients who received placebo and enrolled in the PK sub-study with post-baseline Al(OH)3 plasma and/or urine measurements.

Subject analysis sets values	Mono-sensitized FAS/Depigoid Birch 5000	Mono-sensitized SAF/Depigoid Birch 5000	Mono-sensitized PP Year 3/Depigoid Birch 5000	Mono-sensitized PP Year 5/Depigoid Birch 5000	Mono-sensitized Al PK set/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Co-sensitized SAF/Depigoid Birch 5000	Co-sensitized PP Year 3/Depigoid Birch 5000	Co-sensitized Al PK set/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Mono-sensitized SAF/Placebo	Mono-sensitized PP Year 3/Placebo	Mono-sensitized PP Year 5/Placebo	Mono-sensitized Al PK set/Placebo	Co-sensitized FAS/Placebo	Co-sensitized SAF/Placebo	Co-sensitized PP Year 3/Placebo	Co-sensitized Al PK set/Placebo	Mono- and Co-sensitized Al PK set/Depigoid Birch	Mono- and Co-sensitized Al PK set/Placebo
Number of subjects	161	174	130	116	18	245	260	206	14	79	85	66	63	5	123	130	95	11	32	16
Age categorical
Units: Subjects
Adolescents (12-17 years)	10	11	7	7	0	24	24	23	0	3	3	2	2	0	11	11	10	0	0	0
Adults (18-70 years)	151	163	123	109	18	221	236	183	14	76	82	64	61	5	112	119	85	11	32	16
Age continuous
Units: years
arithmetic mean (standard deviation)	38.4 ± 12.71	38.8 ± 12.96	39.5 ± 12.59	38.6 ± 12.08	41.6 ± 10.48	37.1 ± 13.85	37.3 ± 13.60	37.3 ± 13.86	37.9 ± 11.91	40.8 ± 12.99	41.0 ± 12.84	40.6 ± 12.67	40.9 ± 12.76	48.8 ± 10.66	35.6 ± 13.06	35.9 ± 13.25	35.2 ± 12.98	41.8 ± 12.99	40.0 ± 11.09	44.0 ± 12.41
Gender categorical
Units: Subjects
Female	92	98	75	67	9	128	138	101	8	45	48	37	34	3	68	73	52	6	17	9
Male	69	76	55	49	9	117	122	105	6	34	37	29	29	2	55	57	43	5	15	7
Race
Units: Subjects
White	161	174	130	116	18	244	259	205	14	78	84	65	62	5	122	129	94	11	32	16
Other	0	0	0	0	0	1	1	1	0	1	1	1	1	0	1	1	1	0	0	0
Asthmatic reaction to birch pollen in the past
Units: Subjects
Yes	49	50				65	69			27	28				36	38
No	112	124				180	191			52	57				87	92
Asthmatic status at baseline
Units: Subjects
Yes	58	59				84	88			30	31				44	46
No	103	115				161	172			49	54				79	84
Patients with nasal/ocular symptoms with at least moderate intensity
Units: Subjects
Yes	161	174				245	260			79	85				123	130
No	0	0				0	0			0	0				0	0
Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	73.5 ± 17.81	73.5 ± 17.77	73.3 ± 16.51	73.3 ± 16.53	76.3 ± 17.84	74.8 ± 16.21	74.8 ± 16.03	75.2 ± 16.73	71.1 ± 15.91	72.7 ± 13.75	73.1 ± 13.99	71.6 ± 13.24	71.7 ± 13.54	75.0 ± 11.66	73.0 ± 15.97	73.3 ± 15.91	73.5 ± 16.83	84.4 ± 15.38	74.0 ± 16.95	81.4 ± 14.63
Height
Units: centimeter(s)
arithmetic mean (standard deviation)	171.9 ± 9.58	171.7 ± 9.50	171.5 ± 9.64	171.7 ± 9.41	172.8 ± 10.60	172.4 ± 10.34	172.3 ± 10.18	172.6 ± 10.58	170.6 ± 10.82	169.2 ± 8.80	169.2 ± 8.75	168.8 ± 8.86	168.9 ± 9.05	167.4 ± 10.81	171.5 ± 9.85	171.8 ± 9.91	171.5 ± 10.16	173.7 ± 8.74	171.8 ± 10.58	171.8 ± 9.55
BMI
Units: kilogram(s)/square meter
arithmetic mean (standard deviation)	24.7 ± 4.60	24.7 ± 4.59	24.9 ± 4.27	24.7 ± 4.55	25.3 ± 4.39	25.1 ± 4.42	24.9 ± 4.23	25.1 ± 4.61	24.2 ± 3.68	25.4 ± 4.30	25.5 ± 4.24	25.1 ± 3.97	25.1 ± 4.06	27.0 ± 5.29	24.7 ± 4.01	24.6 ± 3.99	24.8 ± 4.22	27.9 ± 4.44	24.9 ± 4.07	27.6 ± 4.56
Time (years) since the first allergic reaction to birch pollen
Units: Years
arithmetic mean (standard deviation)	12.1 ± 9.56	12.1 ± 9.45	±	±	±	12.8 ± 9.60	12.7 ± 9.60	±	±	10.7 ± 7.58	10.8 ± 8.02	±	±	±	13.7 ± 10.64	13.7 ± 10.48	±	±	±	±

End points

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Reporting group title

Mono-sensitized Year 1-3/Depigoid Birch

Reporting group description

Reporting group title

Co-sensitized Year 1-3/Depigoid Birch

Reporting group description

Reporting group title

Mono-sensitized Year 1-3/Placebo

Reporting group description

Treatment arms are defined here according to the evaluation of the data in the final analysis. Patients in this arm were mono-sensitized according to the Skin Prick Test results at screening. They were randomized to treatment with placebo and completed all 3 years of treatment phase.

Reporting group title

Co-sensitized Year 1-3/Placebo

Reporting group description

Treatment arms are defined here according to the evaluation of the data in the final analysis. Patients in this arm were co-sensitized according to the Skin Prick Test results at screening (against grass and/or weed pollen and/or perennial allergens). They were randomized to treatment with placebo and completed all 3 years of treatment phase.

Reporting group title

Mono-sensitized Year 1-5/Depigoid Birch

Reporting group description

Reporting group title

Mono-sensitized Year 1-5/Placebo

Reporting group description

Treatment arms are defined here according to the evaluation of the data in the final analysis. Patients in this arm were mono-sensitized according to the Skin Prick Test results at screening. They were randomized to treatment with placebo and completed all 5 years of study duration (3 years treatment and 2 years treatment-free follow-up).

Subject analysis set title

Mono-sensitized FAS/Depigoid Birch 5000

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Mono-sensitized SAF/Depigoid Birch 5000

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Mono-sensitized PP Year 3/Depigoid Birch 5000

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Mono-sensitized PP Year 5/Depigoid Birch 5000

Subject analysis set type

Per protocol

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Per Protocol (PP) Year 5/Depigoid Birch 5000 contained all mono-sensitized patients of the FAS in Year 5 who received Depigoid Birch 5000 without major protocol deviations relevant for the statistical evaluation.

Subject analysis set title

Mono-sensitized Al PK set/Depigoid Birch 5000

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Co-sensitized FAS/Depigoid Birch 5000

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Co-sensitized SAF/Depigoid Birch 5000

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Co-sensitized PP Year 3/Depigoid Birch 5000

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Co-sensitized Al PK set/Depigoid Birch 5000

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Mono-sensitized FAS/Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Full Analysis Set (FAS)/Placebo contained all randomized mono-sensitized patients who received placebo and provide at least one primary efficacy assessment after start of treatment. This was equivalent to a modified intention-to-treat (mITT) population.

Subject analysis set title

Mono-sensitized SAF/Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Safety Analysis Set (SAF)/Placebo contained all randomized mono-sensitized patients who received at least one dose of placebo. Patients were assigned to treatment groups as treated.

Subject analysis set title

Mono-sensitized PP Year 3/Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Per Protocol (PP) Year 3/Placebo contained all mono-sensitized patients of the FAS in Year 3 who received placebo without major protocol deviations relevant for the statistical evaluation.

Subject analysis set title

Mono-sensitized PP Year 5/Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Per Protocol (PP) Year 5/Placebo contained all mono-sensitized patients of the FAS in Year 5 who received placebo without major protocol deviations relevant for the statistical evaluation.

Subject analysis set title

Mono-sensitized Al PK set/Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Mono-sensitized patients were those who were identified through a positive skin prick test (SPT) at screening as allergic to birch pollen only. The Mono-sensitized Aluminium Pharmacokinetic (Al PK) set/Placebo contained randomized mono-sensitized patients who received placebo and enrolled in the PK sub-study with post-baseline Al(OH)3 plasma and/or urine measurements.

Subject analysis set title

Co-sensitized FAS/Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Co-sensitized patients were those who were with co-allergies through a positive skin prick test (SPT) at screening, and were subsequently enrolled in the study by signing the ICF. The Co-sensitized Full Analysis Set (FAS)/Placebo contained all randomized co-sensitized patients who received placebo and provide at least one primary efficacy assessment after start of treatment. This was equivalent to a modified intention-to-treat (mITT) population.

Subject analysis set title

Co-sensitized SAF/Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Co-sensitized PP Year 3/Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Co-sensitized Al PK set/Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Mono- and Co-sensitized Al PK set/Depigoid Birch

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Mono- and Co-sensitized Al PK set/Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Mean integrated Symptoms and Medication Score (SMS)

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End point title

Mean integrated Symptoms and Medication Score (SMS)

End point description

Based on the planned second interim analysis for futility, the DMC (agreed with the sponsor and the PEI) recommended to discontinue the Co-sensitized patients from the study. Only the Mono-sensitized patients continued with the follow-up phase. Therefore, full results (Year 1-5) are presented for the Mono-sensitized patients, while only results in the treatment phase (Year 1-3) are presented for the Co-sensitized patients. The primary efficacy endpoint of the study was the mean integrated SMS on nasal and ocular symptoms and their RM score (RMS) per pollen season. The mean integrated SMS per year were compared between treatment groups by means of Wilcoxon-Mann-Whitney (two-sided) and Hodges-Lehmann two-sided 95% CI of the median difference between the treatments. Exploratory analysis based on logistic regression model for superiority testing, with treatment arm and age group as factors accounting for the stratification variables applied for randomization was performed in the FAS.

End point type

Primary

End point timeframe

The results for FAS are presented and summarized by year, i.e. Year 1-5 in the Mono-sensitized patients and Year 1-3 in the Co-sensitized patients.

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Co-sensitized FAS/Placebo
Number of subjects analysed	148 ^[1]	235 ^[2]	77 ^[3]	116 ^[4]
Units: score
arithmetic mean (standard deviation)
Year 1	7.80 ± 4.669	8.38 ± 4.381	9.01 ± 5.222	7.79 ± 4.679
Year 2	7.37 ± 4.131	7.77 ± 4.215	8.93 ± 5.317	7.31 ± 4.814
Year 3	6.49 ± 4.166	7.28 ± 4.526	8.21 ± 4.538	7.06 ± 4.207
Year 4	5.82 ± 3.942	0 ± 0	7.26 ± 5.036	0 ± 0
Year 5	6.27 ± 4.224	0 ± 0	7.88 ± 5.222	0 ± 0

Notes
[1] - No. of subjects analyzed: Year 1: 148; Year 2: 148; Year 3: 137; Year 4: 123; Year 5: 124
[2] - No. of subjects analyzed: Year 1: 235; Year 2: 218; Year 3: 214
[3] - No. of subjects analyzed: Year 1: 77; Year 2: 71; Year 3: 66; Year 4: 63; Year 5: 63
[4] - No. of subjects analyzed: Year 1: 116; Year 2: 111; Year 3: 108

Depigoid Birch vs. placebo(Mono-sensitized Year 1)

Statistical analysis description

Depigoid Birch was considered superior to placebo if lower scores of the primary endpoint were more likely in the active treatment group than in the control group, i.e. if the probability of any random scores recorded per pollen season (1, 2, 3, or 5) for Depigoid Birch being lower than that for placebo was above 0.5. The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.105

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

0.714

Notes
[5] - The mean integrated SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 2)

Statistical analysis description

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.0389

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

2.7

Variability estimate

Standard error of the mean

Dispersion value

0.663

Notes
[6] - The mean integrated SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 3)

Statistical analysis description

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.004

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.612

Notes
[7] - The mean integrated SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 4)

Statistical analysis description

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.0974

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

2.4

Variability estimate

Standard error of the mean

Dispersion value

0.663

Notes
[8] - The mean integrated SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 5)

Statistical analysis description

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.0556

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

2.8

Variability estimate

Standard error of the mean

Dispersion value

0.714

Notes
[9] - The mean integrated SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 1)

Statistical analysis description

Depigoid Birch was considered superior to placebo if lower scores of the primary endpoint were more likely in the active treatment group than in the control group, i.e. if the probability of any random scores recorded per pollen season (1, 2, 3, or 5) for Depigoid Birch being lower than that for placebo was above 0.5. The number of subjects analyzed for both Depigoid Birch 5000 and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Placebo v Co-sensitized FAS/Depigoid Birch 5000

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.1284

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

0.2

Variability estimate

Standard error of the mean

Dispersion value

0.485

Notes
[10] - The mean integrated SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 2)

Statistical analysis description

Depigoid Birch was considered superior to placebo if lower scores of the primary endpoint were more likely in the active treatment group than in the control group, i.e. if the probability of any random scores recorded per pollen season (1, 2, 3, or 5) for Depigoid Birch being lower than that for placebo was above 0.5. The number of subjects analyzed for both Depigoid Birch 5000 and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.2329

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

0.4

Variability estimate

Standard error of the mean

Dispersion value

0.51

Notes
[11] - The mean integrated SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 3)

Statistical analysis description

Depigoid Birch was considered superior to placebo if lower scores of the primary endpoint were more likely in the active treatment group than in the control group, i.e. if the probability of any random scores recorded per pollen season (1, 2, 3, or 5) for Depigoid Birch being lower than that for placebo was above 0.5. The number of subjects analyzed for both Depigoid Birch 5000 and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.9454

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.9

Variability estimate

Standard error of the mean

Dispersion value

0.485

Notes
[12] - The mean integrated SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Secondary: Mean Integrated Symptoms and Medication Score (SMS) (0-6)

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End point title

Mean Integrated Symptoms and Medication Score (SMS) (0-6)

End point description

Based on the planned second interim analysis for futility, the DMC (agreed with the sponsor and the PEI) recommended to discontinue the Co-sensitized patients from the study. Only Mono-sensitized patients continued with the follow-up phase. Therefore, full results (Year 1-5) are presented for the Mono-sensitized patients, while only results in the treatment phase (Year 1-3) are presented for the Co-sensitized patients. The mean integrated SMS (0-6) was calculated as the sum of SS for rhinoconjunctivitis and the RMS according to the EAACI criteria for equal weight of both SS and RMS. The values of the SMS (0-6) for rhinoconjunctivitis range from 0 to 6, whereby higher values indicate worse outcome.

End point type

Secondary

End point timeframe

The results for FAS are presented and summarized by year, i.e. Year 1-5 in the Mono-sensitized patients and Year 1-3 in the Co-sensitized patients.

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Co-sensitized FAS/Placebo
Number of subjects analysed	148 ^[13]	235 ^[14]	77 ^[15]	116 ^[16]
Units: score
arithmetic mean (standard deviation)
Year 1	1.66 ± 0.928	1.73 ± 0.841	1.93 ± 1.002	1.67 ± 0.959
Year 2	1.55 ± 0.877	1.64 ± 0.876	1.89 ± 1.001	1.54 ± 0.923
Year 3	1.36 ± 0.882	1.49 ± 0.912	1.74 ± 0.868	1.47 ± 0.812
Year 4	1.22 ± 0.854	0 ± 0	1.52 ± 0.985	0 ± 0
Year 5	1.30 ± 0.871	0 ± 0	1.68 ± 1.012	0 ± 0

Notes
[13] - No. of subjects analyzed: Year 1-2: 148; Year 3: 137; Year 4: 123; Year 5: 124
[14] - No. of subjects analyzed: Year 1: 235; Year 2: 218; Year 3: 214
[15] - No. of subjects analyzed: Year 1: 77; Year 2: 71; Year 3: 66; Year 4-5: 63
[16] - No. of subjects analyzed: Year 1: 116; Year 2: 111; Year 3: 108

Depigoid Birch vs. placebo(Mono-sensitized Year 1)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.0616

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.153

Notes
[17] - The mean integrated SMS (0-6) between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 2)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.0119

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.128

Notes
[18] - The mean integrated SMS (0-6) between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 3)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.002

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

0.7

Variability estimate

Standard error of the mean

Dispersion value

0.128

Notes
[19] - The mean integrated SMS (0-6) between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 4)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.0482

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.5

Variability estimate

Standard error of the mean

Dispersion value

0.128

Notes
[20] - The mean integrated SMS (0-6) between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 5)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.013

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.7

Variability estimate

Standard error of the mean

Dispersion value

0.153

Notes
[21] - The mean integrated SMS (0-6) between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 1)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

= 0.2612

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.102

Notes
[22] - The mean integrated SMS (0-6) between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 2)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.3477

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.102

Notes
[23] - The mean integrated SMS (0-6) between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 3)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

= 0.9

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.2

Variability estimate

Standard error of the mean

Dispersion value

0.102

Notes
[24] - The mean integrated SMS (0-6) between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Secondary: Mean Integrated Symptom Score (SS)

Top of page

End point title

Mean Integrated Symptom Score (SS)

End point description

Only the Mono-sensitized patients continued with the follow-up phase. Therefore, full results (Year 1-5) are presented for the Mono-sensitized patients, while only results in the treatment phase (Year 1-3) are presented for the Co-sensitized patients. Mean integrated SS was an integrated part of the primary efficacy endpoint but was assessed as secondary efficacy endpoint separately. The daily SS was defined as the mean of the symptoms’ severity scorings per day during a pollen season and was derived from the patient’s eDiary entries. The SS scores ranged from 0 to 18 points derived from 4 nasal (itching, sneezing, rhinorrhea, and obstruction) and 2 ocular (itching/grittiness/redness and tearing) symptoms, each assessed by the patient on 4-point-Likert scale ranging from 0 to 3. Calculations of the SS according to the EAACI criteria were used for statistical analyses.

End point type

Secondary

End point timeframe

The results for FAS are presented and summarized by year, i.e. Year 1-5 in the Mono-sensitized patients and Year 1-3 in the Co-sensitized patients.

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Co-sensitized FAS/Placebo
Number of subjects analysed	148 ^[25]	235 ^[26]	77 ^[27]	116 ^[28]
Units: score
arithmetic mean (standard deviation)
Year 1	5.79 ± 3.299	6.47 ± 3.159	6.51 ± 3.479	5.85 ± 3.494
Year 2	5.73 ± 2.960	6.24 ± 3.053	6.51 ± 3.442	5.61 ± 3.544
Year 3	5.18 ± 2.964	5.83 ± 3.339	6.06 ± 3.079	5.61 ± 3.128
Year 4	4.64 ± 2.691	0 ± 0	5.53 ± 3.580	0 ± 0
Year 5	5.02 ± 3.009	0 ± 0	5.88 ± 3.763	0 ± 0

Notes
[25] - No. of subjects analyzed: Year 1-2: 148; Year 3: 137; Year 4: 123; Year 5: 124
[26] - No. of subjects analyzed: Year 1: 235; Year 2: 218; Year 3: 214
[27] - No. of subjects analyzed: Year 1: 77; Year 2: 71; Year 3: 66, Year 4-5: 63
[28] - No. of subjects analyzed: Year 1: 116; Year 2: 111; Year 3: 108

Depigoid Birch vs. placebo(Mono-sensitized Year 1)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

= 0.1114

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

1.8

Variability estimate

Standard error of the mean

Dispersion value

0.51

Notes
[29] - The mean integrated SS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 2)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

= 0.0715

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

1.7

Variability estimate

Standard error of the mean

Dispersion value

0.459

Notes
[30] - The mean integrated SS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 3)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

= 0.0292

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.485

Notes
[31] - The mean integrated SS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 4)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

= 0.1585

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

1.7

Variability estimate

Standard error of the mean

Dispersion value

0.51

Notes
[32] - The mean integrated SS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 5)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.1885

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

1.8

Variability estimate

Standard error of the mean

Dispersion value

0.536

Notes
[33] - The mean integrated SS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 1)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

= 0.0442

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.383

Notes
[34] - The mean integrated SS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 2)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

= 0.0585

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.383

Notes
[35] - The mean integrated SS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 3)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

P-value

= 0.8259

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

0.7

Variability estimate

Standard error of the mean

Dispersion value

0.383

Notes
[36] - The mean integrated SS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Secondary: Mean Integrated Rescue Medication Score (RMS)

Top of page

End point title

Mean Integrated Rescue Medication Score (RMS)

End point description

Only the Mono-sensitized patients continued with the follow-up phase. Therefore, full results (Year 1-5) are presented for the Mono-sensitized patients, while only results in the treatment phase (Year 1-3) are presented for the Co-sensitized patients. Mean integrated RMS excluding RM for asthmatic patients was an integrated part of the primary efficacy endpoint but was also assessed separately as secondary efficacy endpoint. The RMS was defined as the mean of daily RMS during a pollen season. The RMS calculation was based on score points allocated per application of each single RM product to treat the characteristic allergy related symptoms.

End point type

Secondary

End point timeframe

The results for FAS are presented and summarized by year, i.e. Year 1-5 in the Mono-sensitized patients and Year 1-3 in the Co-sensitized patients.

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Co-sensitized FAS/Placebo
Number of subjects analysed	148 ^[37]	235 ^[38]	77 ^[39]	116 ^[40]
Units: score
arithmetic mean (standard deviation)
Year 1	2.02 ± 2.197	1.91 ± 2.083	2.50 ± 2.399	1.94 ± 1.895
Year 2	1.64 ± 1.803	1.54 ± 1.790	2.42 ± 2.299	1.70 ± 1.964
Year 3	1.31 ± 1.819	1.45 ± 1.911	2.15 ± 2.152	1.45 ± 1.827
Year 4	1.18 ± 1.783	0 ± 0	1.74 ± 2.100	0 ± 0
Year 5	1.25 ± 1.758	0 ± 0	2.00 ± 2.010	0 ± 0

Notes
[37] - No. of subjects analyzed: Year 1-2: 148; Year 3: 137; Year 4: 123; Year 5: 124
[38] - No. of subjects analyzed: Year 1: 235; Year 2: 218; Year 3: 214
[39] - No. of subjects analyzed: Year 1: 77, Year 2: 71, Year 3: 66, Year 4-5: 63
[40] - No. of subjects analyzed: Year 1: 116; Year 2: 111; Year 3: 108

Depigoid Birch vs. placebo(Mono-sensitized Year 1)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

= 0.1184

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.9

Variability estimate

Standard error of the mean

Dispersion value

0.23

Notes
[41] - The mean integrated RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 2)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

P-value

= 0.008

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.23

Notes
[42] - The mean integrated RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 3)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[43]

P-value

= 0.0006

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

1.1

Variability estimate

Standard error of the mean

Dispersion value

0.23

Notes
[43] - The mean integrated RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 4)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

P-value

= 0.0114

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.7

Variability estimate

Standard error of the mean

Dispersion value

0.179

Notes
[44] - The mean integrated RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 5)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[45]

P-value

= 0.0012

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

1.1

Variability estimate

Standard error of the mean

Dispersion value

0.23

Notes
[45] - The mean integrated RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 1)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[46]

P-value

= 0.632

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.4

Variability estimate

Standard error of the mean

Dispersion value

0.153

Notes
[46] - The mean integrated RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 2)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[47]

P-value

= 0.4787

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.3

Variability estimate

Standard error of the mean

Dispersion value

0.102

Notes
[47] - The mean integrated RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 3)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[48]

P-value

= 0.3999

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.3

Variability estimate

Standard error of the mean

Dispersion value

0.102

Notes
[48] - The mean integrated RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Secondary: Mean Integrated Combined Symptom Medication Score (SMS)

Top of page

End point title

Mean Integrated Combined Symptom Medication Score (SMS)

End point description

End point type

Secondary

End point timeframe

The results for FAS are presented and summarized by year, i.e. Year 1-5 in the Mono-sensitized patients and Year 1-3 in the Co-sensitized patients.

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Co-sensitized FAS/Placebo
Number of subjects analysed	148 ^[49]	235 ^[50]	77 ^[51]	116 ^[52]
Units: score
arithmetic mean (standard deviation)
Year 1	9.18 ± 6.037	9.80 ± 5.279	10.71 ± 6.294	9.38 ± 5.682
Year 2	8.78 ± 5.434	9.17 ± 5.226	10.66 ± 6.696	8.78 ± 5.856
Year 3	7.68 ± 5.629	8.63 ± 5.704	9.64 ± 5.520	8.36 ± 5.462
Year 4	6.99 ± 5.162	0 ± 0	8.67 ± 6.678	0 ± 0
Year 5	7.22 ± 5.063	0 ± 0	9.13 ± 6.346	0 ± 0

Notes
[49] - No. of subjects analyzed: Year 1-2: 148; Year 3: 137; Year 4: 123; Year 5: 124
[50] - No. of subjects analyzed: Year 1: 235; Year 2: 218; Year 3: 214
[51] - No. of subjects analyzed: Year 1: 77; Year 2: 71; Year 3: 66; Year 4-5: 63
[52] - No. of subjects analyzed: Year 1: 116; Year 2: 111; Year 3: 108

Depigoid Birch vs. placebo(Mono-sensitized Year 1)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[53]

P-value

= 0.0565

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

3.3

Variability estimate

Standard error of the mean

Dispersion value

0.867

Notes
[53] - The mean integrated combined SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 2)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

P-value

= 0.058

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

3.4

Variability estimate

Standard error of the mean

Dispersion value

0.867

Notes
[54] - The mean integrated combined SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 3)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[55]

P-value

= 0.0057

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

2.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

3.7

Variability estimate

Standard error of the mean

Dispersion value

0.791

Notes
[55] - The mean integrated combined SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 4)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.1739

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

0.765

Notes
[56] - The mean integrated combined SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 5)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[57]

P-value

= 0.0489

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

3.2

Variability estimate

Standard error of the mean

Dispersion value

0.816

Notes
[57] - The mean integrated combined SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 1)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[58]

P-value

= 0.3507

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.612

Notes
[58] - The mean integrated combined SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 2)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[59]

P-value

= 0.3949

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.587

Notes
[59] - The mean integrated combined SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 3)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[60]

P-value

= 0.9001

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

1.1

Variability estimate

Standard error of the mean

Dispersion value

0.612

Notes
[60] - The mean integrated combined SMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Secondary: Mean Integrated Asthmatic Rescue Medication Score (RMS)

Top of page

End point title

Mean Integrated Asthmatic Rescue Medication Score (RMS)

End point description

Only the Mono-sensitized patients continued with the follow-up phase. Therefore, full results (Year 1-5) are presented for the Mono-sensitized patients, while only results in the treatment phase (Year 1-3) are presented for the Co-sensitized patients. The scores of RMS for asthmatic patients only were not considered for the calculation of the primary endpoint but were evaluated separately as a secondary efficacy endpoint, i.e. the asthmatic RMS. The RMS, defined as the mean of daily RMS during a pollen season, was calculated from score points allocated per application of each single RM product to treat the characteristic allergy related symptoms.

End point type

Secondary

End point timeframe

The results for FAS are presented and summarized by year, i.e. Year 1-5 in the Mono-sensitized patients and Year 1-3 in the Co-sensitized patients.

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Co-sensitized FAS/Placebo
Number of subjects analysed	56 ^[61]	87 ^[62]	33 ^[63]	46 ^[64]
Units: score
arithmetic mean (standard deviation)
Year 1	3.97 ± 3.677	3.45 ± 3.217	4.23 ± 3.201	3.52 ± 4.284
Year 2	3.24 ± 3.237	2.97 ± 2.907	4.38 ± 3.567	3.64 ± 4.299
Year 3	2.78 ± 3.346	2.62 ± 2.905	3.86 ± 2.904	3.68 ± 4.283
Year 4	2.77 ± 3.392	0 ± 0	3.32 ± 2.792	0 ± 0
Year 5	2.50 ± 3.315	0 ± 0	3.27 ± 2.602	0 ± 0

Notes
[61] - No. of subjects analyzed: Year 1-3: 56; Year 4-5: 53
[62] - No. of subjects analyzed: Year 1-2: 87; Year 3: 82
[63] - No. of subjects analyzed: Year 1: 33; Year 2: 31; Year 3: 28; Year 4: 28; Year 5: 29
[64] - No. of subjects analyzed: Year 1: 46; Year 2-3: 44

Depigoid Birch vs. placebo(Mono-sensitized Year 1)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 89 in Year 1, 87 in Year 2, 84 in Year 3, 81 in Year 4, and 82 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[65]

P-value

= 0.4571

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.74

Notes
[65] - The mean integrated asthmatic RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 2)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 89 in Year 1, 87 in Year 2, 84 in Year 3, 81 in Year 4, and 82 in Year 5.

Comparison groups

Mono-sensitized FAS/Placebo v Mono-sensitized FAS/Depigoid Birch 5000

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[66]

P-value

= 0.0532

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

2.4

Variability estimate

Standard error of the mean

Dispersion value

0.612

Notes
[66] - The mean integrated asthmatic RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 3)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 89 in Year 1, 87 in Year 2, 84 in Year 3, 81 in Year 4, and 82 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[67]

P-value

= 0.0254

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

2.3

Variability estimate

Standard error of the mean

Dispersion value

0.561

Notes
[67] - The mean integrated asthmatic RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 4)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 89 in Year 1, 87 in Year 2, 84 in Year 3, 81 in Year 4, and 82 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[68]

P-value

= 0.1033

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

1.7

Variability estimate

Standard error of the mean

Dispersion value

0.485

Notes
[68] - The mean integrated asthmatic RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Mono-sensitized Year 5)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 89 in Year 1, 87 in Year 2, 84 in Year 3, 81 in Year 4, and 82 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[69]

P-value

= 0.0321

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

2.2

Variability estimate

Standard error of the mean

Dispersion value

0.561

Notes
[69] - The mean integrated asthmatic RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 1)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 133 in Year 1, 131 in Year 2, and 126 in Year 3.

Comparison groups

Co-sensitized FAS/Placebo v Co-sensitized FAS/Depigoid Birch 5000

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority ^[70]

P-value

= 0.712

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

0.7

Variability estimate

Standard error of the mean

Dispersion value

0.459

Notes
[70] - The mean integrated asthmatic RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 2)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 133 in Year 1, 131 in Year 2, and 126 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority ^[71]

P-value

= 0.6259

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.434

Notes
[71] - The mean integrated asthmatic RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo(Co-sensitized Year 3)

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 133 in Year 1, 131 in Year 2, and 126 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority ^[72]

P-value

= 0.1783

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

1.3

Variability estimate

Standard error of the mean

Dispersion value

0.383

Notes
[72] - The mean integrated asthmatic RMS between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Secondary: Number of Well Days and Hell Days

Top of page

End point title

Number of Well Days and Hell Days

End point description

End point type

Secondary

End point timeframe

The results for FAS are presented and summarized by year, i.e. Year 1-5 in the Mono-sensitized patients and Year 1-3 in the Co-sensitized patients.

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Co-sensitized FAS/Placebo
Number of subjects analysed	148 ^[73]	235 ^[74]	77 ^[75]	116 ^[76]
Units: days
arithmetic mean (standard deviation)
Year 1 - Well days	4.24 ± 6.866	3.35 ± 5.529	3.65 ± 6.458	4.68 ± 6.720
Year 1 - Hell days	3.29 ± 5.097	4.06 ± 5.646	4.61 ± 6.090	4.03 ± 5.826
Year 2 - Well days	4.61 ± 6.989	4.60 ± 6.770	3.83 ± 6.616	5.95 ± 8.345
Year 2 - Hell days	3.56 ± 5.925	3.86 ± 5.615	5.25 ± 6.507	3.86 ± 5.891
Year 3 - Well days	5.64 ± 7.866	5.17 ± 6.856	3.71 ± 6.952	5.40 ± 7.750
Year 3 - Hell days	2.42 ± 4.818	3.01 ± 5.027	4.86 ± 6.442	3.16 ± 5.395
Year 4 - Well days	9.64 ± 11.363	0 ± 0	7.10 ± 10.140	0 ± 0
Year 4 - Hell days	2.29 ± 4.998	0 ± 0	4.25 ± 7.383	0 ± 0
Year 5 - Well days	7.00 ± 8.869	0 ± 0	5.98 ± 9.508	0 ± 0
Year 5 - Hell days	2.44 ± 4.445	0 ± 0	4.43 ± 6.674	0 ± 0

Notes
[73] - No. of subjects analyzed: Year 1-2: 148; Year 3: 137: Year 4: 123; Year 5: 124
[74] - No. of subjects analyzed: Year 1: 235; Year 2: 218; Year 3: 214
[75] - No. of subjects analyzed: Year 1: 77; Year 2: 71; Year 3: 66; Year 4-5: 63
[76] - No. of subjects analyzed: Year 1: 116; Year 2: 111; Year 3: 108

Depigoid Birch vs. placebo (MO Year 1)/Well days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Placebo v Mono-sensitized FAS/Depigoid Birch 5000

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[77]

P-value

= 0.3793

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

Notes
[77] - The mean number of well days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (MO Year 1)/Hell days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[78]

P-value

= 0.0658

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.51

Notes
[78] - The mean number of hell days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (MO Year 2)/Well days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[79]

P-value

= 0.2977

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

Notes
[79] - The mean number of well days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (MO Year 2)/Hell days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[80]

P-value

= 0.0254

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.51

Notes
[80] - The mean number of hell days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (MO Year 3)/Well days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[81]

P-value

= 0.0649

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.255

Notes
[81] - The mean number of well days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (MO Year 3)/Hell days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[82]

P-value

= 0.0019

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.51

Notes
[82] - The mean number of hell days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (MO Year 4)/Well days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[83]

P-value

= 0.109

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.765

Notes
[83] - The mean number of well days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (MO Year 4)/Hell days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[84]

P-value

= 0.0267

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.255

Notes
[84] - The mean number of hell days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (MO Year 5)/Well days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[85]

P-value

= 0.2132

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.255

Notes
[85] - The mean number of well days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (MO Year 5)/Hell days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 225 in Year 1, 219 in Year 2, 203 in Year 3, 186 in Year 4, and 187 in Year 5.

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

225

Analysis specification

Pre-specified

Analysis type

superiority ^[86]

P-value

= 0.0836

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.255

Notes
[86] - The mean number of hell days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (CO Year 1)/Well days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Placebo v Co-sensitized FAS/Depigoid Birch 5000

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[87]

P-value

= 0.0732

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.255

Notes
[87] - The mean number of well days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (CO Year 1)/Hell days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[88]

P-value

= 0.6451

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

Notes
[88] - The mean number of hell days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (CO Year 2)/Well days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[89]

P-value

= 0.2719

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.255

Notes
[89] - The mean number of well days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (CO Year 2)/Hell days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[90]

P-value

= 0.8606

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

Notes
[90] - The mean number of hell days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (CO Year 3)/Well days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[91]

P-value

= 0.7638

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

Notes
[91] - The mean number of well days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Depigoid Birch vs. placebo (CO Year 3)/Hell days

Statistical analysis description

The number of subjects analyzed for both Depigoid Birch and placebo started with total 351 in Year 1, 329 in Year 2, and 322 in Year 3.

Comparison groups

Co-sensitized FAS/Depigoid Birch 5000 v Co-sensitized FAS/Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[92]

P-value

= 0.6366

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

Notes
[92] - The mean number of hell days between treatments were compared using Wilcoxon-Mann-Whitney test (two-sided). Median differences between treatment groups were compared using Hodges-Lehmann estimator with two-sided 95% CI.

Secondary: Immunology - Specific IgE

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End point title

Immunology - Specific IgE

End point description

Only the Mono-sensitized patients continued with the follow-up phase. Therefore, Year 5 (EoS) results are only presented for the Mono-sensitized patients. Serum levels of specific IgE against birch and all co-allergens were evaluated for all patients, with the value at screening as the baseline.

End point type

Secondary

End point timeframe

The results for FAS are presented and summarized by year, i.e. Year 1 (baseline), Year 2 (V2-10), and Year 3 (V3-10) in both Mono- and Co-sensitized patients; and Year 5 (end of study/EoS) in the Mono-sensitized patients only.

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Co-sensitized FAS/Placebo
Number of subjects analysed	118 ^[93]	150 ^[94]	56 ^[95]	63 ^[96]
Units: kU/L
median (full range (min-max))
Baseline	38.20 (0.7 to 97.3)	45.40 (1.4 to 100.0)	29.45 (0.8 to 99.9)	36.80 (2.3 to 95.6)
Year 2 (V2-10)	35.80 (1.0 to 98.3)	40.00 (3.1 to 99.7)	34.40 (0.6 to 94.3)	45.00 (1.1 to 98.9)
Year 3 (V3-10)	20.30 (0.4 to 100.0)	25.95 (1.3 to 98.8)	22.20 (0.6 to 99.9)	28.00 (0.9 to 99.8)
EoS	11.30 (0.5 to 88.8)	0 (0 to 0)	12.70 (0.5 to 75.9)	0 (0 to 0)

Notes
[93] - No. of subjects analyzed: Baseline: 118; Year 2: 117; Year 3: 120; EoS: 121
[94] - No. of subjects analyzed: Baseline: 150; Year 2: 147; Year 3: 176
[95] - No. of subjects analyzed: Baseline: 56; Year 2: 49; Year 3: 54; EoS: 59
[96] - No. of subjects analyzed: Baseline: 63; Year 2: 63; Year 3: 77

No statistical analyses for this end point

Secondary: Immunology - Specific IgG1

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End point title

Immunology - Specific IgG1

End point description

Only the Mono-sensitized patients continued with the follow-up phase. Therefore, Year 5 (EoS) results are only presented for the Mono-sensitized patients. The samples for analysis were collected in selected sites in Germany. Serum levels of specific IgG1 were evaluated, with the value at V1-1 as the baseline.

End point type

Secondary

End point timeframe

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Co-sensitized FAS/Placebo
Number of subjects analysed	39 ^[97]	73 ^[98]	18 ^[99]	34 ^[100]
Units: U/mL
median (full range (min-max))
Baseline	6.10 (1.1 to 418.5)	6.90 (0.5 to 667.1)	25.55 (0.8 to 804.6)	5.60 (1.2 to 278.5)
Year 2 (V2-10)	30.40 (2.0 to 430.4)	21.00 (3.7 to 395.2)	5.95 (2.1 to 235.5)	7.40 (1.5 to 105.6)
Year 3 (V3-10)	7.80 (1.4 to 293.7)	14.80 (2.2 to 533.0)	4.30 (1.6 to 145.9)	4.60 (0.9 to 261.5)
EoS	2.80 (0 to 195.5)	0 (0 to 0)	2.55 (0.4 to 119.8)	0 (0 to 0)

Notes
[97] - No. of subjects analyzed (selected German sites only): Baseline: 39; Year 2: 44; Year 3: 43; EoS:42
[98] - No. of subjects analyzed (selected German sites only): Baseline, Year 2, and Year 3:73
[99] - No. of subjects analyzed (selected German sites only): Baseline, Year 2, Year 3, EoS: 18
[100] - No. of subjects analyzed (selected German sites only): Baseline: 34; Year 2: 35; Year 3: 33

No statistical analyses for this end point

Secondary: Immunology - Specific IgG4

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End point title

Immunology - Specific IgG4

End point description

Only the Mono-sensitized patients continued with the follow-up phase. Therefore, Year 5 (EoS) results are only presented for the Mono-sensitized patients. The samples for analysis were collected in selected sites in Germany. Serum levels of specific IgG4 were evaluated, with the value at V1-1 as the baseline.

End point type

Secondary

End point timeframe

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Co-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo	Co-sensitized FAS/Placebo
Number of subjects analysed	46 ^[101]	82 ^[102]	22 ^[103]	39 ^[104]
Units: ng/mL
median (full range (min-max))
Baseline	13.50 (0.8 to 49.4)	16.25 (0.6 to 236.9)	9.55 (0.8 to 103.8)	19.40 (1.2 to 81.0)
Year 2 (V2-10)	72.70 (2.4 to 890.3)	105.60 (2.9 to 698.1)	12.80 (2.0 to 151.2)	26.10 (4.3 to 156.5)
Year 3 (V3-10)	70.90 (7.5 to 455.7)	112.70 (2.8 to 759.7)	9.85 (1.9 to 181.7)	13.60 (3.3 to 127.8)
EoS	19.00 (2.2 to 372.9)	0 (0 to 0)	9.60 (3.1 to 148.7)	0 (0 to 0)

Notes
[101] - No. of subjects analyzed (selected German sites only): Baseline: 46, Year 2: 43; Year 3: 42; EoS:42
[102] - No. of subjects analyzed (selected German sites only): Baseline: 82; Year 2: 73; Year 3: 73
[103] - No. of subjects analyzed (selected German sites only): Baseline: 22; Year 2: 18; Year 3: 18; EoS:18
[104] - No. of subjects analyzed (selected German sites only): Baseline: 39; Year 2: 35; Year 3: 33

No statistical analyses for this end point

Secondary: Disease-modifying effect After 5 Years

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End point title

Disease-modifying effect After 5 Years

End point description

Only the Mono-sensitized patients continued and completed all 5 years of study duration. Numbers of Mono-sensitized patients who became allergic to other than birch pollen allergen during the study as well as patients who developed asthma or allergic symptoms during the study were evaluated after the 5th pollen season (Year 5). Comparisons between the groups with respect to these disease-modifying effects were performed by means of Fisher’s exact test.

End point type

Secondary

End point timeframe

The results of FAS in Year 5 for the Mono-sensitized patients are presented.

End point values	Mono-sensitized FAS/Depigoid Birch 5000	Mono-sensitized FAS/Placebo
Number of subjects analysed	161	79
Units: subject
Asthmatic - Yes	35	16
Asthmatic - No	126	63
Allergens - Yes	58	24
Allergens - No	103	55

Depigoid Birch vs. placebo (Asthmatic)

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

other ^[105]

P-value

= 0.8675

Method

Fisher exact

Confidence interval

Notes
[105] - Comparisons between the groups with respect to these disease-modifying effects were performed by means of Fisher’s exact test.

Depigoid Birch vs. placebo (Allergens)

Comparison groups

Mono-sensitized FAS/Depigoid Birch 5000 v Mono-sensitized FAS/Placebo

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

other ^[106]

P-value

= 0.4692

Method

Fisher exact

Confidence interval

Notes
[106] - Comparisons between the groups with respect to these disease-modifying effects were performed by means of Fisher’s exact test.

Secondary: Investigator's Global Evaluation

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End point title

Investigator's Global Evaluation

End point description

Both the investigator's global evaluation of efficacy and safety & tolerability were recorded in Year 2, while only the global evaluation of efficacy was recorded at EoS.

End point type

Secondary

End point timeframe

Global evaluation of efficacy and/or safety & tolerability were assessed by the investigator at the end of the 2nd pollen season (Year 2 [V2-10]) for both Mono- and Co-sensitized patients; and at EoS visit (Year 5) for the Mono-sensitized patients

End point values	Mono-sensitized SAF/Depigoid Birch 5000	Co-sensitized SAF/Depigoid Birch 5000	Mono-sensitized SAF/Placebo	Co-sensitized SAF/Placebo
Number of subjects analysed	156 ^[107]	234	74 ^[108]	116
Units: subject
Year 2 - Efficacy/Excellent	28	41	9	22
Year 2 - Efficacy/Good	79	133	28	59
Year 2 - Efficacy/Moderate	29	39	18	21
Year 2 - Efficacy/Insufficient	7	7	8	7
Year 2 - Efficacy/None	1	3	3	0
Year 2 - Efficacy/Missing	12	11	8	7
Year 2 - Safety&Tolerability/Excellent	74	131	29	57
Year 2 - Safety&Tolerability/Good	65	87	35	44
Year 2 - Safety&Tolerability/Moderate	5	3	2	8
Year 2 - Safety&Tolerability/Poor	0	0	0	0
Year 2 - Safety&Tolerability/Unacceptable	0	0	0	0
Year 2 - Safety&Tolerability/Missing	12	13	8	7
EoS - Efficacy/Excellent	29	0	2	0
EoS - Efficacy/Good	65	0	42	0
EoS - Efficacy/Moderate	30	0	15	0
EoS - Efficacy/Insufficient	10	0	13	0
EoS - Efficacy/None	13	0	6	0
EoS - Efficacy/Missing	2	0	0	0

Notes
[107] - No. of subjects analyzed: Year 2: 156; EoS: 174
[108] - No. of subjects analyzed: Year 2: 74; EoS: 85

No statistical analyses for this end point

Secondary: Patient's Global Evaluation

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End point title

Patient's Global Evaluation

End point description

Both the patient's global evaluation of efficacy and safety & tolerability were recorded in Year 2, while only the global evaluation of efficacy was recorded at EoS.

End point type

Secondary

End point timeframe

Global evaluation of efficacy and/or safety & tolerability were assessed by the patient at the end of the 2nd pollen season (Year 2 [V2-10]) for both Mono-sensitized and Co-sensitized patients; and at EoS visit (Year 5) for the Mono-sensitized patients.

End point values	Mono-sensitized SAF/Depigoid Birch 5000	Co-sensitized SAF/Depigoid Birch 5000	Mono-sensitized SAF/Placebo	Co-sensitized SAF/Placebo
Number of subjects analysed	156 ^[109]	234	74 ^[110]	116
Units: subject
Year 2 - Efficacy/Excellent	24	131	29	57
Year 2 - Efficacy/Good	77	87	35	44
Year 2 - Efficacy/Moderate	31	3	2	8
Year 2 - Efficacy/Insufficient	6	0	0	0
Year 2 - Efficacy/None	6	0	0	0
Year 2 - Efficacy/Missing	12	13	8	7
Year 2 - Safety&Tolerability/Excellent	73	110	27	54
Year 2 - Safety&Tolerability/Good	64	99	38	48
Year 2 - Safety&Tolerability/Moderate	7	11	1	7
Year 2 - Safety&Tolerability/Poor	0	1	0	0
Year 2 - Safety&Tolerability/Unacceptable	0	0	0	0
Year 2 - Safety&Tolerability/Missing	12	13	8	7
EoS - Efficacy/Excellent	28	0	8	0
EoS - Efficacy/Good	58	0	32	0
EoS - Efficacy/Moderate	36	0	19	0
EoS - Efficacy/Insufficient	15	0	9	0
EoS - Efficacy/None	10	0	10	0
EoS - Efficacy/Missing	2	0	0	0

Notes
[109] - No. of subjects analyzed: Year 2: 156; EoS: 174
[110] - No. of subjects analyzed: Year 2: 74; EoS: 85

No statistical analyses for this end point

Other pre-specified: Al PK - Plasma concentration

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End point title

Al PK - Plasma concentration

End point description

Because the IMP contains Al(OH)3, the Pediatric Committee has required PK analyses of aluminum. Thus, a PK sub-study was performed to assess the levels of aluminum in plasma and in urine in a subgroup of adult patients. Plasma concentration measurement below the limit of quantification was set to half of the respective value. The results for Year 1-3 were presented for the Al PK set.

End point type

Other pre-specified

End point timeframe

Before the start of treatment (V1-1, within 1h pre-dose), after the first maintenance dose (V1-2) and 1 year of treatment (V1-10). Blood collection for V1-2 and V1-10 was done within 1h pre-dose (0h) and at 1h, 2h, 4h, 8h post-dose.

End point values	Mono- and Co-sensitized Al PK set/Depigoid Birch	Mono- and Co-sensitized Al PK set/Placebo
Number of subjects analysed	32 ^[111]	15 ^[112]
Units: μg/L
arithmetic mean (full range (min-max))
V1-1	2.097 (1.617 to 7.547)	1.725 (1.617 to 3.235)
V1-2 (0h)	1.887 (1.617 to 5.930)	2.224 (1.617 to 5.391)
V1-2 (1h)	1.775 (1.617 to 6.199)	2.241 (1.617 to 5.121)
V1-2 (2h)	1.989 (1.617 to 8.356)	2.089 (1.617 to 5.930)
V1-2 (4h)	11.284 (1.617 to 278.437)	2.055 (1.617 to 5.660)
V1-2 (8h)	2.045 (1.617 to 7.817)	3.319 (1.617 to 24.259)
V1-10 (0h)	2.408 (1.617 to 7.547)	2.041 (1.617 to 5.391)
V1-10 (1h)	1.991 (1.617 to 5.930)	1.868 (1.617 to 5.121)
V1-10 (2h)	2.278 (1.617 to 7.547)	2.156 (1.617 to 4.852)
V1-10 (4h)	2.191 (1.617 to 7.008)	2.041 (1.617 to 3.774)
V1-10 (8h)	2.617 (1.617 to 9.164)	2.176 (1.617 to 6.739)

Notes
[111] - No. of subjects analyzed: V1-1: 32; V1-2: 29; V1-10: 31
[112] - No. of subjects analyzed: V1-1: 15; V1-2: 16; V1-10: 14

No statistical analyses for this end point

Other pre-specified: Al PK - Plasma Concentration/Change from baseline

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End point title

Al PK - Plasma Concentration/Change from baseline

End point description

The absolute changes were calculated as the difference between the baseline value and the value reported at the corresponding visit and time point. The measurement at V1-1 was the baseline. The results for Year 1 to 3 were presented for the Al PK set.

End point type

Other pre-specified

End point timeframe

The absolute changes from baseline at each visit (V1-2 and V1-10) and time point (pre-dose [0h], then 1h, 2h, 4h, and 8h post-dose).

End point values	Mono- and Co-sensitized Al PK set/Depigoid Birch	Mono- and Co-sensitized Al PK set/Placebo
Number of subjects analysed	29 ^[113]	15 ^[114]
Units: μg/L
arithmetic mean (full range (min-max))
V1-2 (0h)	-0.260 (-4.313 to 3.504)	0.539 (-1.617 to 3.774)
V1-2 (1h)	-0.372 (-5.930 to 4.582)	0.557 (-1.617 to 3.504)
V1-2 (2h)	-0.158 (-5.930 to 6.739)	0.395 (-1.617 to 4.313)
V1-2 (4h)	9.137 (-4.313 to 276.820)	0.359 (-1.617 to 4.043)
V1-2 (8h)	-0.102 (-4.313 to 1.887)	1.707 (-1.617 to 22.642)
V1-10 (0h)	0.296 (-4.313 to 5.930)	0.166 (0 to 2.156)
V1-10 (1h)	-0.122 (-4.313 to 4.313)	0 (0 to 0)
V1-10 (2h)	0.165 (-4.313 to 4.043)	0.332 (0 to 2.156)
V1-10 (4h)	0.078 (-2.156 to 2.695)	0.290 (0 to 1.887)
V1-10 (8h)	0.504 (-4.313 to 7.547)	0.394 (0 to 5.121)

Notes
[113] - No. of subjects analyzed: V1-2: 29; V1-10: 31
[114] - No. of subjects analyzed: V1-2: 15; V1-10: 13

No statistical analyses for this end point

Other pre-specified: Al PK - Urine Concentration

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End point title

Al PK - Urine Concentration

End point description

Because the IMP contains Al(OH)3, the Pediatric Committee has required PK analyses of aluminum. Thus, a PK sub-study was performed to assess the levels of aluminum in plasma and in urine in a subgroup of adult patients. The results for Year 1 to 3 were presented for the Al PK set. Data of analysis for samples collected post-dose only (excluding cases in which urine sampling was performed before IMP administration at a visit) are presented here.

End point type

Other pre-specified

End point timeframe

Before the start of treatment (V1-1, over 24 hours before administration of IMP), V1-2 and V1-10 (both over 24 hours beginning from administration of IMP).

End point values	Mono- and Co-sensitized Al PK set/Depigoid Birch	Mono- and Co-sensitized Al PK set/Placebo
Number of subjects analysed	27 ^[115]	15 ^[116]
Units: μg/L
arithmetic mean (full range (min-max))
V1-2	10.542 (2.16 to 58.76)	9.775 (2.43 to 32.61)
V1-10	13.333 (5.93 to 28.84)	15.402 (7.28 to 46.63)

Notes
[115] - No. of subjects analyzed: V1-2: 27; V1-10: 28
[116] - No. of subjects analyzed: V1-2: 15; V1-10: 14

No statistical analyses for this end point

Other pre-specified: Al PK - Urine Concentration/Change from baseline

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End point title

Al PK - Urine Concentration/Change from baseline

End point description

At V1-2 and V1-10, assessments for urine samples from sampling started prior to IMP administration were excluded and were analyzed as missing values. The absolute changes were calculated as the difference between the baseline value and the value reported at the corresponding visit. The measurement at V1-1 was the baseline. The results for Year 1 to 3 were presented for the Al PK set.

End point type

Other pre-specified

End point timeframe

The absolute changes from baseline at each post-dose visit (V1-2 and V1-10).

End point values	Mono- and Co-sensitized Al PK set/Depigoid Birch	Mono- and Co-sensitized Al PK set/Placebo
Number of subjects analysed	26 ^[117]	15 ^[118]
Units: μg/L
arithmetic mean (full range (min-max))
V1-2	1.825 (-23.18 to 56.33)	-1.707 (-37.20 to 24.53)
V1-10	4.813 (-13.21 to 22.64)	3.292 (-27.76 to 37.47)

Notes
[117] - No. of subjects analyzed: V1-2: 26; V1-10: 28
[118] - No. of subjects analyzed: V1-2: 15; V1-10: 14

No statistical analyses for this end point

Other pre-specified: Al PK - Plasma Concentration/Cmax

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End point title

Al PK - Plasma Concentration/Cmax

End point description

PK parameters (Cmax, Tmax, AUC[0-8h]) were derived by non-compartmental analysis at V1-2 and V1-10 using Phoenix WinNonlinTM Software Version 6.3 (Pharsight Corporation, Mountain View, CA 94041-1530, USA). AUC was derived using the (linear) trapezoidal rule. If all aluminum concentration data obtained for a patient were below the limit of quantification at V1-2 or visit V1-10, the AUC was presented as “not determined”. The PK parameters were derived using actual time points (i.e. calculated actual time of sample collection relative to administration time of IMP). Samples that were taken prior to administration of IMP were considered as to be collected at time zero. The results for Year 1 to 3 were presented for the Al PK set.

End point type

Other pre-specified

End point timeframe

The PK parameters were calculated for V1-2 and V1-10.

End point values	Mono- and Co-sensitized Al PK set/Depigoid Birch	Mono- and Co-sensitized Al PK set/Placebo
Number of subjects analysed	29 ^[119]	16 ^[120]
Units: μg/L
arithmetic mean (full range (min-max))
V1-2	12.120 (1.617 to 278.437)	4.279 (1.617 to 24.259)
V1-10	3.165 (1.617 to 9.164)	2.407 (1.617 to 6.739)

Notes
[119] - No. of subjects analyzed: V1-2: 29; V1-10: 31
[120] - No. of subjects analyzed: V1-2: 16; V1-10: 14

No statistical analyses for this end point

Other pre-specified: Al PK - Plasma Concentration/Tmax

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End point title

Al PK - Plasma Concentration/Tmax

End point description

End point type

Other pre-specified

End point timeframe

The PK parameters were calculated for V1-2 and V1-10.

End point values	Mono- and Co-sensitized Al PK set/Depigoid Birch	Mono- and Co-sensitized Al PK set/Placebo
Number of subjects analysed	29 ^[121]	16 ^[122]
Units: hour
arithmetic mean (full range (min-max))
V1-2	1.481 (0 to 8.02)	1.063 (0 to 8.00)
V1-10	1.258 (0 to 8.00)	0.714 (0 to 8.00)

Notes
[121] - No. of subjects analyzed: V1-2: 29; V1-10: 31
[122] - No. of subjects analyzed: V1-2: 16; V1-10: 14

No statistical analyses for this end point

Other pre-specified: Al PK - Plasma Concentration/AUC[0-8h]

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End point title

Al PK - Plasma Concentration/AUC[0-8h]

End point description

End point type

Other pre-specified

End point timeframe

The PK parameters were calculated for V1-2 and V1-10.

End point values	Mono- and Co-sensitized Al PK set/Depigoid Birch	Mono- and Co-sensitized Al PK set/Placebo
Number of subjects analysed	9 ^[123]	7 ^[124]
Units: hour.μg/L
arithmetic mean (full range (min-max))
V1-2	111.875 (15.50 to 845.43)	27.455 (14.82 to 58.22)
V1-10	27.129 (15.36 to 53.88)	30.009 (21.83 to 35.04)

Notes
[123] - No. of subjects analyzed: V1-2: 9; V1-10: 12
[124] - No. of subjects analyzed: V1-2: 7; V1-10: 3

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs were collected from signing of the informed consent until the end of the study (Year 5). Only treatment-emergent AEs (TEAEs) (AEs that started or worsened after first dose of the IMP) reported from V1 until the end-of-study (EoS) visit were analyzed.

Adverse event reporting additional description

Systemic reactions (SR, according to the EAACI grading criteria) and local reactions (LR, according to induration [wheal] size as determined by the largest diameter of the wheal, itching, and pain) were additionally analyzed as separate categories, and are presented here as part of the TEAEs analysis.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Mono-sensitized Year 1-5/Depigoid Birch

Reporting group description

The Mono-sensitized SAF patients who received at least one dose of Depigoid Birch were analyzed for adverse events. Overall TEAEs over all 5 years of the study period are reported in this section.

Reporting group title

Mono-sensitized Year 1-5/Placebo

Reporting group description

The Mono-sensitized SAF patients who received at least one dose of placebo were analyzed for adverse events. Overall TEAEs over all 5 years of the study period are reported in this section.

Reporting group title

Overall Mono-sensitized Year 1-5

Reporting group description

All Mono-sensitized SAF patients who received at least one dose of Depigoid Birch or placebo were analyzed for adverse events. Overall TEAEs over all 5 years of the study period are reported in this section.

Reporting group title

Co-sensitized Year 1-3/Depigoid Birch

Reporting group description

The Co-sensitized SAF patients who received at least one dose of Depigoid Birch were analyzed for adverse events. Overall TEAEs for 3 years (treatment phase only) of the study period are reported in this section.

Reporting group title

Co-sensitized Year 1-3/Placebo

Reporting group description

The Co-sensitized SAF patients who received at least one dose of placebo were analyzed for adverse events. Overall TEAEs for 3 years (treatment phase only) of the study period are reported in this section.

Reporting group title

Overall Co-sensitized Year 1-3

Reporting group description

All Co-sensitized SAF patients who received at least one dose of Depigoid Birch or placebo were analyzed for adverse events. Overall TEAEs for 3 years (treatment phase only) of the study period are reported in this section.

Serious adverse events	Mono-sensitized Year 1-5/Depigoid Birch	Mono-sensitized Year 1-5/Placebo	Overall Mono-sensitized Year 1-5	Co-sensitized Year 1-3/Depigoid Birch	Co-sensitized Year 1-3/Placebo	Overall Co-sensitized Year 1-3
Total subjects affected by serious adverse events
subjects affected / exposed	14 / 174 (8.05%)	7 / 85 (8.24%)	21 / 259 (8.11%)	30 / 260 (11.54%)	14 / 130 (10.77%)	44 / 390 (11.28%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	0 / 174 (0.00%)	1 / 85 (1.18%)	1 / 259 (0.39%)	1 / 260 (0.38%)	1 / 130 (0.77%)	2 / 390 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fallopian tube cancer stage III
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Hypertension
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	2 / 260 (0.77%)	0 / 130 (0.00%)	2 / 390 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemia
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Atrial septal defect repair
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Haemorrhoid operation
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Mitral valve repair
subjects affected / exposed	0 / 174 (0.00%)	1 / 85 (1.18%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Rehabilitation therapy
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Abortion induced
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	2 / 260 (0.77%)	0 / 130 (0.00%)	2 / 390 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bunion operation
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystectomy
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	2 / 260 (0.77%)	0 / 130 (0.00%)	2 / 390 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colporrhaphy
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc operation
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus removal
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal septal operation
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Removal of internal fixation
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine dilation and curettage
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine prolapse repair
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Twin pregnancy
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Foetal death
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	1 / 130 (0.77%)	2 / 390 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hernia
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	1 / 174 (0.57%)	1 / 85 (1.18%)	2 / 259 (0.77%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	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
Endometriosis
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Testicular pain
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Major depression
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Investigations
Arteriogram coronary
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Accident
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenic rupture
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Atrial septal defect
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 174 (0.00%)	1 / 85 (1.18%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Atrial flutter
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Hemiparesis
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Hypoaesthesia
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Loss of consciousness
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Speech disorder
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Sciatica
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Sudden hearing loss
subjects affected / exposed	0 / 174 (0.00%)	1 / 85 (1.18%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Eye disorders
Visual impairment
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal adhesions
subjects affected / exposed	0 / 174 (0.00%)	1 / 85 (1.18%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Abdominal pain upper
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Anal fissure
subjects affected / exposed	0 / 174 (0.00%)	1 / 85 (1.18%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Diarrhoea
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Haemorrhoidal haemorrhage
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Colitis ulcerative
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	2 / 260 (0.77%)	0 / 130 (0.00%)	2 / 390 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Cholestasis of pregnancy
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Skin and subcutaneous tissue disorders
Drug eruption
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Micturition urgency
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Spinal column stenosis
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Intervertebral disc protrusion
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	3 / 260 (1.15%)	0 / 130 (0.00%)	3 / 390 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	2 / 260 (0.77%)	0 / 130 (0.00%)	2 / 390 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Anal abscess
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Chronic hepatitis C
subjects affected / exposed	0 / 174 (0.00%)	1 / 85 (1.18%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Influenza
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Appendicitis
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	2 / 260 (0.77%)	1 / 130 (0.77%)	3 / 390 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	1 / 130 (0.77%)	2 / 390 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious mononucleosis
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	0 / 260 (0.00%)	1 / 130 (0.77%)	1 / 390 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Mono-sensitized Year 1-5/Depigoid Birch	Mono-sensitized Year 1-5/Placebo	Overall Mono-sensitized Year 1-5	Co-sensitized Year 1-3/Depigoid Birch	Co-sensitized Year 1-3/Placebo	Overall Co-sensitized Year 1-3
Total subjects affected by non serious adverse events
subjects affected / exposed	149 / 174 (85.63%)	67 / 85 (78.82%)	216 / 259 (83.40%)	216 / 260 (83.08%)	104 / 130 (80.00%)	320 / 390 (82.05%)
Vascular disorders
Essential hypertension
subjects affected / exposed	0 / 174 (0.00%)	2 / 85 (2.35%)	2 / 259 (0.77%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences all number	0	2	2	0	0	0
Hypertension
subjects affected / exposed	6 / 174 (3.45%)	5 / 85 (5.88%)	11 / 259 (4.25%)	15 / 260 (5.77%)	1 / 130 (0.77%)	16 / 390 (4.10%)
occurrences all number	7	5	12	15	2	17
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	28 / 174 (16.09%)	9 / 85 (10.59%)	37 / 259 (14.29%)	36 / 260 (13.85%)	14 / 130 (10.77%)	50 / 390 (12.82%)
occurrences all number	79	36	115	106	33	139
Injection site nodule
subjects affected / exposed	4 / 174 (2.30%)	1 / 85 (1.18%)	5 / 259 (1.93%)	4 / 260 (1.54%)	3 / 130 (2.31%)	7 / 390 (1.79%)
occurrences all number	4	1	5	5	4	9
Injection site oedema
subjects affected / exposed	6 / 174 (3.45%)	5 / 85 (5.88%)	11 / 259 (4.25%)	12 / 260 (4.62%)	4 / 130 (3.08%)	16 / 390 (4.10%)
occurrences all number	8	11	19	19	4	23
Injection site pain
subjects affected / exposed	7 / 174 (4.02%)	3 / 85 (3.53%)	10 / 259 (3.86%)	4 / 260 (1.54%)	5 / 130 (3.85%)	9 / 390 (2.31%)
occurrences all number	9	18	27	4	19	23
Injection site papule
subjects affected / exposed	2 / 174 (1.15%)	0 / 85 (0.00%)	2 / 259 (0.77%)	7 / 260 (2.69%)	1 / 130 (0.77%)	8 / 390 (2.05%)
occurrences all number	2	0	2	9	1	10
Injection site pruritus
subjects affected / exposed	18 / 174 (10.34%)	2 / 85 (2.35%)	20 / 259 (7.72%)	16 / 260 (6.15%)	6 / 130 (4.62%)	22 / 390 (5.64%)
occurrences all number	71	2	73	47	19	66
Injection site reaction
subjects affected / exposed	42 / 174 (24.14%)	11 / 85 (12.94%)	53 / 259 (20.46%)	63 / 260 (24.23%)	19 / 130 (14.62%)	82 / 390 (21.03%)
occurrences all number	145	72	217	299	122	421
Injection site swelling
subjects affected / exposed	10 / 174 (5.75%)	4 / 85 (4.71%)	14 / 259 (5.41%)	13 / 260 (5.00%)	12 / 130 (9.23%)	25 / 390 (6.41%)
occurrences all number	37	7	44	39	23	62
Injection site urticaria
subjects affected / exposed	2 / 174 (1.15%)	1 / 85 (1.18%)	3 / 259 (1.16%)	9 / 260 (3.46%)	3 / 130 (2.31%)	12 / 390 (3.08%)
occurrences all number	31	1	32	41	19	60
Pyrexia
subjects affected / exposed	4 / 174 (2.30%)	1 / 85 (1.18%)	5 / 259 (1.93%)	3 / 260 (1.15%)	1 / 130 (0.77%)	4 / 390 (1.03%)
occurrences all number	4	1	5	4	1	5
Immune system disorders
Hypersensitivity
subjects affected / exposed	5 / 174 (2.87%)	1 / 85 (1.18%)	6 / 259 (2.32%)	4 / 260 (1.54%)	1 / 130 (0.77%)	5 / 390 (1.28%)
occurrences all number	5	1	6	4	1	5
Respiratory, thoracic and mediastinal disorders
Allergic cough
subjects affected / exposed	0 / 174 (0.00%)	2 / 85 (2.35%)	2 / 259 (0.77%)	0 / 260 (0.00%)	0 / 130 (0.00%)	0 / 390 (0.00%)
occurrences all number	0	2	2	0	0	0
Asthma
subjects affected / exposed	17 / 174 (9.77%)	11 / 85 (12.94%)	28 / 259 (10.81%)	27 / 260 (10.38%)	14 / 130 (10.77%)	41 / 390 (10.51%)
occurrences all number	19	12	31	31	16	47
Cough
subjects affected / exposed	11 / 174 (6.32%)	7 / 85 (8.24%)	18 / 259 (6.95%)	10 / 260 (3.85%)	7 / 130 (5.38%)	17 / 390 (4.36%)
occurrences all number	12	9	21	11	9	17
Dyspnoea
subjects affected / exposed	5 / 174 (2.87%)	5 / 85 (5.88%)	10 / 259 (3.86%)	4 / 260 (1.54%)	4 / 130 (3.08%)	8 / 390 (2.05%)
occurrences all number	8	7	15	4	6	10
Epistaxis
subjects affected / exposed	4 / 174 (2.30%)	0 / 85 (0.00%)	4 / 259 (1.54%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences all number	4	0	4	1	0	1
Nasal congestion
subjects affected / exposed	1 / 174 (0.57%)	2 / 85 (2.35%)	3 / 259 (1.16%)	4 / 260 (1.54%)	4 / 130 (3.08%)	8 / 390 (2.05%)
occurrences all number	1	4	5	4	4	8
Oropharyngeal pain
subjects affected / exposed	4 / 174 (2.30%)	0 / 85 (0.00%)	4 / 259 (1.54%)	7 / 260 (2.69%)	4 / 130 (3.08%)	11 / 390 (2.82%)
occurrences all number	4	0	4	7	4	11
Rhinitis allergic
subjects affected / exposed	4 / 174 (2.30%)	3 / 85 (3.53%)	7 / 259 (2.70%)	8 / 260 (3.08%)	5 / 130 (3.85%)	13 / 390 (3.33%)
occurrences all number	6	4	10	9	7	16
Rhinorrhoea
subjects affected / exposed	5 / 174 (2.87%)	2 / 85 (2.35%)	7 / 259 (2.70%)	8 / 260 (3.08%)	5 / 130 (3.85%)	13 / 390 (3.33%)
occurrences all number	6	2	8	12	6	18
Sneezing
subjects affected / exposed	2 / 174 (1.15%)	3 / 85 (3.53%)	5 / 259 (1.93%)	3 / 260 (1.15%)	1 / 130 (0.77%)	4 / 390 (1.03%)
occurrences all number	2	3	5	4	1	5
Psychiatric disorders
Depression
subjects affected / exposed	1 / 174 (0.57%)	1 / 85 (1.18%)	2 / 259 (0.77%)	1 / 260 (0.38%)	3 / 130 (2.31%)	4 / 390 (1.03%)
occurrences all number	1	1	2	1	3	4
Investigations
Forced expiratory volume decreased
subjects affected / exposed	17 / 174 (9.77%)	8 / 85 (9.41%)	25 / 259 (9.65%)	29 / 260 (11.15%)	9 / 130 (6.92%)	38 / 390 (9.74%)
occurrences all number	53	32	85	51	22	73
Peak expiratory flow rate decreased
subjects affected / exposed	20 / 174 (11.49%)	17 / 85 (20.00%)	37 / 259 (14.29%)	24 / 260 (9.23%)	18 / 130 (13.85%)	42 / 390 (10.77%)
occurrences all number	71	30	101	61	39	100
Pulmonary function test decreased
subjects affected / exposed	2 / 174 (1.15%)	3 / 85 (3.53%)	5 / 259 (1.93%)	9 / 260 (3.46%)	3 / 130 (2.31%)	12 / 390 (3.08%)
occurrences all number	2	3	5	16	5	21
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	3 / 260 (1.15%)	3 / 130 (2.31%)	6 / 390 (1.54%)
occurrences all number	1	0	1	3	3	6
Hand fracture
subjects affected / exposed	1 / 174 (0.57%)	1 / 85 (1.18%)	2 / 259 (0.77%)	3 / 260 (1.15%)	2 / 130 (1.54%)	5 / 390 (1.28%)
occurrences all number	1	1	2	3	2	5
Ligament sprain
subjects affected / exposed	1 / 174 (0.57%)	0 / 85 (0.00%)	1 / 259 (0.39%)	6 / 260 (2.31%)	1 / 130 (0.77%)	7 / 390 (1.79%)
occurrences all number	1	0	1	6	1	7
Nervous system disorders
Headache
subjects affected / exposed	8 / 174 (4.60%)	3 / 85 (3.53%)	11 / 259 (4.25%)	5 / 260 (1.92%)	9 / 130 (6.92%)	14 / 390 (3.59%)
occurrences all number	17	6	23	9	13	22
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 174 (0.00%)	2 / 85 (2.35%)	2 / 259 (0.77%)	2 / 260 (0.77%)	1 / 130 (0.77%)	3 / 390 (0.77%)
occurrences all number	0	2	2	2	1	3
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	4 / 174 (2.30%)	2 / 85 (2.35%)	6 / 259 (2.32%)	0 / 260 (0.00%)	2 / 130 (1.54%)	2 / 390 (0.51%)
occurrences all number	4	2	6	0	2	2
Vertigo
subjects affected / exposed	4 / 174 (2.30%)	1 / 85 (1.18%)	5 / 259 (1.93%)	1 / 260 (0.38%)	1 / 130 (0.77%)	2 / 390 (0.51%)
occurrences all number	7	1	8	1	2	3
Eye disorders
Conjunctivitis allergic
subjects affected / exposed	9 / 174 (5.17%)	6 / 85 (7.06%)	15 / 259 (5.79%)	19 / 260 (7.31%)	6 / 130 (4.62%)	25 / 390 (6.41%)
occurrences all number	12	6	18	19	6	25
Eye pruritus
subjects affected / exposed	4 / 174 (2.30%)	4 / 85 (4.71%)	8 / 259 (3.09%)	12 / 260 (4.62%)	4 / 130 (3.08%)	16 / 390 (4.10%)
occurrences all number	6	7	13	21	7	28
Gastrointestinal disorders
Dyspepsia
subjects affected / exposed	5 / 174 (2.87%)	0 / 85 (0.00%)	5 / 259 (1.93%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences all number	5	0	5	1	0	1
Gastritis
subjects affected / exposed	4 / 174 (2.30%)	2 / 85 (2.35%)	6 / 259 (2.32%)	4 / 260 (1.54%)	4 / 130 (3.08%)	8 / 390 (2.05%)
occurrences all number	4	2	6	4	4	8
Gastrooesophageal reflux disease
subjects affected / exposed	4 / 174 (2.30%)	2 / 85 (2.35%)	6 / 259 (2.32%)	5 / 260 (1.92%)	2 / 130 (1.54%)	7 / 390 (1.79%)
occurrences all number	4	2	6	5	2	7
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 174 (0.00%)	2 / 85 (2.35%)	2 / 259 (0.77%)	1 / 260 (0.38%)	4 / 130 (3.08%)	5 / 390 (1.28%)
occurrences all number	0	2	2	1	4	5
Eczema
subjects affected / exposed	3 / 174 (1.72%)	1 / 85 (1.18%)	4 / 259 (1.54%)	14 / 260 (5.38%)	1 / 130 (0.77%)	15 / 390 (3.85%)
occurrences all number	5	1	6	16	1	17
Urticaria
subjects affected / exposed	7 / 174 (4.02%)	2 / 85 (2.35%)	9 / 259 (3.47%)	7 / 260 (2.69%)	2 / 130 (1.54%)	9 / 390 (2.31%)
occurrences all number	11	2	13	7	2	9
Endocrine disorders
Hypothyroidism
subjects affected / exposed	4 / 174 (2.30%)	2 / 85 (2.35%)	6 / 259 (2.32%)	2 / 260 (0.77%)	1 / 130 (0.77%)	3 / 390 (0.77%)
occurrences all number	4	2	6	2	1	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 174 (4.02%)	1 / 85 (1.18%)	8 / 259 (3.09%)	4 / 260 (1.54%)	1 / 130 (0.77%)	5 / 390 (1.28%)
occurrences all number	7	1	8	4	1	5
Back pain
subjects affected / exposed	13 / 174 (7.47%)	4 / 85 (4.71%)	17 / 259 (6.56%)	15 / 260 (5.77%)	4 / 130 (3.08%)	19 / 390 (4.87%)
occurrences all number	14	5	19	27	6	33
Intervertebral disc protrusion
subjects affected / exposed	0 / 174 (0.00%)	2 / 85 (2.35%)	2 / 259 (0.77%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences all number	0	2	2	1	0	1
Infections and infestations
Acute sinusitis
subjects affected / exposed	1 / 174 (0.57%)	1 / 85 (1.18%)	2 / 259 (0.77%)	3 / 260 (1.15%)	3 / 130 (2.31%)	6 / 390 (1.54%)
occurrences all number	1	1	2	5	3	8
Bronchitis
subjects affected / exposed	12 / 174 (6.90%)	9 / 85 (10.59%)	21 / 259 (8.11%)	22 / 260 (8.46%)	10 / 130 (7.69%)	32 / 390 (8.21%)
occurrences all number	12	12	24	28	12	40
Conjunctivitis
subjects affected / exposed	8 / 174 (4.60%)	3 / 85 (3.53%)	11 / 259 (4.25%)	11 / 260 (4.23%)	9 / 130 (6.92%)	20 / 390 (5.13%)
occurrences all number	11	3	14	12	11	23
Gastroenteritis
subjects affected / exposed	10 / 174 (5.75%)	3 / 85 (3.53%)	13 / 259 (5.02%)	9 / 260 (3.46%)	5 / 130 (3.85%)	14 / 390 (3.59%)
occurrences all number	13	3	16	12	7	19
Influenza
subjects affected / exposed	9 / 174 (5.17%)	3 / 85 (3.53%)	12 / 259 (4.63%)	4 / 260 (1.54%)	3 / 130 (2.31%)	7 / 390 (1.79%)
occurrences all number	9	3	12	4	5	9
Laryngitis
subjects affected / exposed	0 / 174 (0.00%)	3 / 85 (3.53%)	3 / 259 (1.16%)	1 / 260 (0.38%)	0 / 130 (0.00%)	1 / 390 (0.26%)
occurrences all number	0	3	3	1	0	1
Nasopharyngitis
subjects affected / exposed	62 / 174 (35.63%)	15 / 85 (17.65%)	77 / 259 (29.73%)	56 / 260 (21.54%)	33 / 130 (25.38%)	89 / 390 (22.82%)
occurrences all number	129	26	155	96	64	160
Pharyngitis
subjects affected / exposed	14 / 174 (8.05%)	5 / 85 (5.88%)	19 / 259 (7.34%)	17 / 260 (6.54%)	10 / 130 (7.69%)	27 / 390 (6.92%)
occurrences all number	19	8	27	18	11	29
Pneumonia
subjects affected / exposed	0 / 174 (0.00%)	0 / 85 (0.00%)	0 / 259 (0.00%)	1 / 260 (0.38%)	3 / 130 (2.31%)	4 / 390 (1.03%)
occurrences all number	0	0	0	1	3	4
Respiratory tract infection
subjects affected / exposed	6 / 174 (3.45%)	4 / 85 (4.71%)	10 / 259 (3.86%)	16 / 260 (6.15%)	7 / 130 (5.38%)	23 / 390 (5.90%)
occurrences all number	9	6	15	28	11	39
Respiratory tract infection viral
subjects affected / exposed	3 / 174 (1.72%)	2 / 85 (2.35%)	5 / 259 (1.93%)	11 / 260 (4.23%)	3 / 130 (2.31%)	14 / 390 (3.59%)
occurrences all number	3	2	5	16	4	20
Rhinitis
subjects affected / exposed	7 / 174 (4.02%)	5 / 85 (5.88%)	12 / 259 (4.63%)	8 / 260 (3.08%)	6 / 130 (4.62%)	14 / 390 (3.59%)
occurrences all number	8	7	15	8	10	18
Sinusitis
subjects affected / exposed	8 / 174 (4.60%)	4 / 85 (4.71%)	12 / 259 (4.63%)	15 / 260 (5.77%)	6 / 130 (4.62%)	21 / 390 (5.38%)
occurrences all number	9	9	18	18	7	25
Tonsillitis
subjects affected / exposed	10 / 174 (5.75%)	4 / 85 (4.71%)	14 / 259 (5.41%)	15 / 260 (5.77%)	3 / 130 (2.31%)	18 / 390 (4.62%)
occurrences all number	11	5	16	17	3	20
Upper respiratory tract infection
subjects affected / exposed	6 / 174 (3.45%)	4 / 85 (4.71%)	10 / 259 (3.86%)	17 / 260 (6.54%)	8 / 130 (6.15%)	25 / 390 (6.41%)
occurrences all number	6	5	11	22	9	31
Urinary tract infection
subjects affected / exposed	5 / 174 (2.87%)	0 / 85 (0.00%)	5 / 259 (1.93%)	6 / 260 (2.31%)	3 / 130 (2.31%)	9 / 390 (2.31%)
occurrences all number	7	0	7	8	4	12
Viral infection
subjects affected / exposed	4 / 174 (2.30%)	0 / 85 (0.00%)	4 / 259 (1.54%)	5 / 260 (1.92%)	3 / 130 (2.31%)	8 / 390 (2.05%)
occurrences all number	4	0	4	6	3	9

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Were there any global substantial amendments to the protocol? Yes

06 Sep 2012

The global protocol amendment No. 1 was conducted in accordance with the changes requested by German Competent Authorities and the Central EC in Germany. The main changes include: 1. Modification of a few inclusion/exclusion criteria for precise formulation and thereby enhanced patient’s safety. 2. Further clarifications and/or modifications of some study procedures, including: a. Added requirement for venous access prior to administration of IMP in the rush build-up phase b. Adaptations in the escalation scheme for RM c. Added instructions to investigators for recording data in eCRF d. Added assessments of patients’ asthma status, vitamin D in blood, SPT at EoS e. Modified definitions of AE causality categories f. Modifications in the schedule of PK blood sampling g. Added definition for futility analysis population h. Clarifications for PFT scheduling, definition of topical corticosteroids as RM, time window for collection of medical history data, negative SPT control, timing of RQLQ assessments, observation period for AEs, and scoring of SMS (also including asthmatic patients)

30 Nov 2012

This global amendment No. 2 was implemented in the protocol at the request of the sponsor. The main changes include: 1. Extension of patients’ recruitment period (the first recruitment period lasted 3 to 4 months starting September 2012 and the newly added recruitment period was planned to start after termination of birch pollen season 2013 and until December 2013). 2. Extension of the SCR period (from up to 4 weeks to up to 8 weeks). 3. Added clarifications of inclusion criteria No. 9 and 10, and modification of exclusion criterion No. 20 regarding prior use of psychoactive drugs 4. Further specifications on mid-season visit scheduling with respect to birch pollen season 5. Clarifications on the use of permitted RMs and procedures for recording information about RMs 6. Minor modification to type of psychoactive drugs considered prohibited concomitant medication. 7. The PK sub-study was not any longer specified to German sites only. 8. The statistical analysis for futility was further specified.

11 Jul 2013

This global amendment No. 3 was implemented at the request of the sponsor and partly requested by the Paul-Ehrlich-Institut (PEI, German Competent Authority) due to the extended recruitment period that had already been approved with the global amendment No. 2. The main changes include: 1. Adding the number of screened patients needed to attain the required number of randomized patients for statistical analyses. 2. Further specifications/modifications of two exclusion criteria (No. 10 - SCORAD cut off was increased from 30 to 40; No. 19 - “parenthesis” was added) 3. Correction of a typo in the escalation scheme for inhaled corticosteroids 4. The description of primary and futility analyses was adapted due to the addition of a second recruitment period as requested by the PEI, Germany 5. Adding clarifications for handling of AdolRQLQ

11 Oct 2016

This global protocol amendment No. 4 was prepared at the request of the sponsor and submitted to the ECs in Czech Republic, Germany, Latvia, Lithuania, and Poland. In Russia, the protocol amendment was implemented in protocol version 3.0 for Russia, dated 13-OCT-2016, and was submitted for approval as well. Before receiving response from any of the ECs, the sponsor decided to withdraw the global amendment. The reason for withdrawal was the need of additional changes to the protocol based on recommendations of the DMC to continue the study with Mono-sensitized patients only. Thus, all changes in the protocol included in global amendment No. 4 were included in the global amendment No. 5.

11 Jan 2017

This global protocol amendment No.5 was prepared to implement changes in the study conduct following from DMC recommendations based on results of the planned 2nd-year interim analysis and additional analyses of 3rd-year data and post-hoc analyses. The main changes include: 1. Only patients who turned out to be mono-sensitized to birch according to the SPT at SCR could continue participating in the study; the remaining, co-sensitized, patients had to be withdrawn from the study. This decision was supported by the results of the planned 2nd-year interim analysis, the additional analyses of 3rd-year data and the post-hoc analyses of 2nd and 3rd year data performed by the DMC. 2. Cancelation of the planned 3rd- year futility analysis 3. A new stopping rule for individual patients was added: Patients with any co-sensitization documented at SCR according to the SPT were to be withdrawn from the study 4. Immunoblotting analysis of Alnus and Corylus was added for patients who had blood samples still available on storage in the central laboratory 5. Addition of analysis of immediate and delayed SRs

28 Feb 2017

This global amendment No. 6 was prepared at the request of the German Authority PEI and the sponsor and aimed to introduce the following changes in the conduct of the study: 1. Scheduling of a post-study visit for all co-sensitized patients that had to be withdrawn from the study (requested by the PEI) 2. Clarification on additional laboratory evaluations for co-sensitized patients at EoS visit (including hematology, clinical chemistry investigations, serum pregnancy test, vitamin D, immunology parameters and immunoblotting. An immunoblot analysis of birch (Betula) was added to enable comparisons with results of Alnus and Corylus testing at EoS visit

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.

Due to withdrawal of the Co-sensitized patients from the study, only the complete data for Year 1-3 were available for analysis in this arm. Data analysis for Year 1-5 was only done for a subset of Co-sensitized patients who completed Year 4-5.

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Clinical trials

Clinical Trial Results: Multicenter, placebo-controlled, long-term study of Depigoid Birch 5000 in adults and adolescents with allergic rhinitis and/or rhinoconjunctivitis with or without intermittent asthma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean integrated Symptoms and Medication Score (SMS)

Primary: Mean integrated Symptoms and Medication Score (SMS)

Secondary: Mean Integrated Symptoms and Medication Score (SMS) (0-6)

Secondary: Mean Integrated Symptoms and Medication Score (SMS) (0-6)

Secondary: Mean Integrated Symptom Score (SS)

Secondary: Mean Integrated Symptom Score (SS)

Secondary: Mean Integrated Rescue Medication Score (RMS)

Secondary: Mean Integrated Rescue Medication Score (RMS)

Secondary: Mean Integrated Combined Symptom Medication Score (SMS)

Secondary: Mean Integrated Combined Symptom Medication Score (SMS)

Secondary: Mean Integrated Asthmatic Rescue Medication Score (RMS)

Secondary: Mean Integrated Asthmatic Rescue Medication Score (RMS)

Secondary: Number of Well Days and Hell Days

Secondary: Number of Well Days and Hell Days

Secondary: Immunology - Specific IgE

Secondary: Immunology - Specific IgE

Secondary: Immunology - Specific IgG1

Secondary: Immunology - Specific IgG1

Secondary: Immunology - Specific IgG4

Secondary: Immunology - Specific IgG4

Secondary: Disease-modifying effect After 5 Years

Secondary: Disease-modifying effect After 5 Years

Secondary: Investigator's Global Evaluation

Secondary: Investigator's Global Evaluation

Secondary: Patient's Global Evaluation

Secondary: Patient's Global Evaluation

Other pre-specified: Al PK - Plasma concentration

Other pre-specified: Al PK - Plasma concentration

Other pre-specified: Al PK - Plasma Concentration/Change from baseline

Other pre-specified: Al PK - Plasma Concentration/Change from baseline

Other pre-specified: Al PK - Urine Concentration

Other pre-specified: Al PK - Urine Concentration

Other pre-specified: Al PK - Urine Concentration/Change from baseline

Other pre-specified: Al PK - Urine Concentration/Change from baseline

Other pre-specified: Al PK - Plasma Concentration/Cmax

Other pre-specified: Al PK - Plasma Concentration/Cmax

Other pre-specified: Al PK - Plasma Concentration/Tmax

Other pre-specified: Al PK - Plasma Concentration/Tmax

Other pre-specified: Al PK - Plasma Concentration/AUC[0-8h]

Other pre-specified: Al PK - Plasma Concentration/AUC[0-8h]

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
Multicenter, placebo-controlled, long-term study of Depigoid Birch 5000 in adults and adolescents with allergic rhinitis and/or rhinoconjunctivitis with or without intermittent asthma