Conditions: Allergy
Keywords: Allergic rhinoconjunctivitis Children Adolescents Birch
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 952
Healthy volunteers: no

Brief summary:
This is a clinical study in children and adolescents (5-17 years) with allergy to pollen from birch (or related trees). It compares the tree SLIT-tablet with placebo in relieving rhinoconjunctivitis symptoms during the birch/tree pollen season based on the average allergic rhinoconjunctivitis daily total combined score.

The study will also collect health-related quality of life information in the groups treated with the tree SLIT-tablet or with placebo during the pollen season.

The trial medication used is already approved to treat allergic rhinitis caused by birch/tree pollen in adults in several countries?.

Detailed description:
This is a phase III, parallel-group, double-blind, placebo-controlled study to evaluate efficacy and safety of the tree SLIT-tablet in children and adolescents (5-17 years) who have rhinoconjunctivitis (with or without asthma) induced by pollen from birch trees or by trees belonging to the birch homologous group. Approximately 1000 children and adolescents will be enrolled in the trial and will receive either the tree SLIT-tablet or placebo.

The trial consists of 3 periods: a screening period, a treatment period, which includes pre-seasonal and co seasonal treatment, and a follow-up period. The duration is up to 13 months for each participant.

The trial is conducted in several European countries and in Canada.

Arms:
arm 1: Gelatine (fish source), mannitol and sodium hydroxide arm 2: Sublingual allergy immunotherapy tablet, for daily administration SQ tree SLIT-tablet

Interventions: intervention 1: Tree SLIT-tablet intervention 2: Placebo SLIT-tablet
Intervention descriptions: intervention 1: Sublingual allergy immunotherapy tablets intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
Cover page 
Date: 
28-May-2024
Trial ID: TT-06 
Status: 
Final 
Version: 
1.0 
CONFIDENTIAL 
Page: 
1 of 1  
TT-06 TRIAL PROTOCOL COVER PAGE 
Official trial title 
Efficacy and safety of the SQ tree sublingual immunotherapy 
tablet in children and adolescents (5 through 17 years of age) with 
moderate to severe allergic rhinitis and/or conjunctivitis induced 
by pollen from birch and trees belonging to the birch homologous 
group 
NCT number 
NCT04878354 
Document date 
24-May-2022


Clinical trial protocol 
Date: 
24-May-2022
Trial ID: TT-06 
Version: 
3.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
1 of 99 
Clinical trial protocol 
Trial ID: TT-06 
Efficacy and safety of the SQ tree sublingual immunotherapy 
tablet in children and adolescents (5 through 17 years of age) 
with moderate to severe allergic rhinitis and/or conjunctivitis 
induced by pollen from birch and trees belonging to the birch 
homologous group 
Sponsor: 
ALK-Abelló A/S 
Bøge Allé 6-8 
DK-2970 Hørsholm 
Denmark 
Investigational medicinal product: SQ tree SLIT-tablet 
Phase: III 
Regulatory trial identifier number: 
EudraCT No: 2020-004372-17 
Document status: Final 
Date: 24-May-2022 
Version number: 3.0 
Property of ALK 
May not be used, divulged, published or otherwise disclosed without the written consent of ALK 


Clinical trial protocol 
Date: 
24-May-2022 
 
Trial ID: TT-06 
Version: 
3.0 
EudraCT No: 2020-004372-17 
Status: 
Final  
CONFIDENTIAL 
Page: 
2 of 99 
 
 
PROTOCOL SYNOPSIS 
 
Trial ID 
EudraCT no. 
TT-06 
2020-004372-17 
Title of trial 
Efficacy and safety of the SQ tree sublingual immunotherapy tablet in 
children and adolescents (5 through 17 years of age) with moderate to 
severe allergic rhinitis and/or conjunctivitis induced by pollen from birch and 
trees belonging to the birch homologous group 
Main objectives 
Primary objective: 
• 
To compare the efficacy of the SQ tree SLIT-tablet to placebo in the 
treatment of moderate to severe allergic rhinitis and/or conjunctivitis 
induced by pollen from birch and trees belonging to the birch homologous 
group in children and adolescents (5 through 17 years of age) based on 
the average allergic rhinoconjunctivitis daily total combined score# 
(average TCS) during the birch pollen season (BPS) 
# daily total combined score = daily symptom score + daily medication score 
Key secondary objectives: 
To compare the efficacy of the SQ tree SLIT-tablet to placebo based on: 
• 
The average TCS during the tree pollen season (TPS) 
• 
The average allergic rhinoconjunctivitis daily symptom score (average 
DSS) during the BPS and TPS 
• 
The average allergic rhinoconjunctivitis daily medication score (average 
DMS) during the BPS and TPS 
Secondary objectives: 
• 
To compare the safety and tolerability of the SQ tree SLIT-tablet to 
placebo 
• 
To compare the efficacy of the SQ tree SLIT-tablet to placebo using 
additional endpoints based on daily allergic rhinoconjunctivitis symptoms 
and rescue medication use 
• 
To compare the efficacy of the SQ tree SLIT-tablet to placebo based on 
assessments of quality of life 
• 
To compare the efficacy of the SQ tree SLIT-tablet to placebo based on 
patient treatment satisfaction 
• 
To compare the effect of the SQ tree SLIT-tablet to placebo on 
immunological parameters to birch, alder, hazel and oak pollen  
Primary endpoint 
Average TCS during the BPS 
Key Secondary endpoints 
• Average TCS during the TPS 
• Average DSS during the BPS 
• Average DSS during the TPS 
• Average DMS during the BPS 
• 
Average DMS during the TPS 


Clinical trial protocol 
Date: 
24-May-2022 
 
Trial ID: TT-06 
Version: 
3.0 
EudraCT No: 2020-004372-17 
Status: 
Final  
CONFIDENTIAL 
Page: 
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Primary estimand 
The absolute difference between SQ tree SLIT-tablet and placebo treatment 
policies based on the average TCS during the BPS, in the hypothetical 
situation that all subjects complete treatment for the planned duration.  
Secondary estimand 
The absolute difference between SQ tree SLIT-tablet and placebo treatment 
policies based on the average TCS during the BPS, regardless of whether 
subjects complete treatment for the planned duration.  
Trial design 
A phase III, randomised, parallel-group, double-blind, placebo-controlled, 
multi-regional trial in children and adolescents with AR/C (with or without 
asthma) induced by pollen from birch. The trial consists of 3 periods: 
a screening period, a treatment period, which includes pre-seasonal and 
co-seasonal treatment, and a follow-up period. There may be multiple cohorts 
recruited over consecutive seasons to complete the enrolment goal. 
The screening visit can take place up to approximately 6 months prior to 
randomisation. Eligible subjects will be randomised (1:1) to the SQ tree 
SLIT-tablet or placebo. The randomisation will be stratified by geographical 
location and by age group. 
Once randomised, subjects should receive at least 12 weeks pre-seasonal 
treatment prior to the TPS. Treatment will continue until 1 week after the end 
of the TPS for all subjects, corresponding to up to approximately 12 months 
of treatment. 
 
 
 
Open-label rescue medication for allergic rhinoconjunctivitis will be provided 
during the TPS 
 Open-label asthma medication will be provided to 
subjects with asthma during the TPS 
 
A follow-up phone visit will be conducted 1 week after the End-of-treatment 
visit. 
At least 6 in-clinic visits and 4 telephone contacts are planned for each 
subject. The TPS includes hazel, alder, birch and oak pollen seasons. 
A data monitoring committee will be established for the trial. 
Main assessments 
The following data will be collected: 
• 
Demographics 
• 
Medical history (including any allergy, urticaria, asthma, atopic dermatitis, 
and oral allergy syndrome) 
• 
Prior and concomitant medication 
• 
Result of IgE and skin prick testing to a panel of allergens 
Efficacy assessments (eDiary during TPS): 
• 
Allergic rhinoconjunctivitis symptoms 
• 
Allergic rhinoconjunctivitis medication use 
• 
 
• 
 


Clinical trial protocol 
Date: 
24-May-2022 
 
Trial ID: TT-06 
Version: 
3.0 
EudraCT No: 2020-004372-17 
Status: 
Final  
CONFIDENTIAL 
Page: 
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• 
 
• 
Standardised rhinoconjunctivitis quality of life questionnaire (RQLQ(S), 
12-17 years) 
• 
 
 
• 
 
Other efficacy assessments during TPS: 
• 
Paediatric rhinoconjunctivitis quality of life questionnaire (PRQLQ, 
<12 years) 
• 
Patient-rated global evaluation of treatment efficacy 
• 
Patient treatment satisfaction questionnaire for medication (TSQM-9) 
 
• 
 
• 
 
Immunological assessments 
• 
Immunological and serological parameters such as IgE, IgG4 and 
IgE-blocking factor (IgE-BF) and other antibody isotypes against relevant 
allergens as well as other serological components 
Safety assessments 
• 
Adverse events (AEs) 
• 
Vital signs, physical examination, lung function test and clinical laboratory 
values before treatment and at the final site visit. 
Main criteria for inclusion 
Subjects are eligible to be included in the trial only if all the following criteria apply: 
• 
Male or female of any race/ethnicity aged ≥4 to <18 years on the day 
informed consent is obtained from the parent/caregiver; the subject must 
be ≥5 to <18 years old at the randomisation visit 
• 
A documented1, physician diagnosed, clinically relevant history of 
moderate to severe AR/C induced by birch pollen (with or without 
asthma) despite having received treatment with symptom-relieving 
medication during at least 1 previous tree pollen season for ages 
4 through 6 years at screening or at least 2 previous tree pollen seasons 
for ages 7 through 17 years at screening 
• 
Positive skin prick test (SPT) to Betula verrucosa at screening2 
• 
Positive specific IgE3 to Bet v at screening 
• 
Presence of 1 or more of the following Allergic Rhinitis Impact on Asthma 
(ARIA) quality of life items due to AR/C during the previous BPS: 
 
1 If medical records are not available, verbal history from subject/parent/caregiver may be elicited at the screening visit. This must be documented 
by the investigator in the subject study file. 
2 A positive SPT is defined in the SPT guideline. Briefly, a positive SPT is defined as a wheal size of ≥3 mm. If medication that could interfere with the 
SPT, according to prohibited and restricted medication table, has not been washed out, the SPT must be performed after the interfering medication 
has been washed out. 
3 A positive specific IgE is defined as ≥IgE Class 2; ≥0.70 kU/L 


Clinical trial protocol 
Date: 
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Trial ID: TT-06 
Version: 
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EudraCT No: 2020-004372-17 
Status: 
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CONFIDENTIAL 
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a. 
Sleep disturbance 
b. 
Impairment of daily activities, leisure and/or sport 
c. 
Impairment of school or work 
d. 
Troublesome symptoms  
Main criteria for exclusion 
Subjects are excluded from the trial if any of the following criteria apply: 
• 
A clinically relevant history of symptomatic seasonal AR/C caused by an 
allergen source, other than tree pollen from the birch homologous group, 
with a season overlapping the TPS 
• 
A clinically relevant history of symptomatic perennial AR/C caused by an 
allergen source such as animal hair and dander to which the subject is 
exposed during the TPS 
• 
Any clinical deterioration of asthma (i.e. asthma exacerbation) that 
resulted in emergency treatment, hospitalisation or treatment with 
systemic corticosteroids within 3 months prior to randomisation 
• 
Reduced lung function at randomisation defined as forced expiratory 
volume in 1 second (FEV1) <70% of predicted value. For subjects with 
asthma, this is assessed on subject’s usual asthma medication following 
at least a 6-hour wash-out of SABA. This criterion does not need to be 
fulfilled if the subject is <7 years old, cannot perform reproducible FEV1 
manoeuvres despite coaching and is not considered as having a 
diagnosis of asthma 
• 
Ongoing treatment with any allergy immunotherapy product 
• 
Severe chronic oral inflammation 
• 
A diagnosis of eosinophilic oesophagitis 
• 
A relevant history of systemic allergic reaction e.g. anaphylaxis with 
cardiorespiratory symptoms, generalised urticaria or severe facial 
angioedema that in the opinion of the investigator may constitute an 
increased safety concern 
• 
Immunosuppressive treatment (ATC code L04 or L01) within 3 months 
prior to the screening visit 
Investigational medicinal 
products 
SQ tree SLIT-tablet (dose: 12 SQ-Bet) or placebo 
Duration of treatment 
Each randomised subject will receive IMP daily for a maximum of 
approximately 13 months. 
Number of subjects to be 
enrolled 
Approximately 1000 subjects to be randomised. Approximately 45% of the 
subjects should be aged 5-11 years at the time of randomisation.  
Number and distribution 
of trial sites 
Estimated 75-80 sites 
Statistical methods 
The full analysis set (FAS) will consist of all randomised subjects, where 
subjects will be analysed according to the treatment to which they were 
randomised. 
Analyses for the primary estimand and the secondary estimand will be based 
on the FAS. For subjects discontinuing trial treatment, all diary data up to the 
time of discontinuation will be included in the analysis for the primary 
estimand. Whereas for the secondary estimand, all diary data collected 
(including data collected after discontinuation of trial treatment) will be 
included in the analysis. Subjects with missing data for the primary efficacy 
endpoint will be included in the analyses through a multiple imputation 


Clinical trial protocol 
Date: 
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Trial ID: TT-06 
Version: 
3.0 
EudraCT No: 2020-004372-17 
Status: 
Final  
CONFIDENTIAL 
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approach aligned to the respective estimand and assumptions will be 
assessed through sensitivity analyses. An identical statistical analysis will be 
used for the primary and secondary estimands, although the actual datasets 
used in the analyses may vary depending on the number of subjects 
discontinuing trial treatment and the extent of missing data. 
For each analysis based on the primary efficacy endpoint, 1000 multiply 
imputed datasets will be created, and each dataset will be analysed using the 
following model. The primary efficacy endpoint will be square root 
transformed and analysed using a linear mixed effects model assuming 
unequal variances in the 2 treatment groups. The model will include 
treatment, pollen season and age group (5-11 years, 12-17 years) as fixed 
effects, and geographical location as a random effect. The results will be 
back-transformed to the original scale and Rubin’s rule will be used to 
combine the results obtained from the multiply imputed datasets. The p-value 
for the treatment effect, the absolute difference with 95% CI, and the relative 
difference with 95% CI will be presented. 
Primary and secondary estimands based on the key secondary efficacy 
endpoints are defined similarly for the key secondary objectives. Analyses for 
these estimands will be identical to those based on the respective estimand 
defined for the primary objective. 
For the primary estimand, a hierarchical testing strategy will be used for the 
analyses based on the primary efficacy endpoint, key secondary efficacy 
endpoints and quality of life endpoints to control for multiplicity and ensure a 
maximum overall type I error rate of 5%. 
International coordinating 
investigator 
 
 
 
 
 
Sponsor’s name/address 
ALK-Abelló A/S, Bøge Allé 6-8, DK-2970 Hørsholm, Denmark 
 
 


Clinical trial protocol 
Date: 
24-May-2022 
 
Trial ID: TT-06 
Version: 
3.0 
EudraCT No: 2020-004372-17 
Status: 
Final  
CONFIDENTIAL 
Page: 
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TABLE OF CONTENTS 
 
Page 
Protocol synopsis ........................................................................................................................... 2 
Table of contents ............................................................................................................................. 7 
Table of figures .............................................................................................................................. 11 
Table of tables ............................................................................................................................... 11 
List of appendices ......................................................................................................................... 12 
Table of abbreviations .................................................................................................................. 13 
Table of definitions ....................................................................................................................... 15 
Protocol versions .......................................................................................................................... 17 
Flow chart ...................................................................................................................................... 18 
1 
Introduction ............................................................................................................................. 24 
1.1 
Disease background and current treatment modalities................................................. 24 
1.2 
Stage of development ................................................................................................... 24 
1.3 
Trial rationale ................................................................................................................ 25 
1.4 
Benefit-risk assessments .............................................................................................. 26 
1.5 
Considerations regarding COVID-19 ............................................................................ 27 
1.6 
Ethical considerations ................................................................................................... 27 
2 
Objectives, estimands and endpoints .................................................................................. 28 
2.1 
Primary objective .......................................................................................................... 28 
2.2 
Key secondary objectives ............................................................................................. 28 
2.3 
Secondary objectives .................................................................................................... 28 
2.4 
Exploratory objectives ................................................................................................... 28 
2.5 
Primary estimand .......................................................................................................... 29 
2.6 
Secondary estimand ..................................................................................................... 29 
2.7 
Estimands for key secondary objectives ....................................................................... 29 
2.8 
Primary efficacy endpoint ............................................................................................. 29 
2.9 
Key secondary efficacy endpoints ................................................................................ 30 
2.10 
Secondary efficacy endpoints ....................................................................................... 30 
2.11 
Safety and tolerability endpoints ................................................................................... 30 
2.12 
Exploratory endpoints ................................................................................................... 31 
3 
Trial design .............................................................................................................................. 31 
3.1 
Summary of trial design ................................................................................................ 31 
3.2 
Discussion of design ..................................................................................................... 33 
3.3 
Justification of dose ...................................................................................................... 35 
3.4 
End of trial definition ..................................................................................................... 35 
4 
Trial population ....................................................................................................................... 35 
4.1 
Inclusion criteria ............................................................................................................ 35 
4.2 
Exclusion criteria ........................................................................................................... 36 
4.3 
Screening failures ......................................................................................................... 38 
4.3.1 
Re-screening ....................................................................................................... 38 


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5 
Discontinuation of IMP treatment and subject withdrawal ................................................. 39 
5.1 
Criteria for discontinuation from IMP treatment ............................................................ 39 
5.2 
Subject withdrawal from the trial ................................................................................... 39 
5.3 
Lost to follow-up ............................................................................................................ 39 
5.4 
Replacement of subjects .............................................................................................. 40 
6 
Randomisation and treatment blinding/unblinding ............................................................. 40 
6.1 
Subject ID number ........................................................................................................ 40 
6.2 
Randomisation .............................................................................................................. 40 
6.3 
Treatment blinding/unblinding ....................................................................................... 40 
6.4 
Subject card .................................................................................................................. 41 
7 
Restricted and prohibited concomitant medication ............................................................ 41 
8 
Trial products .......................................................................................................................... 43 
8.1 
IMP ............................................................................................................................... 43 
8.2 
Rescue medication ....................................................................................................... 43 
8.2.1 
Rhinoconjunctivitis rescue medication ................................................................. 44 
8.2.2 
Asthma rescue medication .................................................................................. 44 
8.3 
Packaging and labelling ................................................................................................ 46 
8.4 
Handling and storage .................................................................................................... 47 
8.5 
IMP and rescue medication accountability ................................................................... 47 
8.6 
Reporting of technical complaints ................................................................................. 47 
9 
Treatment ................................................................................................................................ 48 
9.1 
Treatment administration .............................................................................................. 48 
9.2 
Precautions in relation to first dosing ............................................................................ 48 
9.3 
Treatment of severe allergic reactions/anaphylaxis ...................................................... 48 
9.4 
Temporary interruption of treatment ............................................................................. 48 
9.5 
Post-trial treatment ....................................................................................................... 49 
10 Visit schedule .......................................................................................................................... 49 
11 Trial procedures ...................................................................................................................... 53 
11.1 
Informed consent .......................................................................................................... 53 
11.2 
Consent to collection of blood samples for storage in biobank ..................................... 54 
11.3 
Consent for collection of blood samples for pharmacogenetic testing .......................... 54 
11.4 
Demographics ............................................................................................................... 54 
11.5 
Height and weight ......................................................................................................... 55 
11.6 
Medical history .............................................................................................................. 55 
11.7 
Smoking habits ............................................................................................................. 55 
11.8 
Prior and concomitant medication ................................................................................ 55 
11.9 
Vital signs ..................................................................................................................... 56 
11.10 Lung function ................................................................................................................ 56 
11.11 Physical examination .................................................................................................... 56 
11.12 Pregnancy test .............................................................................................................. 57 
11.13 Skin prick test ............................................................................................................... 57 
11.14 Blood and urine sampling ............................................................................................. 59 
11.15 Laboratory assessments ............................................................................................... 60 
11.16 Long-term storage of samples ...................................................................................... 61 
11.17 Subject and parent/caregiver reported outcomes ......................................................... 62 
11.17.1 
eDiary assessments ............................................................................................ 62 


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11.17.2 
Assessments entered in the eCRF ...................................................................... 63 
11.17.2.1 
Paediatric quality of life questionnaire .................................................. 63 
11.17.2.2 
Treatment satisfaction evaluation ......................................................... 63 
11.17.2.3 
Patient-rated global evaluation of treatment efficacy ............................ 63 
11.18 Assessment of rhinoconjunctivitis 
 ............................................ 63 
11.19 Assessment of use of rescue medication ..................................................................... 64 
12 Safety procedures................................................................................................................... 65 
12.1 
Definitions ..................................................................................................................... 65 
12.1.1 
Adverse events .................................................................................................... 65 
12.1.2 
Serious adverse events ....................................................................................... 65 
12.1.3 
Events of special interest ..................................................................................... 66 
12.1.4 
Significant laboratory event ................................................................................. 66 
12.1.5 
Medication errors, including overdose, abuse and misuse of the IMP ................ 66 
12.2 
AE assessments ........................................................................................................... 66 
12.2.1 
Severity ................................................................................................................ 66 
12.2.2 
Causal relationship to IMP ................................................................................... 67 
12.2.3 
Outcome .............................................................................................................. 67 
12.3 
Collection, recording and reporting of AEs ................................................................... 67 
12.3.1 
Events of special interest ..................................................................................... 67 
12.3.1.1 
Eosinophilic Oesophagitis ..................................................................... 68 
12.3.2 
Reporting of AEs ................................................................................................. 68 
12.3.3 
Follow-up on AEs and SAEs ............................................................................... 69 
12.3.4 
Reporting of medication errors, including overdose, abuse and misuse ............. 69 
12.3.5 
Reporting of significant laboratory events ........................................................... 69 
12.3.6 
Reporting of pregnancies .................................................................................... 69 
12.3.7 
Reporting of SAE and pregnancies after end of trial ........................................... 70 
12.4 
Safety surveillance ........................................................................................................ 70 
12.5 
DMC .............................................................................................................................. 70 
12.6 
Pregnancy ..................................................................................................................... 70 
13 Early termination of trial......................................................................................................... 71 
14 Data handling .......................................................................................................................... 71 
14.1 
eCRF ............................................................................................................................ 71 
14.2 
eDiary ........................................................................................................................... 71 
14.3 
Query handling ............................................................................................................. 72 
14.4 
Laboratory data ............................................................................................................. 72 
14.5 
Pollen data .................................................................................................................... 72 
14.6 
Database lock ............................................................................................................... 72 
15 Statistical methods ................................................................................................................. 73 
15.1 
Estimands ..................................................................................................................... 73 
15.1.1 
Intercurrent events ............................................................................................... 73 
15.1.2 
Primary estimand ................................................................................................. 74 
15.1.3 
Secondary estimand ............................................................................................ 74 
15.1.4 
Estimands for key secondary objectives ............................................................. 74 
15.2 
Sample size and power considerations ........................................................................ 75 
15.3 
Analysis data sets ......................................................................................................... 76 
15.4 
Subject disposition ........................................................................................................ 76 
15.5 
Baseline characteristics ................................................................................................ 76 


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15.6 
Extent of exposure ........................................................................................................ 77 
15.7 
Medical history .............................................................................................................. 77 
15.8 
Concomitant therapy ..................................................................................................... 77 
15.9 
Derivation of endpoints ................................................................................................. 77 
15.9.1 
Allergic rhinoconjunctivitis daily symptom score (DSS) ....................................... 77 
15.9.2 
Allergic rhinoconjunctivitis daily medication score ............................................... 77 
15.9.3 
Allergic rhinoconjunctivitis daily total combined score (daily TCS) ...................... 78 
15.9.4 
Average allergic rhinoconjunctivitis daily total combined score (average TCS) .. 78 
15.9.5 
Average allergic rhinoconjunctivitis daily symptom score (average DSS) and 
average allergic rhinoconjunctivitis daily medication score (average DMS) ........ 79 
15.9.6 
 ........................... 79 
15.9.7 
Severe, well and symptom-free days during the BPS and TPS .......................... 79 
15.9.8 
Average TCS (EAACI scoring) ............................................................................ 79 
15.9.9 
Rhinoconjunctivitis quality of life (RQLQ(S)) scores ............................................ 80 
15.9.10 
Paediatric rhinoconjunctivitis quality of life (PRQLQ) scores ............................... 81 
15.9.11 
Treatment satisfaction (TSQM) evaluation scores .............................................. 81 
15.9.12 
Patient-rated global evaluation of treatment efficacy ........................................... 81 
15.9.13 
Lung function ....................................................................................................... 81 
15.10 Definition of pollen seasons .......................................................................................... 81 
15.10.1 
Birch pollen season definition .............................................................................. 82 
15.10.2 
Alder, hazel and oak pollen season definition ..................................................... 82 
15.10.3 
Tree pollen season definition ............................................................................... 83 
15.10.4 
 ............................................................................ 83 
15.11 Multiplicity ..................................................................................................................... 83 
15.12 Efficacy analyses .......................................................................................................... 84 
15.12.1 
Main estimator, sensitivity estimator(s) and statistical analysis for the trial 
product and treatment policy estimands .............................................................. 84 
15.12.2 
Handling of intercurrent events and missing data for the trial product 
estimand .............................................................................................................. 84 
15.12.3 
Handling of intercurrent events and missing data for the treatment policy 
estimand .............................................................................................................. 85 
15.12.4 
Estimators for estimands defined for key secondary efficacy objectives ............. 86 
15.12.5 
Supportive analyses ............................................................................................ 86 
15.12.6 
Secondary efficacy analyses ............................................................................... 86 
15.12.7 
Exploratory efficacy analyses .............................................................................. 86 
15.13 Safety analyses ............................................................................................................ 86 
15.13.1 
Evaluation of AEs ................................................................................................ 86 
15.13.2 
Evaluation of other safety parameters ................................................................. 87 
15.14 Interim analyses ............................................................................................................ 87 
15.15 Handling of missing data and sensitivity analyses ........................................................ 87 
16 Quality assurance and control .............................................................................................. 87 
16.1 
Monitoring ..................................................................................................................... 87 
16.2 
Source data and access to source documents ............................................................. 87 
16.3 
Investigator site file – and other trial documentation .................................................... 89 
16.4 
Protocol compliance ..................................................................................................... 89 
16.5 
Audit .............................................................................................................................. 89 
17 Ethics and regulatory procedures ......................................................................................... 90 
17.1 
Statement of compliance .............................................................................................. 90 


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Date: 
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Trial ID: TT-06 
Version: 
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EudraCT No: 2020-004372-17 
Status: 
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CONFIDENTIAL 
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17.2 
Disclosure and confidentiality ....................................................................................... 90 
17.3 
Subject confidentiality ................................................................................................... 90 
17.4 
Data protection ............................................................................................................. 91 
17.5 
IEC/IRB/regulatory authorities ...................................................................................... 92 
17.6 
Inspections .................................................................................................................... 92 
17.7 
Protocol amendments and other changes in trial conduct ............................................ 92 
18 Reporting and publication ..................................................................................................... 93 
18.1 
Clinical trial report ......................................................................................................... 93 
18.2 
Publication and disclosure of results ............................................................................ 93 
19 Finance and insurance ........................................................................................................... 94 
20 Trial organisation .................................................................................................................... 94 
21 Reference list .......................................................................................................................... 95 
 
TABLE OF FIGURES 
 
Page 
Figure 1 
Overall trial design ........................................................................................................ 32 
 
 
..................................................... 33 
 
TABLE OF TABLES 
 
Page 
Table 1 
Restricted and prohibited concomitant medications ..................................................... 42 
Table 2 
IMP details .................................................................................................................... 43 
Table 3 
Schedule for rhinoconjunctivitis rescue medication ...................................................... 44 
Table 4 
Definition of low, medium and high dose ICS for subjects aged 5-11 years as 
defined by the GINA Guideline ..................................................................................... 45 
Table 5 
Definition of low, medium and high dose ICS for subjects aged 12 years and 
above, as defined by the GINA Guideline ..................................................................... 46 
Table 6 
Visit schedule ................................................................................................................ 49 
Table 7 
Physical examination .................................................................................................... 56 
Table 8 
Skin prick test ............................................................................................................... 58 
Table 9 
Medications with a possible interference with SPT ....................................................... 59 
Table 10 
Blood samples drawn by visit ....................................................................................... 59 
Table 11 
Subject’s symptom scoring ........................................................................................... 64 


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Table 12 
Power to meet regulatory criteria for FAS and Observed Case Analyses .................... 76 
Table 13 
Scoring for allergic rhinoconjunctivitis rescue medication usage .................................. 78 
Table 14 
EAACI scoring for allergic rhinoconjunctivitis rescue medication usage ....................... 80 
Table 15 
Hypothetical pollen seasons in the Northern European region ..................................... 82 
LIST OF APPENDICES 
Appendix 1: Protocol signature page 
Appendix 2: Investigator agreement on clinical trial protocol
Appendix 3: List of suppliers 
Appendix 4: Patient reported outcome questionnaires
Appendix 5: Expected pollen seasons 


Clinical trial protocol 
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TABLE OF ABBREVIATIONS 
AE 
Adverse event 
AHPS 
Alder-hazel pollen season 
AIT 
Allergy immunotherapy 
ALK  
ALK-Abelló A/S 
AR/C 
Allergic rhinitis and/or conjunctivitis  
ARIA 
Allergic rhinitis and its impact on asthma 
Bet v 
Betula verrucosa (white birch) 
Bet v 1 
Major allergen 1 of Betula verrucosa (white birch) 
BPS 
Birch pollen season 
CHMP 
Committee for medicinal products for human use 
CI 
Confidence interval 
CL 
Confidence limit(s) 
CRA 
Clinical research associate 
CRO 
Clinical research organisation 
CTS 
Clinical trial supplies 
DMC 
Data monitoring committee 
DMS 
Daily medication score 
DSS 
Daily symptom score 
EAACI 
European Academy of Allergy and Clinical Immunology 
ECC 
Environmental exposure chamber 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
EEC 
Environmental exposure chamber 
EMA 
European medicines agency 
EoE 
Eosinophilic oesophagitis 
ESI 
Events of special interest  
EudraCT 
European Union drug regulating authorities clinical trials database 
FAS 
Full analysis set 
FDA 
Food and drug administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good clinical practice 
GINA 
Global initiative for asthma 
 
 
IB 
Investigators brochure 
ICH 
International conference on harmonisation of technical requirements for registration of 
pharmaceuticals for human use 
ICS 
Inhaled corticosteroid 
ICTR 
Integrated clinical trial report 
IE 
Intercurrent event 
IEC 
Independent ethics committee 
IgE 
Immunoglobulin E 
IgE-BF 
IgE-blocking factor  
IgG4 
Immunoglobulin G4 
IMP 
Investigational medicinal product 


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IRB/IEC 
Institutional review board/Independent ethics committee; terms can be used 
interchangeably 
IRT 
Interactive response technology 
ITT 
Intention to treat 
LABA 
Long-acting β2-agonist 
LME model 
Linear mixed effect model 
LSLV 
Last subject last visit 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MNAR 
Missing not at random 
MedDRA 
Medical dictionary for regulatory activities 
N 
Number 
OAS 
Oral allergy syndrome 
OC 
Observed case 
OPS 
Oak pollen season 
PDCO 
Paediatric committee 
PFS 
Pollen food syndrome 
PRQLQ 
Paediatric rhinoconjunctivitis quality of life questionnaire 
RQLQ(S) 
Standardised rhinoconjunctivitis quality of life questionnaire 
SABA 
Short-acting β2-agonist 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCIT 
Subcutaneous allergy immunotherapy 
SD  
Standard deviation  
SLIT 
Sublingual allergy immunotherapy 
SLIT-tablet 
Sublingual allergy immunotherapy tablet 
SmPC 
Summary of product characteristics 
SOP 
Standard operating procedure 
SPT 
Skin prick test 
TC 
Telephone call 
TCS 
Total combined score (rhinoconjunctivitis symptoms and medication use)  
TEAE 
Treatment-emergent adverse events  
TPS 
Tree pollen season 
TSQM©  
Treatment satisfaction questionnaire for medication  
UV 
Unscheduled visit 
V 
Visit  
WHO 
World Health Organization 


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TABLE OF DEFINITIONS 
Asthma 
A subject must meet at least 1 of the following 4 criteria to be considered as having 
a diagnosis of asthma: 
•
At least 1 episode of wheeze, cough, shortness of breath or chest tightness
and a change in FEV1 ≥12% after β2-agonist administration
•
Recurrent wheeze with or without prolonged phase of forced exhalation
observed at physical examination and an intake of asthma medication which
resulted in a clinically relevant effect
•
Wheezing with or without prolonged phase of forced exhalation observed at
physical examination and a change in FEV1 ≥12% after β2-agonist
administration
•
Using asthma medication
Completed subject 
A randomised subject is considered completed if he/she has not discontinued the 
trial before visit 6 
Concomitant 
medication 
All medications being continued by a subject on entry into the trial and all 
medications given in addition to the background treatment during the trial. 
Date of last contact 
Date of the last contact, either by telephone or in a visit. 
End of trial 
The overall end of the trial is defined as the date of last follow-up phone visit (TC4) 
for the last subject in the trial globally. 
Estimand 
A precise description of the treatment effect reflecting the clinical question of 
interest posed by the trial objective. It summarises at a population-level what the 
outcomes would be in the same patients under different treatment conditions being 
compared (ICH 2020). 
IMP 
A pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical trial, including products with a marketing authorisation used 
or assembled (formulated or packaged) in a way different from the authorised form, 
or when used for an unauthorised indication, or when used to gain further 
information about the authorised form. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or 
existence of the measurements associated with the clinical question of interest. It is 
necessary to address intercurrent events when describing the clinical question of 
interest in order to precisely define the treatment effect that is to be estimated 
(ICH 2020). 
IRT 
Automated system that can be used for managing randomisation, subject 
enrolment and trial supply management in a clinical trial. 
LSLV 
Last subject last visit (Follow-up phone visit TC4). 
Primary completion 
date 
According to EU regulations this is the last subject last visit. However, for 
ClinicalTrials.gov, the primary completion date is the date of the last data collection 
for the primary endpoint which is the end-of-treatment visit (visit 6) for the last 
subject in the trial globally. 


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Trial ID: TT-06 
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Rescue medication 
Medicinal products provided by ALK when the efficacy of the IMP is not sufficient or 
likely to cause an adverse event to the subject or to manage an emergency 
situation in relation to allergy symptoms in agreement with the EMA Definition of 
IMPs and use of AMPs consultation document (EMA 2016). 
Source documents 
Source documents are original documents, data, and records from which the 
subjects' electronic case report form (eCRF) data are obtained. These include, but 
are not limited to, hospital records (from which medical history and concomitant 
medication may be summarised into the eCRF), clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and 
correspondence. 
Systemic 
corticosteroids 
Oral, intramuscular, or intravenously administered corticosteroids including depot 
formulations. 
TEAE 
An adverse event with start date/time on or after the time of first IMP administration 
and no later than 7 days after last IMP administration. 
Trial completion 
The trial is completed once the integrated clinical trial report (ICTR) is signed. 
Trial discontinuation 
date 
Date of subject trial discontinuation. In case of subjects lost to follow-up, the trial 
discontinuation date is defined as the date the investigator/sponsor decides to 
discontinue the subject from the trial. 
 


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PROTOCOL VERSIONS 
Date 
Version Description of document 
Rationale for amendment 
18-Sep-2020 
1.0 
Protocol version 1.0 was updated due 
to minor inconsistencies and was never 
submitted to regulatory authorities or 
ethics committees 
N/A 
16-Oct-2020 
2.0 
Final Protocol 
N/A 
24-May-2022 3.0 
Amendment 1: To eliminate further 
participation of more than one subject 
from the same household in the same 
cohort, and to add minor clarifications 
and correct inconsistencies. 
The amendment is considered non-
substantial and is applicable for all 
countries. 
To prevent unintentional 
swap of trial medication 
(IMP) within subjects from 
the same household. 
 
 


Clinical trial protocol 
EudraCT No: 2020-004372-17 
Date: 
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Status: 
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Trial ID: TT-06 
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FLOW CHART 
Visit ID: 
V1 
TC14 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV5 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off season Pre-TPS 
Start of 
TPS 
Pre-BPS In season 
BPS 
Only for 
cohort 1 
subjects also 
 
 
End-of-treatment 
Follow-
up 
Unsched-
uled 
Scheduled week 
1-26 
weeks 
prior to 
V2 
4-12 
weeks 
prior to V2 
At least 
12 weeks 
prior to 
expected 
start of 
TPS6 
4 weeks 
after V2 
2 weeks 
prior to 
expected 
start of 
TPS 
 
 
2 weeks 
prior to 
expected 
start of 
BPS 
2 weeks 
after 
expected 
start of 
BPS7 
1 week 
after expected 
end of TPS 
1 week after expected 
end of TPS 
1 week 
after V6 
 
Cohort 1 subjects also 
: 
1 week after 
expected end of 
8 
Visit window 
 
 
 
+7 days 
-14 to +7 
days 
-4 days 
+7 days 
+7 days 
+7 days 
+7 days 
+7 days 
 
Administrative procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed consent9 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
Smoking habit 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
Record prior and concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TC to ensure that subject is 
still interested in the trial 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense IMP 
 
 
X 
 
X 
 
 
X 
 
 
 
(X) 
 
4 Only required if V1 (screening) is performed more than 12 weeks prior to randomisation. 
5 Unscheduled visits should be conducted as necessary. The evaluations/examinations listed with brackets should only be performed if deemed necessary by the investigator. 
6 Randomisation (V2) must be performed at least 12 weeks prior to expected TPS but no later than 31 October. 
7 Visit 5 can be scheduled based on the actual BPS start date. 
8 In cohort 1 subjects also 
 V6 is to be performed 1 week after the expected end of 
. End of 
 can be no later than 31 August 2022. 
9 Obtain written informed consent for the trial, storage of serum samples in the ALK Research Biobank, and for pharmacogenetics testing before any other trial procedures are performed. 


Clinical trial protocol 
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Visit ID: 
V1 
TC14 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV5 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off season Pre-TPS 
Start of 
TPS 
Pre-BPS In season 
BPS 
Only for 
cohort 1 
subjects also 
 
 
End-of-treatment 
Follow-
up 
Unsched-
uled 
Instruct the subject in use of 
IMP 
 
 
X 
 
 
 
 
 
 
 
 
(X) 
Collect IMP and perform drug 
accountability 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Perform IMP compliance 
check 
 
 
 
X 
X 
 
 
X 
 
X 
 
 
Dispense rhinoconjunctivitis 
and asthma rescue medication 
 
 
 
 
X 
 
 
X 
 
 
 
(X) 
Collect rescue medication and 
perform drug accountability 
 
 
 
 
 
 
 
X 
 
X 
 
 
Handout eDiary 
 
 
 
 
X 
 
 
 
 
 
 
 
Instruct in the use of the 
eDiary incl. training in 
symptom scoring 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Show and/or discuss trial video 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Inform that TPS is starting  
 
 
 
 
 
X 
 
 
 
 
 
 
Clinical procedures/assessments 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
 
 
 
 
X 
 
(X) 
Height  
 
 
X 
 
 
 
 
 
 
X 
 
(X) 
Weight 
X 
 
X 
 
 
 
 
 
 
X 
 
(X) 
Vital signs 
X 
 
 
 
 
 
 
 
 
X 
 
(X) 
Lung function test10 
 
 
X 
 
 
 
 
 
 
X 
 
(X) 
SPT11 
X 
 
(X) 
 
 
 
 
 
 
 
 
 
Assess AEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess symptoms of 
eosinophilic oesophagitis 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
10 Measure FVC and FEV1 while subject is on their usual asthma medication (if applicable) following at least a 6 hour washout of SABA.  
11 To be taken after a urine pregnancy test (if applicable). A positive SPT is defined in the SPT guideline. Briefly, a positive SPT is defined as a wheal size of ≥3 mm. If medication that could interfere with the SPT, 
according to prohibited and restricted medication table, has not been washed out, the SPT must be performed at V2 after the interfering medication has been washed out. 


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Date: 
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Status: 
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Trial ID: TT-06 
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Visit ID: 
V1 
TC14 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV5 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off season Pre-TPS 
Start of 
TPS 
Pre-BPS In season 
BPS 
Only for 
cohort 1 
subjects also 
 
 
End-of-treatment 
Follow-
up 
Unsched-
uled 
Intake of IMP at clinic 
 
 
X 
 
 
 
 
 
 
 
 
 


Clinical trial protocol 
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Trial ID: TT-06 
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Visit ID: 
V1 
TC14 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV5 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off season Pre-TPS 
Start of 
TPS 
Pre-BPS In season 
BPS 
Only for 
cohort 1 
subjects also 
 
 
End-of-treatment 
Follow-
up 
Unsched-
uled 
All subjects (except for 
cohort 1 subjects with 
) 
Daily eDiary recording: 
• AR/C symptoms 
• AR/C medication 
•
 
•
 
 
 
•
 
•
 
•
 
 
 
Weekly eDiary recording: 
• RQLQ(S)12 
 
 
 
 
 
X --------------------------------------------------------------------------X 
 
 
Cohort 1 subjects with 
 
Daily eDiary recording: 
• AR/C symptoms 
• AR/C medication  
 
 
 
 
 
X --------------------------------------------------------------------------X 
 
 
 
12 RQLQ(S) should be performed only for subjects who were 12-17 years at the randomisation visit. 


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Visit ID: 
V1 
TC14 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV5 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off season Pre-TPS 
Start of 
TPS 
Pre-BPS In season 
BPS 
Only for 
cohort 1 
subjects also 
 
 
End-of-treatment 
Follow-
up 
Unsched-
uled 
Cohort 1 subjects with 
 
Daily eDiary recording: 
•
 
•
 
 
 
•
 
•
 
•
 
 
 
Weekly eDiary recording: 
• RQLQ(S)12 
 
 
 
 
 
X --------------------------------------------------X 
 
 
 
Review eDiary recordings and 
compliance 
 
 
 
 
 
X------------------------------------------------------------------------------X 
 
 
Collect eDiary 
 
 
 
 
 
 
 
 
 
X 
 
 
PRQLQ13  
 
 
 
 
 
 
 
X 
 
 
 
 
All subjects (except for 
cohort 1 subjects with 
): 
• Global evaluation of 
treatment efficacy 
• TSQM-9 
 
 
 
 
 
 
 
 
 
X 
 
 
 
13 Perform PRQLQ interview, only for subjects who were 5-11 years at the randomisation visit. 


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Visit ID: 
V1 
TC14 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV5 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off season Pre-TPS 
Start of 
TPS 
Pre-BPS In season 
BPS 
Only for 
cohort 1 
subjects also 
 
 
End-of-treatment 
Follow-
up 
Unsched-
uled 
Cohort 1 subjects with 
: 
• Global evaluation of
treatment efficacy
• TSQM-9
X 
Laboratory procedures/assessments 
Blood sample for specific IgE 
against Bet v 
X 
(X) 
Blood and urine samples for 
safety laboratory assessments 
X 
X 
(X) 
Urine pregnancy test14 
X 
X 
X 
X 
X 
X 
(X) 
Blood sample for 
Immunological assessments 
X 
X 
X 
(X) 
Blood sample for biobank15 
X 
X 
X 
(X) 
Blood sample for 
pharmacogenetics16 
X 
(X) 
14 For female subjects of childbearing potential only, additional urine pregnancy tests should be performed during the trial, if a menstrual period is missed. 
15 Only for subjects where informed consent for biobank sampling has been obtained. 
16 Only for subjects where informed consent for pharmacogenetics sampling has been obtained. 


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1 
INTRODUCTION 
1.1 
Disease background and current treatment modalities 
Despite differences among countries, the incidence and prevalence of allergic rhinitis and asthma 
are increasing worldwide. AR/C affects between 10 to 30% of all adults and up to 40% of children 
(Pawankar et al. 2011). Sensitisation rates to 1 or more common allergens among school children 
are estimated to be 40%-50% (Pawankar et al. 2011). Tree pollen allergy is common across 
central and northern Europe and North America and is commonly caused by pollen from the birch 
and related trees, also commonly referred to as the birch homologous group (hereafter referred to 
as “birch group”). This group currently includes birch, alder, hornbeam, hazel, beech and oak 
(Lorenz et al. 2009), although more species may be included when additional data on cross-
reactivity and allergen homology becomes available (Heath et al. 2015). AIT guidelines 
recommend treating allergic patients with AIT using a representative allergen within a homologous 
allergen group (Cox et al. 2011; EMEA 2008). 
The trees in the birch group are characterised by having Bet v 1 homologous allergens with a high 
level of structural sequence identity, leading to extensive cross-reactivity at the immune response 
level. Thus, people who are sensitised to pollen from one of the trees often also experience 
symptoms in response to pollen from other members of the birch group. Sensitisation to Bet v 1 
has been estimated up to 24% in adults (Burbach et al. 2009; Chan-Yeung et al. 2010), and 
between 14-16% in children (Schmitz et al. 2013; Stemeseder et al. 2017). The broad cross-
reactivity and sequential pollen seasons of birch related allergens prolong the period of allergic 
symptoms for people with allergy to birch. In previous clinical trials conducted by ALK in Europe 
and North America with the SQ tree SLIT-tablet, more than 90% of participants with AR/C induced 
by birch pollen were also sensitised to alder and hazel (Biedermann et al. 2019a). Furthermore, 
Jantunen et al. showed that 95% of patients diagnosed with birch pollen allergy presented with 
allergic symptoms during the alder season (Jantunen et al. 2012). Cross-reactivity of birch pollen 
allergens also extends to plant food allergens, resulting in the pollen food syndrome (Biedermann 
et al. 2019b). 
Treatment options for AR/C include allergen avoidance, symptomatic medications such as 
antihistamines and corticosteroids, and AIT (Bousquet et al. 2008). Avoidance of pollen is difficult 
to achieve in a normal daily life, and symptom-relieving medication is widely used, however it does 
not offer causal treatment of the allergic disease and up to 44% of patients on optimal symptom-
relieving medication report poor or only partial symptom control (Valovirta et al. 2008). AIT is the 
only available treatment modality that can modify the natural course of the allergic disease by 
induction of tolerance (Bousquet et al. 2008). The use of pollen extract for AIT is well-known, both 
in SCIT formulations (Blumberga et al. 2011; Bousquet et al. 1998a; Lang & Hawranek 2006; 
Winther et al. 2000a; Winther et al. 2000b) and as SLIT-tablets or drops (Demoly et al. 2016; 
Durham et al. 2012). 
1.2 
Stage of development 
The SQ tree SLIT-tablet is a once daily fast-dissolving pharmaceutical formulation (oral 
lyophilisate) containing standardised allergen extract of white birch (Betula verrucosa) for AIT of 
seasonal AR/C induced by pollen from birch and trees belonging to the birch homologous group. 


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The SQ tree SLIT-tablet is approved in 17 European countries for treatment of adults with 
moderate to severe AR/C induced by the pollen from the birch homologous group, while in 
Switzerland this approval encompasses adults and adolescents (12-17 years old). In Canada, the 
SQ tree SLIT-tablet is approved for treatment of adults with moderate to severe AR/C induced by 
pollen from birch, alder and/or hazel. 
The clinical development programme for the SQ tree SLIT-tablet comprises 4 phase I-III 
randomised, double-blind, placebo-controlled clinical trials in Europe and North America. The 
clinical efficacy of the SQ tree SLIT-tablet was confirmed in a phase III in-field trial (TT-04) 
including both adults (≤65 years old) and a small group of adolescents (12-17 years old) in Europe. 
The results demonstrated a statistically significant improvement with the SQ tree SLIT-tablet 
treatment compared to placebo for the average TCS during the BPS, the TPS and the AHPS. The 
average DSS and the average DMS (both components of the total combined score) also showed 
statistically significant improvements compared to placebo during the BPS, TPS and AHPS. A 
pre-specified analysis comparing the treatment effect in the adolescent and adult populations did 
not show a statistically significant difference in treatment effect between the 2 age groups. 
The clinical relevance of the cross-reactivity between birch and oak was demonstrated in a phase 
II environmental exposure chamber trial (TT-03) and was further investigated (post-hoc) in the oak 
pollen season in the phase III in-field trial TT-04. Significant treatment effects were seen after 
exposure to birch as well as oak pollen both in the environmental exposure chamber and post-hoc 
in the phase III clinical field trial. 
The SQ tree SLIT-tablet was generally well-tolerated with a safety profile characterised by frequent 
but transient local allergic events in the first few days of treatment, primarily occurring in or around 
the mouth and throat (e.g. pruritus, irritation, sensation changes, discomfort, swellings, and pain), 
that were typically assessed as mild or moderate in intensity. Severe allergic reactions were 
uncommon. Overall, the SQ tree SLIT-tablet was well-tolerated in subjects with tree pollen allergy 
with no major safety concerns detected. Finally, the safety profile was generally similar across age 
subgroups (adolescent vs adult). 
1.3 
Trial rationale 
The prevalence of allergy induced by birch and cross-reactive tree pollen in children and 
adolescents in the general population is 14-16% (Schmitz et al. 2013; Stemeseder et al. 2017). A 
substantial number of these children and adolescents do not reach sufficient symptom control 
when treated with pharmacotherapy (antihistamines/steroids) (Meltzer et al. 2009). Furthermore, 
most subjects with birch pollen allergy are poly-sensitised to pollen from related trees and may 
experience symptoms to early and/or late flowering trees in the birch homologous group. Thus, the 
symptom burden extends beyond the birch season and therefore this trial will evaluate symptoms 
and medication use during the birch pollen season and also during the alder/hazel, and oak pollen 
seasons. 
The SQ tree SLIT-tablet has been demonstrated in adults with AR/C induced by pollen from the 
birch group to be efficacious in reducing the symptoms of AR/C, and has an acceptable safety and 
tolerability profile with few reported serious AEs (SAEs), of which none were assessed as related 
to the SQ tree SLIT-tablet (12 SQ-Bet). Furthermore, the TT-04 trial did not provide evidence that 
the efficacy and safety profile of the SQ tree SLIT-tablet differs between adults and adolescents. 
The SQ tree SLIT-tablet has yet to be studied in children <12 years old. 


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Currently, there is no approved SLIT product in Europe or North America for the treatment of 
allergy in children with a history of AR/C symptoms induced by pollen from the birch group and 
treatment in adolescents is only authorised in Switzerland. 
Therefore, there is an unmet clinical need to develop a treatment that can expand the treatment 
options for children and adolescents suffering from AR/C induced by pollen from the birch group. 
 
This trial is a part of the phase III development programme for the SQ tree SLIT-tablet. The 
purpose of this trial is to evaluate the efficacy and safety of the SQ tree SLIT-tablet in paediatric 
subjects (5 through 17 years of age) with persistent moderate to severe AR/C (with or without 
asthma) induced by pollen from the birch group despite being treated with symptom-relieving 
medication. 
1.4 
Benefit-risk assessments 
The SQ tree SLIT-tablet provides an alternative formulation and mode of administration of 
immunotherapy that expands the treatment options for children suffering from AR/C induced by 
pollens from the birch group. The orodispersible dosage form is ideally suited for the treatment of 
children as it is easy to administer, and the rapid dispersion makes it difficult to spit out or aspirate 
(EMEA 2006). 
The SQ tree SLIT-tablet is an effective treatment for adult patients for whom AIT is indicated and 
has an acceptable safety profile in this population. In contrast to SCIT treatments, the SQ tree 
SLIT-tablet does not require up- or down-titration and allows for at-home dosing after 
administration of the first dose in a health care setting under the supervision of a physician with 
experience in the treatment of allergic diseases. 
In the current trial, the SQ tree SLIT-tablet may show an effect on symptom relief and reduce the 
use of symptom-relieving medication in children as well. Thus, subjects on active treatment in the 
trial may receive a direct benefit of access to a new treatment that is not yet commercially 
available. 
All subjects participating in the trial will have access to symptom-relieving medication and will 
receive expert medical care. Their participation will contribute to the development of the new 
treatment for children suffering from allergy induced by pollen from the birch group. 
The SQ tree SLIT-tablet has been demonstrated to be well-tolerated and suitable for 
self-administration in adults. Typical adverse reactions are transient local reactions occurring within 
the first few days of treatment. These are expected in paediatric subjects as well. Other potential 
adverse reactions are class effects of AIT/SLIT and include acute worsening of asthma symptoms 
(exacerbation), EoE, anaphylactic reactions, and serious laryngo-pharyngeal reactions. However, 
these reactions are rare and are not expected to increase in the paediatric population. 
Risks in this trial are manageable when the first SLIT-tablet is administered under physician 
supervision and with appropriate education of the subject and parent/guardian about symptoms 
and signs of severe allergic reactions. There is no expectation of an increased safety risk for 
children enrolled in this trial compared with that observed in adults in previous tree pollen trials. 


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This is supported by similar safety profiles in adult and paediatric subjects treated with SLIT-tablets 
in grass pollen and ragweed pollen trials. 
Based on the efficacy/safety trials of SQ tree SLIT-tablet in adults and a small group of 
adolescents, in addition to the results seen for grass and ragweed SLIT-tablet in both adults and 
children (ages 5 to 65 years), the benefit/risk assessment for conducting this paediatric trial of SQ 
tree SLIT-tablet is favourable. 
Additional details regarding specific benefits and risks for subjects participating in this clinical trial 
may be found in the accompanying Investigators Brochure and Informed Consent documents. 
1.5 
Considerations regarding COVID-19 
Participating in this trial, including receiving treatment with AIT, is not expected to increase 
subjects’ risk of contracting communicable diseases, including COVID-19. The risk to subjects with 
asthma is considered unchanged as only subjects with well controlled mild to moderate asthma are 
included. 
The COVID-19 situation and its impact on clinical trial conduct and activities will be continuously 
monitored by the Sponsor to ensure safety of subjects and trial staff. Local guidance requiring the 
use of personal protective equipment or other measures to ensure patient safety should always be 
followed. If regional circumstances related to COVID-19 change, local guidance should be 
followed. 
1.6 
Ethical considerations 
The population selected for this trial includes children with AR/C when exposed to birch pollen. In 
order to minimise the burden of the disease for subjects enrolled in the trial, and to minimise the 
risk related to trial activities, the following measures have been included in the trial protocol: 
•
Each subject will receive a supply of rescue medication to be used as needed. Subjects
diagnosed with asthma will receive asthma rescue medication to be used as needed
•
Each subject will be provided with a pocket-size subject card containing investigator
contact information
•
An independent DMC will be established for safety monitoring of the trial
A placebo group will be used as a control group in the trial because no product with a similar 
formulation as the IMP is available for use as an active comparator. A placebo group is considered 
ethically justifiable since subjects in both treatment groups will be provided with rescue medication 
to treat allergy symptoms during the trial. Furthermore, subjects will be medically monitored during 
the trial and provided with appropriate treatment, if warranted. Finally, subjects can discontinue 
from the trial at any time and without giving a reason, without penalty or loss of benefits to which 
the subject was otherwise entitled, if they find the treatment intolerable. 
The examinations and procedures (e.g. lung function, SPT, blood sampling) included in this trial 
are of minimal burden to subjects and do not include assessment outside what standard medical 
evaluation of allergic subjects would include. 
The number of blood samples, the volumes of samples taken and the number of times each 
subject needs to provide blood have been reduced as much as possible. The volume of blood 
taken on a single day will fulfil the EMA ethical considerations guidelines (Recommendations of the 


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ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to 
good clinical practice in the conduct of clinical trials on medicinal products for human use 2008). 
This clinical trial will follow the principles of the Helsinki Declaration 1964 and subsequent 
amendments and clarifications (World Medical Association 2013). The trial will be approved by the 
local IRB/IEC and regulatory authorities (as applicable) before initiation. 
2 
OBJECTIVES, ESTIMANDS AND ENDPOINTS 
2.1 
Primary objective 
To compare the efficacy of the SQ tree SLIT-tablet to placebo in the treatment of moderate to 
severe allergic rhinitis and/or conjunctivitis induced by pollen from birch and trees belonging to the 
birch homologous group in children and adolescents (5 through 17 years of age) based on the 
average TCS17 during the BPS. 
2.2 
Key secondary objectives 
To compare the efficacy of the SQ tree SLIT-tablet to placebo based on: 
•
The average TCS during the TPS
•
The average DSS during the BPS and TPS
•
The average DMS during the BPS and TPS
2.3 
Secondary objectives 
The additional secondary objectives are to: 
•
Compare the safety and tolerability of the SQ tree SLIT-tablet to placebo
•
Compare the efficacy of the SQ tree SLIT-tablet to placebo using additional endpoints
based on daily allergic rhinoconjunctivitis symptoms and rescue medication use
•
Compare the efficacy of the SQ tree SLIT-tablet to placebo based on assessments of
quality of life
•
Compare the efficacy of the SQ tree SLIT-tablet to placebo based on patient treatment
satisfaction
•
Compare the effect of the SQ tree SLIT-tablet to placebo on immunological parameters to
birch, alder, hazel and oak pollen
2.4 
Exploratory objectives 
The exploratory objectives are to: 
•
•
17 daily total combined score = daily symptom score + daily medication score 


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•
•
2.5 
Primary estimand 
The primary estimand is the absolute difference between the SQ tree SLIT-tablet and placebo 
treatment policies based on the average TCS during the BPS, in children and adolescents 
(5-17 years of age) with moderate to severe allergic rhinitis and/or conjunctivitis caused by pollen 
from birch, in a population defined by the trial inclusion and exclusion criteria, in the hypothetical 
situation that all subjects complete treatment for the planned duration regardless of whether they 
take rescue medication. 
This estimand will be referred to as the ‘trial product estimand’. The trial product estimand 
assesses the anticipated effect of the SQ tree SLIT-tablet if it is taken as instructed. This estimand 
is considered to be of most relevance to the patient, as it describes the potential benefit they could 
obtain from the SQ tree SLIT-tablet if they adhere to treatment for the planned duration. Adherence 
to treatment is considered important in immunotherapy since the optimal effect of immunotherapy 
is expected when taken consistently for a longer period. 
2.6 
Secondary estimand 
The secondary estimand is the absolute difference between SQ tree SLIT-tablet and placebo 
treatment policies based on the average TCS during the BPS, in children and adolescents 
(5-17 years of age) with moderate to severe allergic rhinitis and/or conjunctivitis caused by pollen 
from birch, in a population defined by the trial inclusion and exclusion criteria, regardless of 
whether subjects complete treatment for the planned duration or take rescue medication. 
This estimand will be referred to as the ‘treatment policy estimand’. The treatment policy estimand 
assesses the treatment effect regardless of adherence to treatment and provides a broad 
perspective of the treatment effect in clinical practice in the selected population of patients. This 
estimand is in line with to the ‘intention to treat’ principle and provides a robust assessment of the 
efficacy of the SQ tree SLIT-tablet. 
2.7 
Estimands for key secondary objectives 
The trial product estimand and treatment policy estimand, specified for the primary objective in 
Sections 2.5 and 2.6 respectively, are defined for each of the key secondary objectives in a similar 
manner. 
2.8 
Primary efficacy endpoint 
Average TCS during the BPS. 
The average TCS during the BPS is based on the allergic rhinoconjunctivitis daily symptom score 
and daily medication score. See Section 15.9.4 for details of the derivation of the primary endpoint. 


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2.9 
Key secondary efficacy endpoints 
•
Average TCS during the TPS
•
Average DSS during the BPS
•
Average DSS during the TPS
•
Average DMS during the BPS
•
Average DMS during the TPS
2.10 Secondary efficacy endpoints 
Additional secondary efficacy endpoints are: 
•
Average TCS, average DSS and average DMS during the alder-hazel (AHPS) and oak
pollen seasons (OPS)
•
Number of severe days during the BPS and TPS, where a severe day is defined by a DSS
≥6 and where ≥2 symptoms are assessed as moderate or 1 symptom is assessed as
severe
•
Number of well days during the BPS and TPS, where a well day is defined as no use of
rescue medication and DSS ≤2
•
Number of symptom-free days during the BPS and TPS, where a symptom-free day is
defined as one with no symptoms and with no use of rescue medication
•
Percentage of patients free of symptoms and with no use of rescue medication during the
BPS and TPS
•
Average TCS (EAACI scoring) during the BPS and TPS
•
Average weekly overall RQLQ score during the BPS and TPS (12-17 years only)
•
Overall PRQLQ score during the BPS (5-11 years only)
•
Treatment satisfaction (TSQM-9) evaluations
•
Patient-rated global evaluation of treatment efficacy
Immunology endpoints: 
•
Change from baseline in birch specific IgE and IgG4
•
Change from baseline in alder, hazel and oak specific IgE and IgG4 (for a subgroup of
randomised subjects only)
•
Change from baseline in birch, alder and hazel specific IgE-BF (for a subgroup of
randomised subjects only)
2.11 Safety and tolerability endpoints 
Safety and tolerability endpoints are: 
•
Treatment-emergent adverse events (TEAEs)
•
Events of special interest (ESI)
o
Systemic allergic reactions including anaphylaxis
o
Events treated with adrenaline/epinephrine
o
Severe local swelling or oedema of the mouth and/or throat
o
EoE
o
Oral allergy syndrome
o
Asthma exacerbations


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•
Vital signs, physical examination, lung function tests and clinical laboratory values during
treatment and at the end-of-treatment visit
•
Local application site reactions (defined according to a pre-specified list of MedDRA
preferred terms)
2.12 Exploratory endpoints 
The exploratory endpoints are: 
3 
TRIAL DESIGN 
3.1 
Summary of trial design 
This is a phase III, randomised, parallel-group, double-blind, placebo-controlled, multi-regional trial 
in children (5-11 years) and adolescents (12-17 years) with AR/C, with or without asthma, induced 
by pollen from birch. Based on previous trials, it is anticipated that most subjects allergic to birch 
will also have AR/C induced by pollen from the birch group. Approximately 1000 subjects will be 
randomised (1:1) to receive treatment with the SQ tree SLIT-tablet or placebo. The randomisation 
will be stratified by geographical location and by age group (5-11 years and 12-17 years). 
Approximately 45% of the subjects should be aged 5-11 years at the time of randomisation. 
The trial consists of 3 periods: a screening period, a treatment period, which includes pre-seasonal 
and co-seasonal treatment, and a follow-up period (Figure 1). There may be multiple cohorts 
recruited over consecutive seasons to complete the enrolment goal. 
The screening visit can take place up to approximately 6 months prior to randomisation. Once 
randomised, subjects should be treated for at least 12 weeks prior to the start of the TPS. 
Treatment will continue until 1 week after the end of the TPS, corresponding to up to 
approximately 12 months of treatment. 
 
 
 


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Open-label rescue medication for allergic rhinoconjunctivitis will be provided during the TPS 
 
 Open-label asthma medication will be provided to subjects with asthma during the TPS 
 
 
A follow-up phone visit will be conducted 1 week after the final treatment. 
The expected start and stop dates of the relevant pollen seasons in each region are specified in 
Appendix 5. If monitoring of the daily pollen counts identifies a change to the expected start or stop 
date of a pollen season for any country or region, the affected site will be notified and the eDiary 
will be updated to allow for additional data collection. The TPS includes the hazel, alder, birch and 
oak pollen seasons. 
Figure 1 
Overall trial design 


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3.2 
Discussion of design 
The design for the present trial has been selected based on the recommendation from the EMA 
guideline on the clinical development of products for AIT for the treatment of allergic diseases 
(EMEA 2008), and the needs stated in the WHO position paper on AIT for development of SLIT 
(Bousquet et al. 1998b). The trial design is also based on the experience from previous ALK trials 
with AIT. 
The population selected by the eligibility criteria reflects a population that may benefit from 
treatment with AIT. The subjects eligible for the trial are children and adolescents with a clinical 
history of moderate to severe AR/C induced by birch pollen despite having received symptom-
relieving medication for the past 2 BPSs prior to trial entry (only 1 past BPS for children aged 
4-6 years at screening). Although a history of allergic rhinitis/rhinoconjunctivitis requiring
symptomatic treatment during at least 2 consecutive seasons is recommended (EMA & PDCO
2015), 1 season was set for children below 7 years of age to facilitate enrolment of the younger
children in the trial. The minimum age at screening will be 4 years (5 years at randomisation),
which would require a clinical history from 2-3 years old, which is not considered feasible.
The primary endpoint is the average TCS during the BPS, which is the average of the daily sum of 
the DSS and DMS during the BPS. As symptom-relieving medications are allowed in the trial, it is 
reasonable to adjust the reported symptom score to account for the symptom-relieving medications 
used, in order to get a more accurate representation of symptomatology. Further, the primary 
endpoint presented as a single combined variable is believed to be consistent with current global 
regulatory positions on appropriate reporting of results from AIT trials. The World Allergy 
Organization has stated that since symptoms and symptom-relieving medication utilisation are 


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interdependent variables when assessing the effect of AIT, a combined score more accurately 
reflects efficacy (Canonica et al. 2009). EMA has also stated in their guidance on AIT that the 
primary endpoint for trials should be reflective of both severity of symptoms and the intake of 
rescue medications (EMEA 2008). 
The symptom score is constructed as recommended in the EMA guideline (EMEA 2008) and is 
identical to the score used in previous ALK trials in the SQ tree SLIT-tablet development 
programme. 
The medication score has been used in the previous field trials with the SQ tree SLIT-tablet (TT-02 
and TT-04), in numerous clinical trials performed with grass and ragweed SLIT-tablets (Blaiss et al. 
2011; Bufe et al. 2009; Creticos et al. 2013; Durham et al. 2006; Maloney et al. 2014; Nelson et al. 
2011; Nolte et al. 2013), and was developed by ALK based on recognised guidelines (Canonica et 
al. 2007; EMEA 2008) and thorough discussions with key opinion leaders/specialists within the 
field of allergy. The proposed weighting of the different medications has been chosen to mirror the 
reduction of symptoms, i.e. the higher ability to reduce symptoms the higher maximum daily score. 
The relative treatment effect for the primary endpoint in this trial is anticipated to be at least 25% 
and a previous trial with the SQ tree SLIT-tablet has demonstrated a treatment effect considerably 
higher than this (Biedermann et al. 2019a). As such, it is expected that this trial will satisfy the 
requirements of EMA (point estimate of the absolute treatment effect greater than 1), FDA (point 
estimate of the relative treatment effect to be greater than 15% (Massie 2011)) and also meet the 
World Allergy Organisation task force recommendation of a clinically relevant difference of 20% 
(Canonica et al. 2007). 
It is anticipated that pollen exposure will vary with location, therefore, the randomisation will be 
stratified by geographical location. To ensure a balanced target population with respect to age, 
randomisation will also be stratified by age group (5-11 years and 12-17 years) in accordance with 
EMA/PDCO recommendations (EMA & PDCO 2015). 
A double-blinded design has been chosen to minimise the potential biases resulting from 
differences in management, treatment, or assessment of subject or interpretation of results that 
could arise as a result of subject or investigator knowledge of the assigned treatment. 
Placebo has been chosen as the comparator on which to evaluate the efficacy of the SQ tree 
SLIT-tablet, since no well-established active comparator treatment exists. All subjects should be 
randomised at least 12-weeks before the anticipated start of the TPS. This is a reduction compared 
to the 16 weeks used in earlier trials with the SQ tree SLIT-tablet and has been introduced to 
reduce the trial burden on subjects. This is based on experience from other SLIT-tablet trials for 
pollen-induced allergies (grass, ragweed), which have shown 12 weeks pre-seasonal treatment to 
be sufficient to induce a clinical effect in paediatric and adult populations 
 
 
 
 
 
Safety endpoints for this trial have been based on previous trials with SLIT AIT include AEs, vital 
signs, lung function and laboratory values. 


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3.3 
Justification of dose 
The basic principle for AIT dose selection is to use the highest tolerable and safe dose. The 
highest tolerable/safe and effective dose of the SQ tree SLIT-tablet has been shown to be 
12 SQ-Bet in adults. The TT-04 trial did not provide evidence that the efficacy and safety profile of 
the SQ tree SLIT-tablet differs between adults and adolescents. Further, practice guidelines do not 
recommend dose adjustment in children as allergens act on the immune system and are neither 
systemically absorbed nor metabolized by the liver and kidneys. This has also been demonstrated 
for grass and ragweed SLIT-tablets, where the same dose is used regardless of age. 
Therefore, the 12 SQ-Bet dose of the SQ tree SLIT-tablet approved for use in adults will also be 
used in children in this trial. 
3.4 
End of trial definition 
The end of the trial is defined as the date of the last follow-up phone visit (TC4) for the last subject 
in the trial. 
4 
TRIAL POPULATION 
Subjects randomised will be children and adolescents 5 through 17 years of age with moderate to 
severe birch pollen AR/C, with or without asthma, despite use of symptom-relieving medication. 
Approximately 45% of the subjects will be 5 through 11 years of age at the time of randomisation. 
No more than one subject from the same household can be enrolled in the same cohort. Subjects 
from the same household can be enrolled in separate cohorts. 
4.1 
Inclusion criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
I1. 
Written informed consent obtained from parents/caregivers before any trial related 
procedures are performed. Consent or assent from the subject must be obtained according to 
national requirements. 
I2. 
Male or female of any race/ethnicity aged ≥4 to <18 years on the day informed consent is 
obtained from the parent/caregiver. The subject must be ≥5 to <18 years old at the 
randomisation visit 
I3. 
A female subject of child-bearing potential18 must have a negative pregnancy test and be 
willing to practise appropriate19 contraceptive methods until the follow-up TC 
18 Females are considered of child-bearing potential after their first menstrual period 
19 For the purpose of this protocol the following contraceptive methods are considered appropriate: oral contraceptives, trans dermal patches or 
depot injection of a progestogen drug (starting at least 4 weeks prior to IMP administration); double barrier method: condom or occlusive cap 
(diaphragm or cervical/vault caps) plus spermicidal agent; IUD, IUS, implant, or vaginal ring (placed at least 4 weeks prior to IMP administration); or 
male partner sterilisation (vasectomy with documentation of azoospermia) prior to the female subject's entry into trial and is the sole sexual 
partner for that female subject. Sexual abstinence is acceptable as contraceptive if it is true abstinence and in line with the usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. However, national requirements regarding contraception should always be followed.


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I4. 
A documented,20 physician diagnosed, clinically relevant history of moderate to severe AR/C 
induced by birch pollen (with or without asthma) despite having received treatment with 
symptom-relieving medication during at least 1 previous tree pollen season for ages 
4 through 6 years at screening or at least 2 previous tree pollen seasons for ages 7 through 
17 years at screening 
I5. 
Positive skin prick test (SPT) to Betula verrucosa at screening21 
I6. 
Positive specific IgE22 to Bet v at screening 
I7. 
Presence of one or more of the following Allergic Rhinitis Impact on Asthma (ARIA) quality of 
life items due to AR/C during the previous BPS: 
a.
Sleep disturbance
b.
Impairment of daily activities, leisure and/or sport
c.
Impairment of school or work
d.
Troublesome symptoms
I8. 
Subject must be willing and able to comply with trial protocol 
4.2 
Exclusion criteria 
Subjects are excluded from the trial if any of the following criteria apply: 
E1. 
Previously randomised in this trial. 
E2. 
Is participating or planning to participate in any other interventional clinical trial during the 
duration of this trial 
E3. 
A clinically relevant history of symptomatic seasonal AR/C caused by an allergen source, 
other than tree pollen from the birch homologous group, with a season overlapping the TPS 
E4. 
A clinically relevant history of symptomatic perennial AR/C caused by an allergen source 
such as animal hair and dander to which the subject is exposed during the TPS. 
E5. 
Asthma requiring high daily doses23 of inhaled corticosteroids within 3 months prior to the 
randomisation visit 
E6. 
Any clinical deterioration of asthma (i.e. asthma exacerbation) that resulted in emergency 
treatment, hospitalisation or treatment with systemic corticosteroids within 3 months prior to 
randomisation 
20 If medical records are not available, verbal history from subject/parent/caregiver may be elicited at the Screening Visit and can be used to fulfil 
this criterion if documented in the subject study file by the investigator.
21 A positive SPT is defined in the SPT guideline. Briefly, a positive SPT is defined as a wheal size of ≥3 mm. If medication that could interfere with 
the SPT, according to prohibited and restricted medication table, has not been washed out, the SPT must be performed after the interfering 
medication has been washed out. 
22 A positive specific IgE is defined as ≥IgE Class 2; ≥0.70 kU/L 
23 For acceptable/prohibited ICS doses see Table 4 (for children) or Table 5 (for adolescents) 


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E7. 
Reduced lung function at randomisation defined as FEV1 <70% of predicted value. For 
asthmatic subjects this is assessed on subject’s usual asthma medication following at least a 
6-hour wash-out of SABA.
This criterion does not need to be fulfilled if the subject is <7 years old, cannot perform
reproducible FEV1 manoeuvres despite coaching and is not considered as having a
diagnosis of asthma.
E8. 
SLIT treatment with pollen allergen extracts from birch and trees belonging to the birch 
homologous group for more than 1 month within the last 5 years. In addition, any SLIT 
treatment with birch pollen or a cross-reactive/homologous tree pollen allergen extracts 
within the previous 12 months. 
E9. 
SCIT treatment with pollen allergen extracts from birch and trees belonging to the birch 
homologous group reaching the maintenance dose within the last 5 years. In addition, any 
SCIT treatment with birch pollen or a cross-reactive/homologous tree pollen allergen extracts 
within the previous 12 months. 
E10. Ongoing treatment with any allergy immunotherapy product 
E11. Severe chronic oral inflammation 
E12. Any nasal or naso/oropharyngeal condition that could confound the efficacy or safety 
assessments (e.g. hypertrophy of the pharyngeal/palatine tonsils, clinically relevant nasal 
polyps, a history of paranasal sinus surgery or surgery of nasal turbinates) 
E13. A diagnosis of EoE 
E14. A history of chronic urticaria (>6 weeks) and/or chronic angioedema (>6 weeks) within the 
last 2 years prior to screening that in the opinion of the investigator may constitute and 
increased safety concern 
E15. A relevant history of systemic allergic reaction e.g. anaphylaxis with cardiorespiratory 
symptoms, generalised urticaria or severe facial angioedema that in the opinion of the 
investigator may constitute an increased safety concern 
E16. Any clinically relevant chronic disease incl. malignancy that in the opinion of the investigator 
would interfere with the trial evaluations or the safety of the subject 
E17. Active or poorly controlled autoimmune diseases, immune defects, immunodeficiencies, 
immunosuppression or malignant neoplastic diseases with current disease relevance 
E18. Immunosuppressive treatment (ATC code L04 or L01) within 90 days prior to the screening 
visit 
E19. Treatment with medications with potential impact on efficacy endpoints. For example: 
- Treatment with anti-IgE drugs within 130 days/5 half-lives of the drug (which ever longest)
prior to randomisation
- Treatment with antidepressant within 14 days prior to randomisation
- Treatment with antipsychotic medications with antihistaminic effect within 7 days prior to
randomisation
E20. Treatment with an investigational drug within 30 days/5 half-lives of the drug (which ever 
longest) prior to screening 


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E21. A history of allergy, hypersensitivity or intolerance to the IMP (except to the active ingredient) 
or any of the background treatment provided in this trial 
E22. Female who is pregnant or breast-feeding 
E23. Has a direct or indirect business or personal relationship with trial staff or sponsor who is 
directly involved with the conduct of the trial 
E24. A history of alcohol or drug abuse 
4.3 
Screening failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to in/exclusion criteria and subsequently not randomly assigned 
to trial intervention. 
A minimal set of screen failure information will be recorded to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. 
4.3.1 
Re-screening 
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria, 
however, the following exceptions applies: a subject is allowed to be re-screened once if failing 
inclusion criterion I2. Re-screening is allowed once for a subject who met all inclusion and 
exclusion criteria but were not able to meet the closing data of randomisation in that cohort. A re-
screened subject is required to sign a new ICF, and a new subject ID number will be allocated.  
Resampling of central laboratory samples is not allowed for any failed inclusion or exclusion 
criteria. Only in cases when laboratory samples are lost or haemolysed, resampling is allowed. 
Subjects with evidence of current, clinically significant, intercurrent illness (e.g., significant cold or 
flu) at screening may be rescheduled for a new screening visit on resolution of their illness.  


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5 
DISCONTINUATION OF IMP TREATMENT AND SUBJECT 
WITHDRAWAL 
5.1 
Criteria for discontinuation from IMP treatment 
All efforts should be made to keep the subject on IMP treatment. However, the subject has the 
right to discontinue IMP treatment at any time without prejudice or may be discontinued from IMP 
treatment at the discretion of the investigator due to safety concerns. 
Subjects must be discontinued from IMP treatment under the following circumstances: 
•
If a subject becomes pregnant
•
The subject experiences severe or persistent symptoms of oesophagitis or have a confirmed
diagnosis of EoE
•
The subject’s asthma becomes difficult to control
•
If, in the investigator’s opinion, continuation with IMP treatment would be detrimental to the
subject’s well-being
•
Simultaneous or previous participation (within 30 days or 5 half-lives of the product, whichever
is longer, before randomisation) in other clinical trials of an approved or non-approved IMP
•
If treatment is unblinded for the subject or investigator
If found required by ALK after discussion with the investigator, subjects may be discontinued from 
IMP treatment as a result of a protocol deviation. 
Subjects that discontinue IMP treatment should be encouraged to continue to participate in the trial 
and to continue with all scheduled visits/site contacts and complete all assessments and the 
patient eDiary according to the protocol. Subjects must be educated about the continued scientific 
importance of their data, even if they discontinue trial product. 
5.2 
Subject withdrawal from the trial 
The subject and/or the subject’s parent/caregiver will be advised in the informed consent form that 
he/she has the right to withdraw from the trial at any time without prejudice. 
If a subject withdraws consent, the investigator must ask the subject if he/she is willing, as soon as 
possible, to have assessments performed according to visit 6. 
Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. 
Where the reasons are obtained, the primary reason for withdrawal must be specified in the 'End of 
study' form in the eCRF and in the subject’s medical records. 
Final drug accountability must be performed even if the subject is not able to come to the site. 
5.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and 
is unable to be contacted by the site by the time of the subject’s last scheduled visit (V6). Reasonable effort 
should be made to contact any subject who does not return to the site for scheduled visits during the 
course of the trial, in order to complete assessments and retrieve any outstanding data and 


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medication/supplies. Should the subject continue to be unreachable, he/she will be considered lost to 
follow-up, and the effort taken to contact the subject should be documented in the subject’s medical 
record. 
Efforts to regain contact should continue until the end of the subject’s last scheduled site visit (V6). 
5.4 
Replacement of subjects 
Subjects who withdraw consent or discontinue IMP treatment will not be replaced. 
6 
RANDOMISATION AND TREATMENT 
BLINDING/UNBLINDING 
6.1 
Subject ID number 
All subjects enrolled must be identifiable throughout the trial. Each subject will be allocated a 
5-digit subject number in combination with a 3-digit site number to create a unique subject id (e.g.
101-50001).
The subject number will be generated when the subjects’ data are entered in the eCRF at the 
screening visit. 
6.2 
Randomisation 
The randomisation list will be generated by a trial-independent statistician and will not be 
accessible to trial personnel involved in the conduct of the trial, until the database has been locked. 
The randomisation will be administered centrally via IRT and will be stratified based on 
geographical location and age group. 
The randomisation codes will only be made available for data analysis when the clinical database 
has been locked and all protocol deviations have been identified and evaluated. 
6.3 
Treatment blinding/unblinding 
A double-blind setup will be used; the active IMP and their matching placebo will be similar in 
appearance and taste and will be packaged identically to maintain the treatment blind. The 
treatment will be blinded to the subject, the investigator and sponsor personnel or delegates who 
are involved in the treatment administration or clinical evaluation of the subject. 
The treatment for a particular subject may be unblinded by the investigator (or another treating 
physician) in a medical emergency if knowledge of the IMP is necessary for the optimal treatment 
of the subject. If possible, the trial site must contact ALK prior to unblinding the subject's treatment. 
However, in case of an emergency, unblinding and appropriate treatment should be the very first 
action by the site. 
The emergency unblinding will be performed via IRT for this trial. The time, date and reason for 
unblinding as well as the initials of the person breaking the randomisation code must be recorded. 
Unblinding may also be done by the Qualified person responsible for pharmacovigilance. 


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The IRT will notify the CRA and the sponsor’s safety department immediately after the 
randomisation code is broken. The subject must be discontinued from IMP treatment after 
randomisation code breaking. 
It may also be necessary to unblind an individual subject’s treatment by the sponsor’s safety 
department, for the purposes of expedited reporting to the authorities and/or ethics committees 
(e.g. in case of a suspected unexpected serious adverse reactions). In that situation, blinding of 
other sponsor personnel and of the investigator and subject must be maintained during the trial. 
6.4 
Subject card 
All subjects who have signed the informed consent form must be given a subject card at screening 
by the investigator or qualified designee, identifying them as participants in a clinical trial. The card 
will contain trial site information (including direct telephone number) to be utilised in an emergency. 
7 
RESTRICTED AND PROHIBITED CONCOMITANT 
MEDICATION 
All concomitant medications must be appropriately documented in the eCRF. The use of any 
concomitant medication must relate to the documented medical history, prophylaxis or an AE. 
The medication listed in Table 1 is restricted or prohibited unless it is provided by ALK. All 
listed medications interfere with safety assessments or rhinoconjunctivitis 
 
assessments. 


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Table 1 
Restricted and prohibited concomitant medications 
Drug 
Time window 
An investigational drug other than the IMP 
≤30 days/5 half-lives of the drug (whichever 
longest) before visit 1 and until TC4  
Antihistamine, unless provided by the sponsor 
• Oral, intravenous, nasal or ocular
• Long-acting (astemizole)
• From visit 4 and until visit 6
• ≤90 days before visit 4 and until visit 6
Antidepressant medications24: 
•
Antidepressant medication with antihistaminic effect
(e.g. doxepin, mianserine)
•
Tricyclic antidepressants (e.g. amitriptyline,
clomipramine)
•
Monoamine oxidase inhibitors (MAOIs)
≤14 days before visit 2 and until TC4 
Antipsychotic medications with antihistaminic effects (e.g. 
chlorpromazine, levomepromazine, clozapine, 
olanzapine, tioridazine) 
≤7 days before visit 2 and until TC4 
Biologic asthma treatments, including, but not limited to 
anti-IgE, anti-IL5, anti-IL5R and anti-IL4R treatment 
(e.g. omalizumab, mepolizumab, benralizumab, 
reslizumab and dupilumab) 
<130 days/5 half-lives of the drug (whichever 
longest) prior to visit 2 and until TC4 
Glucocorticosteroids 
-unless provided by the sponsor (see section 8.2)
-does not include inhaled corticosteroids (ICS), however
a subject must have been on a stable regimen (daily dose
unchanged) of ICS for at least 4 weeks before
randomisation (visit 2)
•
topical (nasal or ocular)
•
with systemic effect25
- any oral tablets (oral corticosteroid use is allowed in
cases of asthma exacerbation)
- any parenteral formulations (intravenous, intra-
articular or intramuscular) or depot formulations
regardless of treatment days and dose
•
topical: from 30 days before visit 4 and until
visit 6
•
oral: from 60 days before visit 4 and until
visit 6
•
parenteral or depot: from 90 days before
visit 4 and until visit 6
Systemic immunosuppressive treatments (ATC code L04, 
L01) other than glucocorticosteroids 
≤90 days before visit 1 and until TC4 
Immunotherapy with any other allergen(s) 
From visit 1 and until TC4 
Inhaled, topical or oral nedocromil or cromolyn sodium 
≤14 days before visit 4 and until TC4 
24Tricyclic antidepressants and MAOIs may potentiate the effect of adrenaline/epinephrine 
25Estimated equipotent doses (i.v. or p.o.); 20 mg Hydrocortisone = 5 mg Prednisolone = 5 mg Prednisone = 4 mg Methylprednisolone = 0.75 mg 
Dexamethasone (Liu et al, 2013) 


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Drug 
Time window 
Long-acting β2-agonist (LABA) monotherapy (low and 
medium dose ICS/LABA in combination are allowed). 
From 30 days before visit 4 and until TC4 
Leukotriene receptor antagonists (e.g. montelukast, 
zafirlukast) 
From visit 1 and until TC4. If treatment has 
begun at least 30 days prior to visit 1 dose can 
be kept unchanged during trial. 
Nasal or ocular decongestants 
≤7 days before visit 4 and until TC4 
SABA, unless provided as rescue medication in the trial 
From visit 4 and until visit 6 
8 
TRIAL PRODUCTS 
8.1 
IMP 
All IMP is manufactured and provided by ALK. The placebo is similar to the active treatment with 
regard to appearance, smell and taste. 
Please refer to Table 2 for details regarding IMP. 
Table 2 
IMP details 
IMP dispensing 
The treatment will start at visit 2 (the randomisation visit) where the IMP will be dispensed. 
Hereafter, the IMP will be dispensed at visit 4 (pre-TPS visit) and visit 5 (in season BPS visit). 
8.2 
Rescue medication 
During the trial, subjects may experience allergy symptoms that require additional treatment. 
Medication to treat rhinoconjunctivitis or asthma symptoms (only for subjects with asthma) will be 
provided by the sponsor and can be used in addition to the IMP to which the subjects have been 
randomised. All medication should be used in accordance with the product's labelling (e.g. SmPC). 
Active treatment 
Placebo 
IMP name: 
SQ tree SLIT-tablet 
Placebo 
Active ingredients: 
Betula verrucosa, allergen extract 
N/A 
Dosage form: 
Oral lyophilisate 
Oral lyophilisate 
Excipients: 
Gelatine (fish source), mannitol and 
sodium hydroxide 
Gelatine (fish source), mannitol and 
sodium hydroxide 
Route of administration: 
Sublingual 
Sublingual 
Dose/strength: 
12 SQ-Bet 
- 
Dosing instruction: 
1 oral lyophilisate daily preferably in 
the morning. 
1 oral lyophilisate daily preferably in 
the morning. 


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8.2.1 
Rhinoconjunctivitis rescue medication 
For the treatment of allergic rhinoconjunctivitis symptoms, the subject will be provided with: 
•
Oral antihistamine tablets (Loratadine tablets 10 mg) or oral antihistamine solution
(Desloratadine oral solution 0.5 mg/mL)
•
Olopatadine eye drops, 1 mg/mL
•
Mometasone furoate nasal spray, 50 µg/dose
The dosing instructions for these medications are provided in Table 3. 
Rescue medication for allergic rhinoconjunctivitis will be provided by the sponsor before the start of 
the TPS as pre-defined, open-labelled medication and can be used as needed, in addition to the 
IMP to which the subjects have been randomised. An adequate initial supply of each of these 
rescue medications will be dispensed to the subject at visit 4 but must not be used before the 
investigator has informed the subject that the TPS has started (TC2). The subjects must be 
instructed to start with antihistamine tablets and/or eye drops and continue with nasal 
corticosteroids only if antihistamine tablets and/or eye drops cannot alleviate the symptoms. The 
medication is to be used according to investigators instructions (and according to the package 
insert/leaflet for the individual medications). 
Table 3 
Schedule for rhinoconjunctivitis rescue medication 
Rhinoconjunctivitis rescue 
medication 
Subject dosage instructions 
Rhinitis 
Loratadine, 10 mg 
5-12 years old and >30 kg: 1 tablet once daily as needed
>12 years old: 1 tablet once daily as needed
Desloratadine, 0.5 mg/mL 
5 years old: 2.5 mL solution once daily as needed 
6-11 years old: 5.0 mL solution once daily as needed
≥12 years old: 10 mL solution once daily as needed 
Mometasone, 50 µg/dose 
5-11 years old: 1 puff in each nostril once daily as needed
≥12 years old: 2 puffs in each nostril once daily as needed 
Conjunctivitis 
Olopatadine eye drops, 1 mg/mL 
1 drop in the affected eye(s) twice daily, morning and evening as 
needed 
8.2.2 
Asthma rescue medication 
SABA (i.e. salbutamol inhaler, 100 mcg/puff) will be provided to subjects with asthma at visit 4 and 
at subsequent visits as necessary. The salbutamol inhaler should be used when necessary 
according to the label. 
Other medications for asthma will not be provided or reimbursed. Subjects who are taking low or 
medium daily dose ICS alone or in combination with LABA for asthma management will be allowed 


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to continue with the same medications during the trial. A subject must have been on a stable 
regimen (daily dose unchanged) for at least 4 weeks before randomisation (visit 2). Low and 
medium daily doses of ICS are defined in Table 4 and Table 5. 
If a subject requires additional asthma medications, the subject should follow recommendations 
regarding medication adjustments provided by his/her physician. Medication use should be 
recorded in the eCRF. 
Table 4 
Definition of low, medium and high dose ICS for subjects aged 5-11 years as 
defined by the modified GINA Guideline 
Inhaled corticosteroid 
Low daily dose 
(micrograms (µg)) 
Medium daily dose 
(micrograms (µg)) 
High daily dose 
(micrograms (µg)) 
Beclomethasone dipropionate 
(pMDI, standard particle, HFA) 
100 – 200 
>200 – 400
>400
Beclomethasone dipropionate 
(pMDI, extrafine particle*, HFA) 
50 – 100 
>100 – 200
>200
Budesonide (DPI) 
100 – 200 
>200 – 400
>400
Budesonide (nebules) 
250 – 500 
>500 – 1000
>1000
Ciclesonide (pMDI, extrafine 
particle*, HFA) 
80 
>80 –160
>160
Fluticasone furoate (DPI) 
50 
n.a.
Fluticasone propionate (DPI) 
50 – 100 
>100 – 200
>200
Fluticasone propionate (pMDI, 
standard particle, HFA) 
50 – 100 
>100 – 200
>200
Mometasone furoate (pMDI, 
standard particle, HFA) 
100 
200 
>200
DPI: dry powder inhaler; HFA: hydrofluoroalkaline propellant; ICS: inhaled corticosteroid; n.a.: not applicable; 
pMDI: pressurised metered dose inhaler (non-cholofluorocarbon formulations). 
* See product information.
Note: Dose delivery by method or modality other than those noted above must be equivalent 
Source: modified from GINA (GINA Executive Committee 2020) 


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Table 5 
Definition of low, medium and high dose ICS for subjects aged 12 years and 
above, as defined by the modified GINA Guideline 
Inhaled corticosteroid 
Low daily dose 
(micrograms (µg)) 
Medium daily dose 
(micrograms (µg)) 
High daily dose 
(micrograms (µg)) 
Beclomethasone dipropionate 
(pMDI, standard particle, HFA) 
200 – 500 
>500 – 1000
>1000
Beclomethasone dipropionate 
(pMDI, extrafine particle*, HFA) 
100 – 200 
>200 – 400
>400
Budesonide (DPI) 
200 – 400 
>400 – 800
>800
Ciclesonide (pMDI, extrafine 
particle*, HFA) 
80 – 160 
>160 – 320
>320
Fluticasone furoate (DPI) 
100 
100 
200 
Fluticasone propionate (DPI) 
100 – 250 
>250 – 500
>500
Fluticasone propionate (pMDI, 
standard particle, HFA) 
100 – 250 
>250 – 500
>500
Mometasone furoate (DPI) 
200 
200 
400 
Mometasone furoate (pDMI, 
standard particle, HFA) 
200 - 400 
200 – 400 
>400
DPI: dry powder inhaler; HFA: hydrofluoroalkaline propellant; ICS: inhaled corticosteroid; n.a.: not applicable; 
pMDI: pressurised metered dose inhaler (non-cholofluorocarbon formulations). 
* See product information.
Note: Dose delivery by method or modality other than those noted above must be equivalent
Source: modified from GINA (GINA Executive Committee 2020)
8.3 
Packaging and labelling 
The IMP will be supplied in blister cards containing 10 tablets. The blister cards will be packed in 
specific boxes containing a sufficient number of tablets to cover the treatment period between the 
dispensing visits and the end of trial visit. 
IMP will be packaged and labelled according to EU Annex 13 and national requirements. 
The IMP will be uniquely numbered and identified by a unique medication number per pack. 
Rescue medication supplied by the sponsor will be supplied with labels and patient information 
leaflets in local language. 
Packaging and labelling will be outsourced (See Appendix 3). 
In exceptional circumstances where ALK is not able to provide rescue medication, it may be 
provided locally by ALK or by the trial site and reimbursed by sponsor. 


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8.4 
Handling and storage 
The trial products provided by ALK (IMP, rescue medication and SPT materials) are to be used 
only for this trial and not for any other purpose. 
The trial products must be stored in a secure, limited-access location separate from normal clinic 
stocks and according to label specifications. IMP and rescue medication returned by the subject 
must be stored separate from other medication, e.g. unused IMP that has not yet been dispensed. 
Site storage conditions for all trial products must be monitored by the site staff for adherence to 
label specifications and reviewed by the CRA during monitoring visits. 
Monitoring must be done using a calibrated, stationary and continuously recording system. As a 
minimum a calibrated min/max thermometer is required. 
8.5 
IMP and rescue medication accountability 
The investigator or appropriate delegated staff must maintain records of the IMP and rescue 
medication delivered to the trial site. 
The site must maintain records of: 
•
Inventory at the site
•
Dispensing to each subject
•
Return by each subject to site
•
Return by site to ALK
These records must include dates, quantities, batch/serial numbers, expiry dates and the unique 
IMP code number assigned to the subject. Investigators must maintain records that document 
adequately that the subjects were provided the doses specified by the protocol and must reconcile 
all IMP and rescue medication received from ALK. 
All IMP and rescue medication accountability logs and records will be verified by the CRA during 
the monitoring visits in accordance with the monitoring plan. 
Full drug accountability will be performed for the IMP. Subjects must be instructed to bring all 
residual and unused IMPs and all empty packaging to the site at every drug accountability visit. 
Compliance will be assessed by SLIT-tablet counts. If IMP compliance is less than 80% or more 
than 100%, the investigator should discuss the reason and educate the subject to comply with the 
dosing regimen. 
Drug accountability for rescue medication will be performed on a pack level. 
After LSLV at site, the investigator will return all unused and partly used IMP and rescue 
medication and a copy of the completed drug accountability form to the CRA or to the sponsor 
address provided. 
The investigator must not destroy any IMP or rescue medication without written agreement with 
ALK. 
8.6 
Reporting of technical complaints 
Any technical complaint related to the trial products provided by ALK (IMP, rescue medication, 
SPT) must be reported to ALK. The information must be accompanied by samples or a picture of 
the item. 


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9 
TREATMENT 
9.1 
Treatment administration 
The IMP should be taken with dry fingers from the blister unit immediately after opening the blister 
and placed under the tongue, where it will disperse. Swallowing should be avoided for 
approximately 1 minute. Wash hands after handling the tablet. 
Food and beverages should not be taken for the following 5 minutes after intake of IMP. The daily 
dose of IMP is 1 SLIT-tablet, which should preferably be taken in the morning. 
9.2 
Precautions in relation to first dosing 
First intake of IMP should be at the clinic with a subsequent 30 minute observation period. 
For subjects with severe oral inflammation (e.g. oral lichen planus, mouth ulcers or thrush), oral 
wounds or following oral surgery, including dental extraction, or following tooth loss, initiation of 
IMP treatment should be postponed to allow healing of the oral cavity. 
For subjects with symptoms of or in treatment for upper respiratory tract infection, acute sinusitis, 
acute otitis media or other relevant infections, initiation of IMP treatment should be postponed until 
the condition has improved. 
If first dosing is postponed, the first intake of IMP should still be at the clinic with a subsequent 
30 minutes observation period. 
9.3 
Treatment of severe allergic reactions/anaphylaxis 
The subject/parent/caregiver will be provided with educational information regarding symptoms of 
anaphylaxis and treatment. 
In the event of symptoms or treatment of anaphylaxis, the subject/parent/caregiver must 
immediately call the local emergency number and the 24-hour investigational site emergency 
number indicated on the subject identification card. An unscheduled visit will be arranged to further 
evaluate the subject. The investigator or designee must notify the Sponsor within 1 working day of 
first becoming aware of symptoms or treatment of anaphylaxis. The symptoms and/or 
circumstances that triggered symptoms or treatment of anaphylaxis must be clearly recorded on 
the eCRF. 
9.4 
Temporary interruption of treatment 
Treatment may be temporarily interrupted for the following reasons: 
•
In case of oral surgery, including dental extraction, or shedding of a deciduous tooth, to
allow healing of the oral cavity
•
Inflammatory conditions in the oral cavity
•
Upper airway viral infection in subjects with asthma
•
Other reasons if deemed necessary by the investigator
Interruptions should be kept to a minimum, but the event causing the interruption should be 
resolved before re-initiating the treatment. If IMP is interrupted for more than 7 days in a row, the 
investigator should be contacted before restarting the treatment. The investigator should evaluate 


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based on the length of the IMP interruption and previously experienced AEs if the subject should 
re-initiate treatment again at the clinic. 
9.5 
Post-trial treatment 
After the end of the trial, the investigator must advise trial subjects on access to appropriate and 
available treatment. Post-trial treatment will not be sponsored by ALK. 
10 VISIT SCHEDULE 
The assessments that should be performed at each visit are described in Table 6. The 
assessments are listed in the chronological order in which they should preferably be performed: 
Table 6 
Visit schedule 
Visit ID 
Assessments to be performed at the visit 
Visit 1 
(screening) 
Visit window: 
1 to 26 weeks prior to randomisation visit 2 
• Obtain written informed consent for the trial before any other assessment is
performed
• Obtain written informed consent for collection and storage of serum samples in the
ALK Research Biobank and for pharmacogenetic testing, if applicable, before any
other assessments are performed
• Assess compliance with inclusion and exclusion criteria
• Obtain demographic data (sex, month and year of birth, race and ethnicity)
• Record smoking habits
• Record medical history
• Record use of relevant prior and concomitant medications
• Perform physical examination
• Measure weight
• Measure vital signs
• Perform urine pregnancy test (if appropriate)
No data is available for SPT in pregnant subjects, therefore for female subjects
of child-bearing potential, perform the urine pregnancy test before SPT 
• Perform SPT and evaluate results (to be performed at visit 2, if wash-out of
concomitant medication is required)
• Assess AEs
• Assess symptoms of eosinophilic oesophagitis
• Collect blood and urine sampling for safety laboratory assessments
• Collect blood sampling for specific IgE against Bet v and immunological
assessments
• If the specific consent has been obtained, collect the biobank blood sample
• Schedule the date for the retention visit TC1 and/or visit 2 and complete this in the
eCRF


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TC1 
(Retention) 
Visit window: 
4 to 12 weeks prior to visit 2. Only required if screening is more than 12 weeks prior to 
randomisation 
• Confirm subject’s continued interest in trial participation
• Assess AEs occurring since the last visit
• Record concomitant medication
• Reconfirm date for visit 2
Visit 2 
(Randomisation 
and first IMP 
administration) 
Visit window: 
1 to 26 weeks after screening visit 1 
• Re-assess compliance with inclusion and exclusion criteria
• Randomise the subject
• Record concomitant medication
• Perform physical examination
• Measure height and weight
• Lung function:
-
All subjects who are 7 years of age or older must perform the lung function
test related to Exclusion criterion 7.
-
Subjects who are less than 7 years of age may not have to perform the
lung function test depending on the following:

Does the subject have asthma?
•
If yes, the lung function test needs to be performed
•
If no, can the subject produce reproducible FEV1 results if
they are coached on how to do this?
o
If yes, the lung function test needs to be
performed
o
If no, then the subject is exempt from performing
the lung function test and the attempt to perform
the lung function test is to be recorded in the
subject journal
• Perform urine pregnancy test, if applicable
• For subjects requiring wash-out of concomitant medication as per visit 1, SPT
should be performed and results evaluated
• Assess AEs occurring since the last visit
• Assess symptoms of eosinophilic oesophagitis
• Dispense IMP to the subject
• Instruct the subject in how to use the IMP
• First intake of IMP at the clinic. The first dose will be administered at the clinic with a
subsequent 30 minutes observation period
• Schedule the date for visit 3
Visit window: 
4 weeks after V2 (+ 7 days) 


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Visit 3 
(Off season) 
• Record changes to concomitant medication
• Perform IMP compliance check (see Section 8.5)
• Assess AEs occurring since the last visit
• Assess symptoms of eosinophilic oesophagitis
• Perform urine pregnancy test, if applicable
• Schedule the date for visit 4
Visit 4 (Pre-TPS) 
Visit window: 
2 weeks prior to the expected start of TPS specified for the country/region (-14 to +7 
days) 
• Record changes to concomitant medication
• Dispense IMP to the subject
• Collect used IMP, perform drug accountability and the compliance check (see 
Section 8.5)
• Dispense rhinoconjunctivitis 
, if applicable
• Issue and instruct the subject/parent/caregiver in the use of the eDiary including 
training in symptom scoring
• Show and discuss the trial video
• Assess AEs occurring since the last visit
• Assess symptoms of eosinophilic oesophagitis
• Perform urine pregnancy test, if applicable
• Collect blood sample for immunological assessments
• If the specific consent has been obtained, collect the biobank blood sample
• Schedule the date for TC2 and visit 5
TC2 
(Start of TPS) 
Visit window: 
Expected start of TPS (-4 days) 
• Record changes to concomitant medication
• Inform subjects that TPS has started and eDiary recording should begin
• Re-instruct in the use of the eDiary including training in symptom scoring as needed
• Remind the subject to watch the trial video as needed
• Assess AEs occurring since the last visit
• Assess symptoms of eosinophilic oesophagitis
TC3 
(Pre-BPS) 
Visit window: 
2 weeks prior to the expected start of BPS (+ 7 days) 
• Record changes to concomitant medication
• Re-instruct in the use of the eDiary including training in symptom scoring as needed
• Remind the subject to watch the trial video as needed
• Assess AEs occurring since the last visit
• Assess symptoms of eosinophilic oesophagitis
Visit 5 
(In season BPS) 
Visit window: 
2 weeks after the expected start of the BPS (+ 7 days) 
• Record changes to concomitant medication
• Dispense IMP to the subject
• Collect used IMP, perform drug accountability and the compliance check (see 
Section 8.5)
• Dispense rhinoconjunctivitis 
, if applicable


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• Collect rescue medication, as applicable, and perform drug accountability
• Review eDiary recordings and check eDiary compliance
• Re-instruct in the use of the eDiary including training in symptom scoring as needed
• Remind the subject to watch the trial video as needed
• Assess AEs occurring since the last visit
• Assess symptoms of eosinophilic oesophagitis
• Perform PRQLQ interview for children 5 through 11 years of age at randomisation
• Perform urine pregnancy test, if applicable
•
TC 
 
(Cohort 1 
subjects with 
 
 
Visit window: 
1 week after the expected end of TPS specified for the country/region (+ 7 days) 
• Perform the interview for global evaluation of treatment efficacy
• Perform the interview for the TSQM-9
• Record changes to concomitant medication
• Review eDiary recordings and check eDiary compliance
• Re-instruct in the use of the eDiary including training in symptom scoring as needed
• Assess AEs occurring since the last visit
• Assess symptoms of eosinophilic oesophagitis
• Schedule the date for visit 6
Visit 6 
(End-of-
treatment) 
Visit window: 
1 week after the expected end of TPS specified for the country/region (+ 7 days) 
Important: for subjects in cohort 1 with 
, visit 6 should take place 
1 week (+ 7 days) after expected end of 
 
 
• Record changes to concomitant medication
• Collect used IMP, perform drug accountability and the compliance check (see 
Section 8.5)
• Collect rescue medication, as applicable, and perform drug accountability
• Perform physical examination
• Measure height and weight
• Measure vital signs
• Perform lung function test
• Assess AEs occurring since the last visit
• Assess symptoms of eosinophilic oesophagitis
• Collect the eDiary
• Perform the interview for global evaluation of treatment efficacy (subjects with 
 
 from cohort 1 will complete this during the TC 
• Perform the interview for the TSQM-9 (subjects with 
 from cohort 
1 will complete this during the TC 
)
• Collect blood and urine sampling for safety laboratory assessments
• Perform urine pregnancy test (if appropriate)
• Collect blood sampling for immunological assessments
• If the specific consent has been obtained, collect the biobank blood sample
• If the specific consent has been obtained, collect the pharmacogenetic blood sample 
for analysis


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• Schedule the date for a telephone follow-up contact (TC4)
Follow-up phone 
visit 
(TC4) 
Visit window: 
1 week (+ 7 days) after visit 6 
• Record changes to concomitant medication
• Assess AEs occurring since the last visit
• Assess symptoms of eosinophilic oesophagitis
11 TRIAL PROCEDURES 
This section outlines the trial procedures that will be performed during the trial. For further 
details on the specific timing, please refer to the visit schedule in Section 10. 
The tasks listed below must be performed by a physician with experience in paediatric research: 
•
Obtainment of informed consent
•
Evaluation of inclusion and exclusion criteria
•
Physical examination
•
Assessment of AEs/SAEs
•
Assessment of lung function (FVC, FEV1) and laboratory results
•
Decision to unblind treatment for individual subjects
Review of completed diaries, questionnaires, laboratory reports etc. must be documented either on 
the documents or in the subject’s source documents. If clarification of entries or discrepancies in 
the diary or questionnaires is needed, the subject must be questioned, and a conclusion made in 
the subject’s source documents. Care must be taken not to bias the subject. 
11.1 Informed consent 
All subjects must provide informed consent in accordance with the origins of the Declaration of 
Helsinki (World Medical Association 2013) and the applicable laws of the country. The written 
informed consent must be obtained before any trial activities are performed, incl. any period for 
wash-out of concomitant medication. 
For minors, the legal written informed consent must be obtained from the legal parent(s)/ guardian 
in accordance with national/local regulations. If the minor can understand the risks and benefits of 
the trial, he/she should also be informed and, if capable, provide written assent. Subjects turning 
18 years (or according to local requirement) during the trial must sign the adult informed consent 
form. 
It is the responsibility of the principal investigator or a sub-investigator to obtain the written 
informed consent and assent. 
The investigator must explain the nature of the trial, its purpose, the assessments involved, the 
expected duration, the potential risks and benefits involved and any discomfort it may entail and 
provide the subject with a copy of the information sheet and the consent form. Information to a 


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subject can be delegated to a nurse, but the investigator must be available for questions and both 
the nurse and the investigator must sign the consent form to document this. 
The parent(s)/ guardian and subject must be given sufficient time to consider the trial before 
deciding whether to participate. Each subject must be informed that participation in the trial is 
voluntary and that he/she may withdraw from the trial at any time and that withdrawal of consent 
will not affect his/her subsequent medical treatment or relationship with the treating physician. 
The parent(s)/ guardian and subject must sign and date the informed consent/ assent forms before 
entering the trial (i.e. before any trial related activity). The investigator must give a copy of the 
signed informed consent to the subject. The investigator should keep the original. 
If information becomes available that may be relevant to the subject’s willingness to continued 
participation in the trial the subject information sheet will be updated by ALK and approved by an 
IEC/IRB and the Competent authorities. The parent(s)/ guardian and subject must be informed in a 
timely manner about the updated subject information sheet and written informed consent must be 
obtained. 
11.2 Consent to collection of blood samples for storage in biobank 
Storage of blood samples in a biobank is planned for this trial (see Section 11.16). Participation in 
the trial does not depend on giving consent to donating blood samples for biobank storage. 
When the subject/parent/guardian is asked to consent/assent to the participation in the trial, 
children with a body weight over 19 kg will be asked specifically if they will donate a blood sample 
(5 mL each) 3 times during the trial. The answer to this question will be recorded on the consent 
form for retention of blood samples for future research, as well as in the eCRF. If specific consent 
is not provided, the samples must not be drawn. 
11.3 Consent for collection of blood samples for pharmacogenetic 
testing 
Storage of a DNA/RNA sample for pharmacogenetic testing is planned for this trial (see Section 
11.16). Participation in the trial does not depend on giving consent to donating pharmacogenetic 
samples. 
When the subject/parent/guardian is asked to consent/assent to the participation in the trial, 
children with a body weight over 19 kg will be asked specifically if they can accept sampling for 
storage of a DNA and RNA sample for pharmacogenetic testing. The answer to this question will 
be recorded on the consent form for retention of samples for future pharmacogenetic testing, as 
well as in the eCRF. If specific consent is not provided, the samples must not be drawn. 
11.4 Demographics 
The following data will be recorded: 
•
Month and year of birth
•
Age
•
Race and ethnicity
•
Sex


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11.5 Height and weight 
The subject’s height without shoes will be recorded. 
The subject’s weight will be recorded. 
11.6 Medical history 
The relevant medical history, including diseases present at trial entry and any allergy, urticaria, 
asthma, atopic dermatitis and OAS, must be recorded in the eCRF. 
The asthma history should include a detailed description of all asthma exacerbations including 
information on visits to emergency rooms, hospitalisations and changes in asthma treatment during 
the past 2 years. Those subjects suspected of having a history of asthma must meet at least one of 
the following 4 criteria to be considered as having a diagnosis of asthma (and documented as such 
in the eCRF): 
•
At least one episode of wheeze, cough, shortness of breath or chest tightness and a change in
FEV1 ≥12% after β2-agonist administration
•
Recurrent wheeze with or without prolonged phase of forced exhalation observed at physical
examination and an intake of asthma medication which resulted in a clinically relevant effect
•
Wheezing with or without prolonged phase of forced exhalation observed at physical
examination and a change in FEV1 ≥12% after β2-agonist administration
•
Using asthma medication
The OAS history should include a description of food triggers and symptoms. 
11.7 Smoking habits 
Information on exposure to tobacco smoke (active and passive) will be collected. 
11.8 Prior and concomitant medication 
The subjects’ use of concomitant medication including allergy and asthma medication must be 
recorded. Relevant prior medication should also be recorded. This includes allergy and asthma 
pharmacotherapy taken for the past 2 years. Other prior medication taken by the subject should 
also be recorded if considered relevant by the investigator. 
Medication not provided as a part of this trial should be kept to a minimum during the trial. 
However, if considered necessary for the subject’s well-being, concomitant medication may be 
given at the discretion of the investigator according to the local standard of care. 
At each visit and phone visit the investigator should ask the subject about use of concomitant 
medication. All concomitant medication must be documented in the subject’s medical records and 
in the eCRF. Furthermore, each change in concomitant medication (e.g. new treatment, 
discontinuation of treatment and change in dosage/routine) during the trial must be documented in 
the same way. 


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11.9 Vital signs 
Vital signs will include measurement of blood pressure and heart rate in a seated position 
(after ≥3 minutes of seated inactivity). 
Significant findings that are present at screening must be recorded as medical history in the eCRF. 
Significant findings found at visit 6, which meet the definition of an AE, must be recorded on an AE 
page in the eCRF. 
11.10 Lung function 
The assessment of the lung function will include measurements of forced vital capacity (FVC), FVC 
percent predicted, FEV1 and FEV1 percent predicted for all subjects (exception: a subject who does 
not have asthma and who is <7 years of age and cannot perform a reproducible lung function test 
despite coaching from site staff, will not be required to perform the lung function test. The attempts 
to perform the test and coach the subject must be documented). Lung function measurements will 
be performed with a spirometer available at the clinic. FVC and FEV1 should be recorded from a 
series of at least 3 valid measurements. The lung function measurement with the highest recorded 
FEV1 is to be entered in the eCRF. 
Lung function will be measured according to the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) spirometry recommendations (Reddel et al. 2009). Values of FVC, FVC 
percent predicted, FEV1 and FEV1 percent predicted reported by the site will use the site’s pre-
programmed spirometric reference equations. The reference equations and resulting values of 
predicted FVC and predicted FEV1 should be documented on every lung function report. For 
subjects with asthma, a 6-hour wash-out of SABA will be required before measurement of lung 
function. 
11.11 Physical examination 
The physical examination should be performed by a physician and should be based on the body 
systems described in Table 7. 
Table 7 
Physical examination 
Body system 
Minimum examinations to be completed 
General appearance 
Nutritional status, consciousness, skin colours, temperature and developmental 
status (in children) 
Head (ears, eyes, nose 
and throat) 
Ears - Inspection of auricles and external canal (otoscopy is not required) 
Oral inspection 
Inspection of lips, mucosa and tongue 
Respiratory 
• Assessment of respiratory effort, including respiratory rate and use of
accessory respiratory muscles
• Palpation and percussion of chest
• Auscultation/stethoscopy of lungs
Heart 
It is up to the investigators discretion to evaluate whether a physical examination 
of the heart is necessary based on auscultation/stethoscopy of the heart. A full 
physical examination will not be performed 


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Abdomen 
A physical examination will not be performed. It is up to the investigators 
discretion to evaluate whether a physical examination of the abdomen is 
necessary based on questions regarding pain, tenderness and swelling 
Urogenital 
A physical examination will not be performed. It is up to the investigators 
discretion to evaluate whether a physical examination of the genitourinary 
system is necessary based on questions regarding sores, lesions, pain, 
frequency or pattern change, incontinence, infections etc. For females, 
questions regarding birth control, menstrual regularity, menopause etc. must be 
asked 
Musculoskeletal and 
neurological 
It is up to the investigators discretion to evaluate whether a physical examination 
is necessary*. Based on questions regarding pain, tenderness and swelling of 
joints and/or musculature, sores lesions, disturbance of sensation and 
examination and observations of gait, station and agility at displacements the 
musculoskeletal/neurological systems are assessed as normal/abnormal 
Lymph nodes 
A physical examination will not be performed. It is up to the investigators 
discretion to evaluate whether a physical examination of the lymph nodes is 
necessary based on the questions regarding pain, tenderness and swelling 
Skin 
Inspection and palpation of skin and subcutaneous tissue 
Other abnormality 
If applicable 
Significant findings that are present at screening must be recorded as medical history in the eCRF. 
Significant findings found at the following visits, which meet the definition of an AE, must be 
recorded on an AE page in the eCRF. 
11.12 Pregnancy test 
For female subjects of child-bearing potential, a urine pregnancy test will be performed at all site 
visits. For female subjects who have their first menstrual period during the trial, a urine pregnancy 
test will be performed at all subsequent visits. Further the test will be performed during the trial, if a 
menstrual period is missed. 
The urine pregnancy tests will be performed by dipstick at the trial site. 
11.13 Skin prick test 
Skin prick testing will be performed to confirm hypersensitivity to Bet v extract. SPTs must be 
performed according to the guideline provided by ALK. No data are available for SPT in pregnant 
subjects, therefore a urine pregnancy test must be performed before the SPT. Subjects enrolled in 
the trial will be tested for the allergens listed in Table 8. 
All skin prick testing supplies will be provided by the Sponsor or designee. 
Some medications may affect the outcome of the SPT and should be washed out before 
performing the SPT (see Table 9). 


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Table 8 
Skin prick test 
Country 
Allergen 
All Countries 
HDM - Dermatophagoides pteronyssinus 
HDM - Dermatophagoides farinae 
Cat - Felis domesticus 
Dog - Canis familiaris 
Mould - Alternaria alternata* 
Grass – Phleum pratense 
Weed – Ambrosia artemisiifolia 
Weed – Artemisia vulgaris 
Tree – Betula verrucosa 
Positive control – Histamine 
Negative control – Saline 
*Not applicable in Germany


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Table 9 
Medications with a possible interference with SPT 
Drug26 
Recommended wash-
out period prior to 
performing SPT 
Antihistamine 
• Oral, intravenous or topical (skin)
3 days 
• Long-acting (astemizole)
100 days 
Tricyclic antidepressant medications and antidepressant medication with 
antihistaminic effects (e.g. doxapine, mianserine) 
14 days 
Antipsychotic medications with antihistaminic effects (e.g. chlorpromazine, 
levomepromazine, clozapine, olanzapine, tioridazine)  
7 days 
Glucocorticosteroid 
• Local application of ultra-high and high potency27 (on skin area used for SPT)
21 days 
• Oral
30 days 
• Short-acting parenteral
30 days 
• Long-acting parenteral (intra-articular or intramuscular)
90 days 
Pizotifene 
7 days 
11.14 Blood and urine sampling 
The following types of blood samples will be drawn during the trial (Table 10), totalling an 
approximate blood volume of 18 mL (if the subject consents to the pharmacogenetic and biomarker 
samples, the total blood volume will be approximately 35.5 mL). 
Table 10 
Blood samples drawn by visit 
Visit 
V1 
V4 
V6 
Purpose 
Approximate blood volume (mL) 
Safety / Haematology 
2 
2 
Screening / IgE 
5 
Safety / Blood chemistry 
5 
Immunology 
4 
Long-term storage - Biobank (optional) 
(5) 
(5) 
(5) 
Long-term storage - DNA (optional) 
(2.5) 
Total (mL) 
7 mL 
(12 mL) 
4 mL 
(9 mL) 
7 mL 
(14.5 mL) 
26 If medication that could interfere with the SPT, according to Table 9, has not been washed out, the SPT must be performed after the interfering 
medication has been washed out. 
27 Augmented betamethasone dipropionate 0.05%; clobetasol propionate 0.05%; diflorasone diacetate 0.05%; fluocinonide 0.1%; flurandrenolide 4 
mcg per m2; halobetasol propionate 0.05%; amcinonide 0.1%; betamethasone dipropionate 0.05%; desoximetasone; halcinonide 0.1%


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The following urine samples will be drawn: 
Purpose 
Volume 
Number 
of urine 
samples 
during 
the trial 
Safety/Urinalysis 
10 mL 
2 
Pregnancy tests 
NA 
At each 
visit (if 
applicable) 
11.15 Laboratory assessments 
All safety laboratory assessments and screening IgE will be performed centrally at one or more 
certified laboratories, except for urine dipsticks, which will be handled on site. 
The clinical laboratory values will be reported to the investigator by the laboratory, and he/she must 
immediately review them for significance. 
Laboratory assessments are described in a separate laboratory manual that also details blood 
sampling and shipment procedures. 
In case of lost or haemolysed samples, the subject may be requested to have an additional blood 
sample drawn to enable analyses and ensure results.  
The following analyses will be conducted: 
Haematology - Automated differential 
Erythrocytes, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular 
haemoglobin (MCH), platelets, leukocytes, and differential count (including absolute and relative 
amount of neutrophils, eosinophils, basophils, lymphocytes, and monocytes). 
Blood chemistry 
Creatinine, blood urea nitrogen (BUN), total bilirubin, alkaline phosphatase, aspartate 
aminotransferase (AST)/ serum glutamic-oxaloacetic transaminase (SGOT), alanine 
aminotransferase (ALT)/ serum glutamic pyruvic transaminase (SGPT), lactate dehydrogenase 
(LDH), sodium, potassium, calcium, glucose, albumin and chloride. 
Urinalysis 
pH, protein, glucose, ketone, urobilinogen, bilirubin, haemoglobin, nitrite, leukocytes, and specific 
gravity. 
IgE for inclusion criteria 
To assess the inclusion criteria, blood samples will be drawn at the screening visit (visit 1) for 
determination of specific IgE against Bet v. 
These samples will be analysed together with the samples for the safety laboratory assessments 
(see above), and the results will be reported to sites for assessment of subject eligibility. 


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Immunology 
To assess the immunological response of the treatment, blood samples will be drawn for 
determination of antigen-specific antibodies e.g. IgE, IgG4 and IgE-BF) and other immunological 
parameters at visit 1, 4 and 6. Immunological parameters to birch will be assessed for all 
randomised subjects. Immunological parameters to alder, hazel and oak will only be assessed for 
a stratified random subset sample of subjects in each treatment group for cohort 1. The subset 
sample will be stratified by age group. 
11.16 Long-term storage of samples 
The blood samples for storage in the biobank and for pharmacogenetic analysis are for research 
purposes only and will not be used for the generation of any trial endpoints. As such, no biomarker 
or pharmacogenetic endpoints will be reported in the ICTR. 
Blood sample for storage in Biobank 
These blood samples will only be drawn if the subject consents to long-term storage of blood 
samples. 
If long-term storage is accepted, a 5.0 mL blood sample will be drawn at visits 1, 4 and 6, where 
blood sampling is already planned. The subject will consequently only donate extra blood, no 
additional venepuncture is required. 
The purpose of the biobank blood samples is to continue the research into the immunological 
processes involved in the observed clinical effects in subjects treated with allergy immunotherapy, 
which today are not fully understood. One of the goals of this research is to identify one or more 
surrogate markers, which can predict clinical efficacy in the individual subject, i.e. which can help 
ensuring optimal treatment for future children and adults with allergies. The surrogate markers may 
be antibody levels, cytokine profiles, cell surface markers, specific set of proteins or metabolites, 
combinations hereof, etc. Although the exploratory biomarker analyses will help to increase our 
understanding, the efforts described in this protocol are strictly research based. Thus, as the 
complex interactions between allergy immunotherapy, rhinoconjunctivitis and asthma are currently 
not characterised to a level that translates to a meaningful clinical advantage, individual results 
from the exploratory biomarker analyses will not be given to the subjects. For the same reasons, 
individual results will not be added to the subjects’ medical records. 
The subjects will have no direct benefit from the exploratory biomarker analyses. 
The samples will be stored at ALK after end of trial and until marketing authorisation approval or 
until the research project terminates, but no longer than 25 years from end of trial after which they 
will be destroyed. 
If ALK publishes results obtained from biomarker studies based on samples obtained in the trial, 
the results will be published in such a way that it cannot be tied to an individual subject. 
Blood sample for pharmacogenetics 
This blood sample will only be drawn if the subject consents to long-term storage of a DNA/RNA 
sample. 
If pharmacogenetic sampling is accepted, a 2.5 mL blood sample will be drawn at visit 6 where 
blood sampling is already planned. The subject will consequently only donate extra blood, no 


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additional venepuncture is required. 
DNA/RNA material will be extracted from the blood sample. The DNA/RNA material will be used to 
investigate various genetic causes for how subjects may respond to the treatment. Studies may 
include analyses for identifying, e.g. genomic markers of atopic diseases, efficacy of allergy 
treatment, AEs, or other genomic markers relevant for the atopic disease and treatment of allergy. 
Pharmacogenetic results may be compared to pharmacodynamic results or clinical outcomes. Any 
significant pharmacogenetic relationships to outcome will require validation in future clinical trials. 
Since the complex interactions between allergy immunotherapy, rhinoconjunctivitis and asthma are 
currently not characterised to a level that translates to a meaningful clinical advantage, individual 
results from the pharmacogenetic analyses will not be given to the subjects. For the same reasons, 
individual results will not be added to the subjects’ medical records. 
The subjects will have no direct benefit from the exploratory biomarker analyses. 
The samples will be stored at ALK after end of trial and until marketing authorisation approval or 
until the research project terminates, but no longer than 25 years from end of trial after which they 
will be destroyed. 
If ALK publishes results obtained from genotyping studies based on samples obtained in the trial, 
the results will be published in such a way that it cannot be tied to an individual subject. 
11.17 Subject and parent/caregiver reported outcomes 
To minimise the burden to the subjects, a number of outcomes will be reported by the subjects 
using an eDiary rather than at site visits. 
11.17.1 
eDiary assessments 
During the trial, the subject and/or their parent/caregiver will complete an eDiary. 
Children <12 years must fill in the eDiary together with a parent/caregiver and the same person 
should assist the child for the duration of the trial. 
The eDiary is a hand-held electronic device that will be issued to the subjects at visit 4. 
Subjects/parents/caregivers will be instructed by the investigator in how to fill in the eDiary. In 
addition, a training video describing use of the eDiary and symptom scoring will be available to 
subjects/parents/caregivers during the trial. 
The following items should be answered in the eDiary on a daily basis during the TPS period: 
•
Rhinoconjunctivitis symptoms (see Section 11.18)
•
Use of symptom-relieving rescue medication for treatment of rhinoconjunctivitis (see Section
11.19)
•
•
•
•
•
•


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The following questionnaire should be answered in the eDiary on a weekly basis during the TPS 
period: 
•
RQLQ(S) (for all subjects aged 12-17 years of age at randomisation)
 
 
•
•
11.17.2 
Assessments entered in the eCRF 
11.17.2.1 
Paediatric quality of life questionnaire 
The quality of life in children (5 through 11 years of age) will be assessed by an interviewer using 
the standardised PRQLQ (Juniper et al. 1998) at visit 5. The PRQLQ and details on the scoring 
principles are described in Appendix 4. 
11.17.2.2 
Treatment satisfaction evaluation 
Treatment satisfaction will be evaluated using the 9-item treatment satisfaction questionnaire for 
medication (TSQM-9). 
This evaluation will be performed at V6 for most subjects. For those subjects in cohort 1 with 
 
 this evaluation will be performed during a TC approximately 1 week after the TPS. 
11.17.2.3 
Patient-rated global evaluation of treatment efficacy 
Subjects will be asked the following question regarding their perception of the efficacy of the 
treatment they received during the birch/tree pollen season: “Compared to your rhinitis and/or 
conjunctivitis symptoms in the previous birch/tree pollen season, how have you felt overall in this 
birch/tree pollen season?” 
Subjects will respond to the question using a 5-point scale (much better, better, the same, worse, 
much worse). 
This evaluation in the eCRF will be performed at V6 for most subjects. For those subjects in cohort 
1 with 
, this evaluation will be performed during a TC approximately 1 week 
after the TPS. 
11.18 Assessment of rhinoconjunctivitis 
 
During the diary completion period, subjects will record their daily rhinoconjunctivitis 
 
symptoms in an eDiary, with assistance from their parent/caregiver as appropriate. Symptoms 
should be recorded in the eDiary each evening. 
A total of 10 allergic symptoms, 6 rhinoconjunctivitis symptoms 
 will be 
assessed on a scale from no symptoms to severe symptoms. 
Subjects will be instructed by the investigator or delegated staff on how to record their symptoms 
in the eDiary using the definitions in Table 11. In addition, a training video describing use of the 
eDiary and symptom scoring will be available to subjects/parents/caregivers during the trial. 


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Details of the derivation of the daily rhinoconjunctivitis symptom score 
 
 are provided in Sections 15.9.1 
 
Table 11 
Subject’s symptom scoring 
Scored by 
subject 
Definition of score 
No symptoms 
No sign/symptom evident 
Mild symptoms 
Symptom clearly present, but minimal 
awareness; easily tolerated 
Moderate 
symptoms 
Definite awareness of symptom that is 
bothersome but tolerable 
Severe 
symptoms 
Symptoms that are hard to tolerate; causes 
interference with activities of daily living 
and/or sleeping 
The 
 symptoms are classified 
 as follows: 
Rhinoconjunctivitis symptoms: 
•
Runny nose
•
Blocked nose
•
Sneezing
•
Itchy nose
•
Gritty feeling/red/itchy eyes
•
Watery eyes
11.19 Assessment of use of rescue medication 
Rhinoconjunctivitis rescue medication 
Subjects are provided with open-label rhinoconjunctivitis rescue medication to be used as needed 
for treatment of their rhinoconjunctivitis symptoms not controlled by the IMP. 
Subject/parents/caregiver will be instructed by the investigator or delegated staff on how to record 
their use of rhinoconjunctivitis rescue medication daily in the eDiary. Usage of rescue medication 
should be recorded in the eDiary each evening during the diary completion period. If appropriate, 
subjects may receive assistance from their caregiver when completing the eDiary. 
Details of the derivation of the DMS are provided in Section 15.9.2. 
Asthma (SABA) medication 
Subjects with asthma are provided with open-label asthma rescue medication to be used as 
needed for treatment of their asthma symptoms not controlled by the IMP.
 


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12 SAFETY PROCEDURES 
Information about AEs, whether reported by the subject, discovered by the investigator by 
reviewing eDiary records, detected through physical examination, laboratory test or other means, 
must be collected and recorded on the AE form and followed up as appropriate. Evaluation of AEs 
including severity, causality, outcome and seriousness assessments must be performed by a 
physician. 
Any AE occurring from the time the informed consent is signed by the subject and until the last 
follow-up phone contact must be recorded and reported on the AE page in the eCRF. This includes 
all AEs, even AEs occurring before the subject is administered the IMP and whether or not AEs are 
observed in connection with the trial assessments and conduct of the trial. 
12.1 Definitions 
12.1.1 
Adverse events 
An AE is any untoward medical occurrence in a clinical trial subject and which does not necessarily 
have a causal relationship with the administered IMP. 
An AE can therefore be any unfavourable and unintended sign (including e.g. an abnormal 
laboratory finding or medication error), symptom, or disease, whether or not considered related to 
the IMP. 
The following events should not be recorded as AEs: 
•
A pre-planned procedure, e.g. a surgical intervention, unless the condition for which the
procedure was planned has worsened since the informed consent form was signed.
•
Pre-existing conditions documented as medical history. However, any worsening in severity or
frequency of a pre-existing condition during the clinical trial period must be regarded as an AE.
12.1.2 
Serious adverse events 
An SAE is any untoward medical occurrence or effect that at any dose: 
•
Results in death
•
Is life-threatening (this refers to an event in which the subject was at risk of death at the time of
the event; it does not refer to an event that hypothetically might have caused death if it had
been more severe)
•
Requires in-subject hospitalisation, regardless of duration, or prolongation of existing
hospitalisation
•
Results in persistent or significant disability or incapacity
•
Is a congenital anomaly or birth defect
•
Is judged to be medically important (this refers to an event that may not be immediately life-
threatening or result in death or hospitalisation, but may jeopardise the subject or may require
intervention to prevent one of the other outcomes listed above)


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12.1.3 
Events of special interest 
Selected AEs (non-serious or serious) will be considered ESIs. ESIs are events that are 
considered critical for the evaluation of the product’s safety profile and for which additional data will 
be collected on a separate eCRF form. ESIs for this trial are: 
•
Systemic allergic reactions including anaphylaxis
•
Events treated with adrenaline/epinephrine
•
Severe local swelling or oedema of the mouth and/or throat
•
Oral allergy syndrome
•
EoE
•
Severe asthma exacerbations and clinically relevant asthma exacerbations
12.1.4 
Significant laboratory event 
A significant laboratory event should be recorded as an AE if one of the following is applicable: 
•
It is abnormal and clinically significant (medical judgement by investigator)
•
It leads to a change or discontinuation of treatment
•
It fulfils a seriousness criterion
•
It indicates a potential safety risk to the subject
•
If Hy's law is fulfilled; AST and/or ALT ≥3 times upper normal limit and bilirubin ≥2 times upper
normal limit and ALP is not >2 times upper normal limit
12.1.5 
Medication errors, including overdose, abuse and misuse of the IMP 
Medication error, misuse, overdose and abuse of IMP(s) must always be collected in line with 
adverse event reporting, with or without associated AEs. 
•
Medication error: Any unintended failure in the medication treatment process that leads to, or
has the potential to lead to, harm to the subject.
•
Overdose: Any cumulative dose taken in one day that exceeds the dose intended by this
protocol, regardless of whether the dose has caused any AEs.
•
Abuse: Persistent or sporadic, intentional excessive use which is accompanied by harmful
physical or psychological effects.
•
Misuse: Intentional and inappropriate use.
12.2 AE assessments 
12.2.1 
Severity 
The severity of an AE is a clinical observation assessed by the investigator using the following 
definitions: 
•
Mild: Transient symptoms, no interference with the subject’s daily activities
•
Moderate: Marked symptoms, moderate interference with the subject’s daily activities
•
Severe: Considerable interference with the subject’s daily activities, unacceptable


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12.2.2 
Causal relationship to IMP 
The causal relationship between an AE and the IMP is assessed by the investigator using the 
following definitions: 
•
Possible: A reasonable possibility of a causal relationship between the event and the IMP
•
Unlikely: The event is most likely caused by a different aetiology than the IMP
For SAEs assessed as unlikely and possible related to IMP, the most likely alternative aetiology 
should be provided. 
12.2.3 
Outcome 
The outcome of an AE is assessed by the investigator using the following definitions: 
•
Recovered: Fully recovered or the condition has returned to baseline
•
Recovered with sequelae: As a result of the AE the subject suffered persistent
disability/incapacity. If the sequelae meet an SAE criterion, the AE must be reported as an SAE
•
Not recovered: The condition has not returned to baseline; however, symptoms may have
improved
•
Fatal: Event that results in death
•
Unknown: The outcome is unknown. This term should only be used when no other definition is
possible e.g. the subject is lost to follow-up
12.3 Collection, recording and reporting of AEs 
At each contact with the trial site, the subject must be asked about AEs in an objective manner 
such as “Have you experienced any problems since the last contact?" 
AEs must be recorded on the AE form in the eCRF. One single AE form must be used per AE from 
start to resolution. For SAEs and ESIs, specific SAE and ESI data fields in the eCRF must also be 
filled in. 
In case of concomitant medication for treatment of the AE, the concomitant medication form must 
be filled in. 
If the same type of AE reoccurs more than 1 day in a row with the same pattern (e.g. itching in the 
mouth for 5-10 minutes after intake of IMP) it is considered a recurrent AE. The AE form should be 
filled in with the start date, approximate daily duration in minutes and the description. Once the AE 
no longer reoccurs, the AE form should be completed with a stop date. If the AE then re-appears 
on a subsequent day, a new AE form should be filled in. 
The investigator should record the diagnosis, if available. If no diagnosis is available, the 
investigator should record each sign and symptom as individual AEs. Further, the diagnosis of the 
underlying disease should be reported instead of a procedure performed due to the disease (e.g. if 
a subject undergoes surgery due to appendicitis, appendicitis (and not the surgery performed) 
should be reported). 
12.3.1 
Events of special interest 
ESIs must be recorded via the eCRF. For each of the 6 pre-defined ESIs, investigator must fill out 
a specific eCRF ESI form with additional questions, in order to ensure that all relevant data is 
captured. EoE symptoms will be assessed at each visit according to Section 12.3.1.1. 


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12.3.1.1 
Eosinophilic Oesophagitis 
During the trial, subjects will be monitored for emerging symptoms of EoE at the scheduled visits. 
At each contact with a subject, the investigator should assess if any of the following has occurred 
since the last contact: 
•
food impaction requiring medical intervention
•
dysphagia/difficulty swallowing requiring the subject to drink large quantities of water to swallow
food
•
choking or gagging with meals
•
persistent (8 weeks or more) dysphagia
•
a sensation of food becoming lodged in the throat
•
persistent (8 weeks or more) vomiting without evidence of infection
•
persistent (8 weeks or more) early satiety
•
unexplained weight loss in combination with other gastrointestinal symptoms
If a subject presents with any of the above, or there is any clinical suspicion of eosinophilic 
oesophagitis, the investigator should refer the subject to a gastroenterologist for evaluation. 
12.3.2 
Reporting of AEs 
The investigator must report all SAE information (initial as well as follow-up) to ALK within 24 hours 
after obtaining knowledge of the SAE information. 
SAEs must be recorded via the eCRF. The initial eCRF SAE report must contain as much 
information as possible including relevant eCRF pages (e.g. medical history, concomitant 
medication). SAEs will automatically be sent to ALK via the eCRF system. In case the eCRF 
system is unavailable during the 24-hour reporting timeline, SAEs must be reported by email to 
ALK. 
Email address: 
 
Emergency phone: 
ESIs and non-serious AEs should be reported within 5 working days after obtaining knowledge of 
the information. 
If requested, please forward supporting documents to ALK via email. Please state the trial ID 
(TT-06) and the subject and site ID on all documents. 
IMPORTANT: Any information that could reveal the identity of the trial subject must be hidden or 
removed in the source documentation. Also, information that is not relevant for the subject and the 
subject’s condition must be hidden or removed. 
The assessment of listedness for SAEs is performed by ALK according to the current version of the 
Investigators Brochure section 6. 
ALK will inform the regulatory authorities and IECs/IRBs in accordance with local requirements in 
force and the ICH guidelines for Good Clinical Practice (GCP) (ICH 1996). 


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12.3.3 
Follow-up on AEs and SAEs 
SAEs must be followed up until the outcome of the event is “recovered”, “recovered with sequelae” 
or “fatal” and until all queries have been resolved. The investigator must respond to SAE follow-up 
requests from ALK without delay and no later than 7 days after receiving the request. 
Ongoing SAEs can be closed at the subject’s last follow-up telephone contact with the term “not 
recovered” for chronic diseases (as evaluated upon medical evaluation by the investigator or the 
sponsor). 
The investigator must ensure that the worst-case severity and seriousness of an event is kept 
throughout the trial. 
Non-serious AEs must be followed up until resolution or until the last follow-up telephone contact. 
12.3.4 
Reporting of medication errors, including overdose, abuse and misuse 
Medication errors, including events of overdose, abuse or misuse must be reported on an AE form 
within 7 calendar days of obtaining the information. Reporting of overdoses must be based on 
actual IMP exposure and not on drug accountability procedures. For overdose cases, the 
descriptive terms accidental or intentional overdose should be used. If an event is classified as an 
SAE, it must be reported as such. 
12.3.5 
Reporting of significant laboratory events 
All laboratory reports must be reviewed by the investigator for significance. 
Significant laboratory events present at screening should be recorded in the medical history 
section in the eCRF. Significant laboratory events found at the following visits, and which meet the 
definition of an AE, must be recorded on an AE form in the eCRF. 
A significant laboratory event should be recorded as an AE if one of the following is applicable: 
•
It is abnormal and clinically significant (medical judgement by investigator)
•
It leads to a change or discontinuation of treatment
•
It fulfils a seriousness criterion
•
It indicates a potential safety risk to the subject
The following constellation of laboratory values should, by definition, be considered an AE and 
reported accordingly: 
•
An elevated AST or ALT (≥3 times the normal upper limit) and an elevated total bilirubin
(≥2 times the normal upper limit), at the same time an alkaline phosphatase is not >2 times
the normal upper limit (Hy’s law) as determined by protocol-specified laboratory testing or
unscheduled laboratory testing
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying aetiology. 
12.3.6 
Reporting of pregnancies 
The investigator must report information on pregnancy and pregnancy follow-up information within 
14 calendar days of obtaining the information, using the pregnancy form. For further information 
see Section 12.6. 


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12.3.7 
Reporting of SAE and pregnancies after end of trial 
SAEs that in the opinion of the investigator are related to IMP that are brought to the attention of 
the investigator after the last follow-up telephone contact must be reported immediately by using 
the contact details listed in this section. 
All pregnancies occurring in trial subjects while exposed to IMP that are brought to the attention of 
the investigator after the last follow-up telephone contact must be reported within 14 days by using 
the contact details listed in this section. 
12.4 Safety surveillance 
Safety surveillance will be performed by ALK at pre-specified intervals to evaluate safety data and 
perform ongoing evaluation of AEs and SAEs. 
12.5 DMC 
A DMC will be established. The DMC will consist of external clinical experts within the area of 
allergy. 
The DMC will convene at pre-specified intervals in accordance with a written procedure to evaluate 
safety data and perform ongoing safety evaluation (i.e. AE, SAE, ESI and laboratory data). Based 
on the review of safety data, the DMC will make recommendations suggesting appropriate actions 
in case of safety issues. 
Specific details regarding composition, responsibilities, and governance, including the roles and 
responsibilities of the various members and the sponsor; meeting facilitation; the trial governance 
structure; and requirements for and proper documentation of DMC reports, minutes, and 
recommendations will be described in a separate charter that is reviewed and approved by the 
DMC. 
12.6 Pregnancy 
Female subjects must be advised to notify the investigator immediately if they become pregnant. If 
a female subject becomes pregnant, she must discontinue IMP intake but may continue to be 
enrolled in the trial. 
The investigator must report any pregnancy reported during the trial to ALK. Subjects will be 
informed that the investigator will report any pregnancy during the trial to ALK and that she will be 
asked to provide information about her pregnancy, delivery and health of her infant until the age of 
one month. If deemed relevant to collect information from the male partner, a separate informed 
consent must be obtained. 
Complications in relation to pregnancy must be reported as AEs. In case of spontaneous abortion, 
any malformation of the foetus, foetal death, stillbirth or a congenital anomaly/birth 
defect/developmental delay, the event must be reported and followed up as an SAE. 
Any abnormalities observed in a child (up to 2 years of age) and suspected to be related to 
intra-uterine exposure to the IMP should be reported to ALK. 


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13 EARLY TERMINATION OF TRIAL 
ALK reserves the right to terminate the trial due to safety concerns and/or recommendation by the 
DMC. 
If the trial is prematurely terminated or suspended, the investigator should promptly inform the 
subjects and ensure appropriate therapy and follow-up. Furthermore, the investigator and/or ALK 
should promptly inform the pertinent IEC/IRBs and provide a detailed written explanation. The 
pertinent regulatory authorities should be informed according to national regulations. 
14 DATA HANDLING 
14.1 eCRF 
Data generated by the trial site and relevant for the trial will be recorded in the eCRF. 
The sponsor or its representative will supply sites with access to the eCRF. The sponsor will make 
arrangements to train the site staff in the use of the eCRF. There will be no access to the eCRF 
without documented training in the system. 
All eCRF data must be verified and approved by an investigator at the site. 
The CRA will review the eCRF for completeness and accuracy and instruct the personnel at the 
trial site to make any required corrections or additions according to an eCRF completion guideline. 
The information entered into the database is systematically checked, and errors or omissions will 
result in queries, which will appear in the eCRF for resolution. Concomitant medications entered 
into the database will be coded using the World Health Organisation Drug Reference List (WHO 
Drug, March 2020 or higher). 
Medical history and AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
(version 23.0 or higher). 
14.2 eDiary 
Diary data should be entered daily by the adolescent subject or by the child subject’s 
parent/caregiver together with the subject, and the same person should assist the child for the 
duration of the trial. This data will be transferred to the vendor database daily. If the subject has 
missed more than 2 days in a row the investigator/designee will be notified by email and must 
contact the subject. In addition, if the total compliance for a period is less than 80% the 
investigator/designee must contact the subject and retrain the subject in the use of the eDiary. The 
aim is for the daily diary compliance to be greater than or equal to 80% and for the weekly RQLQ 
compliance to be greater than or equal to 80%. 
There will be no other source documentation for these data than the vendor database. 
Once all electronic diary data has been collected, the diary database will be closed and transferred 
from the vendor to ALK. The investigator will be provided with an electronic copy of the diary data 
collected at the specific site at the latest 3 months after end of trial by the vendor. The eDiary data 
will be subject to periodical review by the sponsor. Findings during the review of the eDiary data 
must be evaluated by the investigator. Any corrections to the data can only be approved by the 


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investigator after confirmation by the adolescent subject or by subject’s parent/caregiver. 
Documentation of the data transfer from the electronic diary vendor to ALK will be described in the 
data management report. 
14.3 Query handling 
Query handling at the trial site will be performed according to the guidelines for the eCRF system. 
Queries are created by programmed validation checks according to an edit check specification. 
Queries will also be created based on manual data checks. 
All data changes/query decisions are created with an audit trail capturing the old information, the 
new information, identification of the user making the correction, the date the correction was made, 
and the reason for change. 
14.4 Laboratory data 
The safety and screening IgE laboratory samples processed by a central laboratory selected by 
ALK. When the samples are analysed and the data released, a laboratory report will be sent to the 
investigator and the data will be transferred electronically to the eCRF. The investigator must 
review the laboratory data in the eCRF. Results out of reference range must be classified as non-
significant/significant in the eCRF by the investigator. 
The transfer of laboratory data to the eCRF will be described in a data transfer specification. 
Immunological data will be analysed by ALK. Data will be provided electronically after database 
lock to data management. 
Documentation of receipt and quality control of laboratory and immunological data will be provided 
in a data management report. 
14.5 Pollen data 
Pollen data from relevant pollen stations will be provided to ALK regularly during the trial by a 
professional provider (see Appendix 3). 
14.6 Database lock 
When the database has been declared to be complete and accurate by sponsor, the database will 
be locked, and data will be unblinded. All accesses to the eCRF will be set as “read only”. CRAs 
and non-sponsor staffs' “read only” accesses will be revoked from the eCRF when PDF-files are 
received by site. 
If changes to trial data become necessary after database lock this must be performed according to 
the current ALK procedure. 
A data archive for the site subject data files (eCRF, eDiary and Laboratory data) is produced and 
sent to the site. 
The investigator must sign and date the data archive approval form and send it back to the 
sponsor. 


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15 STATISTICAL METHODS 
Statistical analyses will be carried out by ALK. All computation will be performed using SAS® 
version 9.4, or a later version if applicable at the time of reporting. 
All analyses requiring significance testing will be two-sided at a 5% significance level, unless 
otherwise specified. All confidence intervals will be two-sided 95% confidence intervals. In all 
analyses, the null hypothesis will be one of no difference between treatment groups and the 
alternative hypothesis will be one of a difference. 
Numerical variables will be summarised in tables including mean, standard deviation, median, 
5%-quantile, 25%-quantile, 75%-quantile, 95%-quantile, minimum and maximum. 
Categorical variables will be summarised by tables displaying numbers and percentage of subjects 
in each category. 
Before database lock, a separate statistical analysis plan (SAP) detailing the specifications given 
below will be prepared and agreed upon. 
Any changes in the statistical methods compared to the final SAP will be documented in the ICTR. 
Post-hoc analyses, if any, will be clearly indicated. 
15.1 Estimands 
A primary and secondary estimand is defined for each of the primary and key secondary 
objectives (see Sections 2.5-2.7 and 15.1.2-15.1.4) and a discussion of intercurrent events 
relevant for their definition is given in Section 15.1.1. The main estimator and sensitivity estimators 
for each estimand are given in Sections 15.12.1 and 15.12.4. Approaches for handling intercurrent 
events and missing data are given in Section 15.12.2, 15.12.3 and 15.15. 
15.1.1 
Intercurrent events 
Intercurrent events (IE) are events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with the clinical question of 
interest. It is necessary to address IEs when describing the clinical question of interest in order to 
precisely define the treatment effect that is to be estimated. 
The IE that has been identified as relevant is discontinuation of trial treatment. 
Due to the long duration of allergy immunotherapy clinical trials, rescue medication is dispensed to 
every subject for ethical reasons. The use of rescue medication is, therefore, part of the treatment 
policy and as such, it is not classified as an intercurrent event for this trial. 
If additional unforeseen and relevant IEs occur during trial conduct, they will be included in the 
specification and estimation of the trial estimands. The details of their inclusion and the strategies 
taken to address them for each estimand will be documented in the ICTR. 


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15.1.2 
Primary estimand 
Using the framework proposed in the ICH E9 (R1) addendum, the trial product estimand can be 
described by: 
A. Treatment: SQ tree SLIT-tablet or placebo, with rescue medication taken as required
B. Population: Children and adolescents (5-17 years of age) with moderate to severe AR/C
caused by pollen from birch
C. Variable: Average TCS during the BPS
D. How to account for intercurrent events: under the hypothetical situation where all
subjects have completed treatment for the planned duration (hypothetical strategy)
E. Population summary: Absolute difference between treatment policies
A hypothetical strategy will be used to address the intercurrent event of discontinuation of trial 
treatment. As such, if a subject discontinues trial treatment, only diary data up until the time of 
discontinuation will be included in the analysis. Any diary data recorded after discontinuation of trial 
treatment will be excluded from the analysis. Details of the handling of IEs and missing data are 
provided in Section 15.12.2. 
15.1.3 
Secondary estimand 
The treatment policy estimand can similarly be described by: 
A. Treatment: SQ tree SLIT-tablet or placebo, with rescue medication taken as required
B. Population: children and adolescents (5-17 years of age) with moderate to severe AR/C
caused by pollen from birch
C. Variable: Average TCS during the BPS
D. How to account for intercurrent events: regardless of whether subjects complete
treatment for the planned duration (treatment policy strategy)
E. Population summary: Absolute difference between treatment policies
A treatment policy strategy will be used to address the intercurrent event of discontinuation of trial 
treatment. As such, if a subject discontinues trial treatment, all available diary data will be included 
in the analysis, regardless of adherence to treatment. Details of the handling of IEs and missing 
data are provided in Section 15.12.3. 
15.1.4 
Estimands for key secondary objectives 
The trial product estimand and treatment policy estimand, specified for the primary objective in 
Sections 15.1.2 and 15.1.3 respectively, are defined similarly for each of the key secondary 
objectives, where the relevant key secondary endpoint of interest is specified in attribute C. 


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15.2 Sample size and power considerations 
Sample size calculations are based on the primary endpoint, the average TCS during the BPS, 
which will be square root transformed prior to analysis in order to better approximate the normal 
distribution. Based on previous ALK SLIT-tablet studies in both adult and paediatric populations, it 
is assumed that the mean of the square root transformed average TCS during the BPS in the 
placebo group is 2.5 with corresponding common standard deviation of 1.4 in both placebo and 
active groups. 
Analyses for the primary and secondary estimands will include all randomised subjects and use 
different multiple imputation strategies to account for missing data. For the purposes of sample 
size estimation, it is assumed that 5% of observations in the active arm are imputed from the 
placebo arm. A true relative treatment effect of 25% is assumed, which corresponds to an effective 
relative treatment effect of 23.75% after placebo imputation. 
For a range of sample sizes and a 1:1 randomisation ratio between active and placebo groups, 
1000 trial datasets were simulated under the above assumptions and each trial was analysed 
using a linear model with a fixed term for treatment. For each choice of sample size, the probability 
of the trial fulfilling the regulatory requirements of both the EMA and FDA for the primary endpoint 
was assessed over all the simulated trials. 
The following regulatory requirements were considered: 
1.
Statistical significance of the absolute treatment effect (EMA)
2.
Point estimate of the absolute treatment effect greater than 1 (EMA)
3.
Point estimate of the relative treatment effect greater than 15% (FDA)
4. Lower limit of the 95% CI for the relative treatment effect greater than 10% (FDA)
Based on the results of the simulation study, 500 randomised subjects per arm (1000 subjects in 
total) was chosen to provide at least 85% power to satisfy regulatory requirements 1, 2 and 3 for 
the analyses based on all randomised subjects (assuming 5% imputation of placebo in the active 
arm for missing data). Assuming 10% of the 1000 randomised subjects do not have any diary data 
during the BPS, the power for an observed case (OC) analysis to meet the requirements is also 
presented. 


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Table 12 
Power to meet regulatory criteria for FAS and Observed Case Analyses 
Statistical 
significance of 
absolute treatment 
effect 
Point estimate 
of absolute 
treatment effect 
>1
Point estimate 
of relative 
treatment 
effect >15% 
Lower limit of 95% 
CI for relative 
treatment effect 
>10%
FAS analysis1,3 
n=5002 per arm 
95.0% 
88.3% 
92.8% 
60.2% 
OC analysis1,4 
n=4502 per arm3 
94.7% 
89.9% 
93.9% 
62.2% 
1 FAS analysis includes all randomised subjects, OC analysis includes all randomised subjects with diary data in the BPS
2 n=number of subjects included in the analysis
3 Assumptions: placebo mean=2.5, SD=1.4 (active & placebo), true relative treatment effect=25%, 5% of active arm 
imputed from placebo 
4 Assumptions: placebo mean=2.5, SD=1.4 (active and placebo), true relative treatment effect=25%, no MI, 10% of 
1000 randomised subjects excluded due to missing data 
15.3 Analysis data sets 
The total analysis set comprises all subjects who entered the trial. This analysis set includes 
screening failures. The total population will be used for listing reasons for screening failure and 
AEs before randomisation. 
The FAS is defined as all randomised subjects in accordance with the ICH intent-to-treat (ITT) 
principle. Subjects will be analysed according to the treatment to which they were randomised, 
regardless of the treatment they actually received. This analysis set will be the primary set for all 
efficacy analyses. The FAS will be used for all baseline/demography tables, efficacy tables, and 
corresponding subject listings. 
The safety analysis set is defined as all randomised subject who received at least one dose of IMP. 
Subjects will be analysed according to the treatment they actually received, regardless of the 
treatment to which they were randomised. The safety analysis set will be used for all safety tables 
and corresponding subject listings. 
15.4 Subject disposition 
A table of subject disposition by treatment group displaying number and percentage of subjects 
screened, included in the FAS, discontinued from trial and the primary reason for discontinuation 
from trial will be presented. 
In addition, a Kaplan-Meier plot of time to discontinuation (all causes) will be generated. 
15.5 Baseline characteristics 
Demography and baseline characteristics will be summarised by treatment group displaying 
number of subjects, mean, standard deviation, median, 25- and 75-percentiles, minimum and 
maximum for continuous variables, and frequency tables for categorical variables. 


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15.6 Extent of exposure 
The extent of IMP exposure will be assessed based on tablet counts, where the number of tablets 
taken is the difference between the number of tablets dispensed and the number of tablets 
returned/lost. Lost tablets will be accounted for if explicitly recorded in the eCRF. Treatment 
duration (days) will be calculated from the date of randomisation up until (and including) the date of 
last IMP intake. Compliance (%) will be assessed as the number of tablets taken divided by the 
number of treatment days multiplied by 100. 
The number of tablets taken, treatment duration (days) and treatment compliance (%) will be 
summarised by treatment group. 
15.7 Medical history 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarised by treatment group, system organ class (SOC) and preferred term (PT). 
15.8 Concomitant therapy 
Prior and concomitant medication will be coded according to the World Health Organization (WHO) 
drug dictionary and summarised by treatment group. 
15.9 Derivation of endpoints 
15.9.1 
Allergic rhinoconjunctivitis daily symptom score (DSS) 
The allergic rhinoconjunctivitis daily symptom score (DSS) is derived as the sum of the 6 allergic 
rhinoconjunctivitis symptom scores (see Table 11) using the following numerical scores: no 
symptoms =0, mild symptoms =1, moderate symptoms =2 and severe symptoms =3). The DSS 
takes values between 0 (no symptoms) and 18 (severe symptoms for all 6 allergic 
rhinoconjunctivitis symptoms assessed). 
15.9.2 
Allergic rhinoconjunctivitis daily medication score 
The allergic rhinoconjunctivitis daily medication score (DMS) is derived using the scoring system in 
Table 13 and takes values between 0 and 20 (maximum allowable daily rescue medication used). 


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Table 13 
Scoring for allergic rhinoconjunctivitis rescue medication usage 
Rescue medication 
Dosage 
Score/ 
Dose unit 
Max 
daily 
score 
Loratadine, 10 mg 
Or 
Desloratadine, oral 
solution 0.5 mg/mL 
6-12 years old and >30 kg: 1 tablet once
daily as needed
6 per tablet 
6 
>12 years old: 1 tablet once daily as needed
5 years old: 2.5 mL solution once daily as 
needed 
6 per 2.5mL 
6-11 years old: 5.0 mL solution once daily as
needed
6 per 5 mL 
≥12 years old: 10 mL solution once daily as 
needed  
6 per 10 mL 
Olopatadine eye 
drops, 1 mg/mL 
1 drop in the affected eye(s) twice daily, 
morning and evening as needed 
1.5 pr. drop 
6 
Mometasone nasal 
spray, 50 µg/dose 
5-11 years old: 1 puff in each nostril once
daily as needed (max 2 puffs)
4 per puff 
8 
≥12 years old: 2 puffs in each nostril once 
daily as needed (max 4 puffs) 
2 per puff 
Maximum allergic rhinoconjunctivitis daily medication score (DMS) 
20 
15.9.3 
Allergic rhinoconjunctivitis daily total combined score (daily TCS) 
The allergic rhinoconjunctivitis daily total combined score is the sum of the daily symptom and 
medication scores (that is, daily TCS=DSS+DMS) and takes values between 0 and 38. 
15.9.4 
Average allergic rhinoconjunctivitis daily total combined score (average 
TCS) 
The average TCS during a given pollen season is the mean of all non-missing daily TCS over all 
days in the selected pollen season. Average TCS will be derived for the BPS, TPS, AHPS, OPS 
 The definitions of the pollen 
seasons are provided in Section 15.10. 


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15.9.5 
Average allergic rhinoconjunctivitis daily symptom score (average DSS) 
and average allergic rhinoconjunctivitis daily medication score (average 
DMS) 
The average DSS (average DMS) during a given pollen season is the mean of all non-missing 
DSS (DMS) over all days in the selected pollen season. Average DSS and average DMS will be 
derived for the BPS, TPS, AHPS, OPS 
 
 
 
 
 
 
15.9.7 
Severe, well and symptom-free days during the BPS and TPS 
A severe day is defined as one with a DSS ≥6 and either at least 2 moderate or 1 severe allergic 
rhinoconjunctivitis symptom(s). A well day is defined as one with no use of allergic 
rhinoconjunctivitis rescue medication and a DSS ≤2. A symptom-free day is defined as one with no 
allergic rhinoconjunctivitis symptoms and with no use of rescue medication (i.e. daily TCS=0). The 
number of severe days, well days and symptom-free days will be calculated during the BPS and 
TPS. 
15.9.8 
Average TCS (EAACI scoring) 
The average TCS will also be derived using the system proposed in an EAACI position paper on 
the standardisation of clinical outcomes (Pfaar et al. 2014). The rhinoconjunctivitis daily 
medication score with EAACI scoring (DMSEAACI) takes values 0, 1 or 2 (see Table 14). The 
allergic rhinoconjunctivitis daily total combined score with EAACI scoring is the sum of the DSS/6 
and the DMSEAACI and takes a range of (non-integer) values between 0 and 5. The average TCS 
(EAACI scoring) is the mean of the daily non-missing values of the allergic rhinoconjunctivitis daily 
TCS with EAACI scoring. The average TCS (EAACI scoring) will be derived in the BPS and TPS. 


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Table 14 
EAACI scoring for allergic rhinoconjunctivitis rescue medication usage 
Rescue medication 
Dosage 
EAACI 
component score 
if medication is 
used 
(0 otherwise) 
Loratadine, 10 mg 
Or 
Desloratadine, oral 
solution 0.5 mg/mL 
6-12 years old and >30 kg: 1 tablet once daily as
needed
1 
>12 years old: 1 tablet once daily as needed
5 years old: 2.5 mL solution once daily as 
needed 
6-11 years old: 5.0 mL solution once daily as
needed
≥12 years old: 10 mL solution once daily as 
needed  
Olopatadine eye 
drops, 1 mg/mL 
1 drop in the affected eye(s) twice daily, morning 
and evening as needed 
1 
Mometasone nasal 
spray, 50 µg/dose 
5-11 years old: 1 puff in each nostril once daily
as needed (max 2 puffs)
2 
≥12 years old: 2 puffs in each nostril once daily 
as needed (max 4 puffs) 
Maximum allergic rhinoconjunctivitis daily medication score (DMSEAACI) 
2 
DMSEAACI is defined as the greatest of the EAACI components for each rescue medication 
type i.e. DMSEAACI can takes values of 0, 1, or 2. 
Note that in DMSEAACI can take a value of 3 if a subject uses “Oral corticosteroids 
with/without INS, with/without H1A” (Pfaar et al. 2014). This is not relevant for this trial as oral 
corticosteroids are not supplied as rescue medication.  
15.9.9 
Rhinoconjunctivitis quality of life (RQLQ(S)) scores 
The RQLQ(S) consists of 28 items covering 7 domains (activities, sleep, no-nose/eye symptoms, 
practical problems, nasal symptoms, eye symptoms, emotional). Each item is scored on a 7-point 
(0-6) scale, where lower scores indicate better quality of life and all items within each domain are 
weighted equally. The domain scores are derived as the mean of all item scores within each 
domain. The overall RQLQ score is the mean of the 28 item scores. 
The RQLQ(S) is completed weekly in the eDiary by subjects aged 12-17 years at randomisation. 


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15.9.10 
Paediatric rhinoconjunctivitis quality of life (PRQLQ) scores 
The PRQLQ consists of 23 items covering 5 domains (nasal symptoms, eye symptoms, practical 
problems, activity limitation and other symptoms). Each item is scored on a 7-point (0-6) scale, 
where lower scores indicate better quality of life and all items within each domain are weighted 
equally. The domain scores are derived as the mean of all item scores within each domain. The 
overall PRQLQ score is the mean of the 23 item scores. 
The PRQLQ is completed once during the BPS by subjects aged 5-11 years at randomisation. 
15.9.11 
Treatment satisfaction (TSQM) evaluation scores 
The TSQM-9 consists of 9 items covering 3 domains (Effectiveness, Convenience, Global 
satisfaction). Items are scored on either a 5-point (1-5) scale or 7-point (1-7) scale, where higher 
scores indicate greater treatment satisfaction. For each domain, item scores are summed and 
normalised to a 0-100 scale, where 0 is the worst possible level of satisfaction and 100 is the best 
possible level of satisfaction. 
15.9.12 
Patient-rated global evaluation of treatment efficacy 
Subjects will be asked the following question regarding their perception of the efficacy of the 
treatment they received during the birch/tree pollen season: “Compared to your rhinitis and/or 
conjunctivitis symptoms in the previous birch/tree pollen season, how have you felt overall in this 
birch/tree pollen season?” 
Subjects will respond to the question using the 5-point scale: much better, better, the same, worse, 
much worse. 
15.9.13 
Lung function 
Measurements of FVC, FVC percent predicted, FEV1 and FEV1 percent predicted will be recorded 
by the trial sites. The formulae used for calculating predicted FVC and predicted FEV1 can vary 
slightly depending on the spirometer used at each site. Therefore, for reporting purposes, FVC 
percent predicted and FEV1 percent predicted will be recalculated using values of predicted FVC 
and predicted FEV1 calculated from the Quanjer equations (Quanjer et al. 1995). This is to ensure 
a standard approach to the derivation of the endpoints. The Quanjer formulae for predicted FVC 
and FEV1 are a function of age, height and race. 
15.10 Definition of pollen seasons 
The different pollen seasons will vary across the selected pollen regions in both intensity and 
duration. Hypothetical pollen seasons in 2022 for an arbitrary location are shown in Table 15. 


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Table 15 
Hypothetical pollen seasons in the Northern European region 
2021 
2022 
Nov Dec Jan Feb Mar Apr May Jun Jul Aug 
Hazel pollen season 
Alder pollen season 
Birch pollen season 
Oak pollen season 
Tree pollen season  
For each pollen, start and stop dates will be defined for the respective pollen season based on 
actual daily pollen counts. Before defining the start and stop dates for the pollen seasons, days 
where the pollen counts are missing (after the first occurrence of pollen) will be replaced by 
applying the last observation carried forward method. 
In addition, a visual inspection of the pollen plots (pollen grains/m3 versus time) for all species will 
be made to validate the pollen counts in the season based on the criteria described below. This 
procedure can identify long periods with low pollen counts within the season e.g. due to rain or 
measurement errors and may lead to corrections of the start and stop dates. 
Pollen seasons (i.e. start and stop dates) will be derived for the relevant pollens during the trial. 
The final pollen seasons will be defined prior to database lock and further specified in the SAP. 
15.10.1 
Birch pollen season definition 
For each pollen region, the BPS is defined for each year as follows: 
Start date:  The start date of the BPS is defined as the first day of 3 consecutive days with 
birch pollen count larger than or equal to 30 grains/m3 
Stop date:  The stop date of the BPS is defined as the last day in the last occurrence of 
3 consecutive days with birch pollen count larger than or equal to 30 grains/m3 
15.10.2 
Alder, hazel and oak pollen season definition 
For each pollen region, the hazel, alder and oak pollen seasons is defined in each year as follows: 
Start date:  The start date of the pollen season is defined as the first day of 3 consecutive 
days with pollen count larger than or equal to 10 grains/m3 
Stop date:  The stop date of the pollen season is defined as the last day in the last 
occurrence of 3 consecutive days with pollen count larger than or equal to 
10 grains/m3 


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Based on experience from trial TT-04, it is anticipated that there will be a high degree of overlap 
between the alder and hazel seasons. As such, a combined alder-hazel season is defined for each 
pollen region as follows: 
Start date:  The start date of the alder-hazel pollen season is the earliest of the alder season 
start date and hazel season start date 
Stop date:  The stop date of the alder-hazel pollen season is the latest of the alder season 
stop date and the hazel season stop date 
15.10.3 
Tree pollen season definition 
For each pollen region, the TPS is defined as all days included in any of the hazel, alder, birch and 
oak pollen seasons. The TPS is not necessarily a continuous period. 
 
 
 
  
 
  
 
 
 
15.11 Multiplicity 
For the trial product estimands based on the primary efficacy endpoint and the key secondary 
efficacy endpoints, the analyses for the main estimators will be controlled for multiplicity to ensure 
a maximum overall type I error rate of 5% in the hypothesis testing of these endpoints. The control 
for multiplicity will be performed through hierarchical testing, using a pre-specified order of 
hypothesis to be tested. For each endpoint, the null hypothesis to be tested is the hypothesis of no 
difference between placebo and active SQ tree SLIT-tablet. 
The order of the hypotheses to be tested is: 
1.
The primary efficacy analysis of average TCS during BPS
2.
The key secondary efficacy analysis of average TCS during TPS
3.
The key secondary efficacy analysis of average DSS during BPS
4.
The key secondary efficacy analysis of average DSS during TPS
5.
The key secondary efficacy analysis of average DMS during BPS
6. The key secondary efficacy analysis of average DMS during TPS
The first hypothesis in the hierarchy will be tested at a 5% significance level. Testing will proceed 
to the second hypothesis only if the first test is statistically significant (p<0.05). Similarly, testing will 
proceed to the next level of the hierarchy, only if the previous comparison is statistically significant 
at the 5% level. If a test is not statistically significant (p >0.05) then no further testing within the 


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hierarchy will be conducted. Thus, the 2nd, 3rd, 4th, 5th and 6th hypothesis tests in the hierarchy will 
only be conducted if all previously tested hypotheses are statistically significant at the 5% level. 
Furthermore, analysis of the quality of life endpoints will be included as the final steps in the testing 
hierarchy, where the order of the hypotheses to be tested is: 
7.
The secondary efficacy analysis of average weekly overall RQLQ score during the BPS
8.
The secondary efficacy analysis of average weekly overall RQLQ score during the TPS
9. The secondary efficacy analysis of overall PRQLQ score during the BPS
Additional endpoints and analyses are supportive in nature and are not controlled for multiplicity. 
15.12 Efficacy analyses 
15.12.1 
Main estimator, sensitivity estimator(s) and statistical analysis for the trial 
product and treatment policy estimands 
The main estimator and sensitivity estimator(s) for both estimands will be the absolute treatment 
difference. 
The main estimator and sensitivity estimator(s) for both estimands will be based on an identical 
method of statistical analysis (specified below), although the actual data used in each analysis may 
vary according to the different strategies taken for the handling of IEs and missing data. Further 
details of the different strategies for each estimand are provided in Sections 15.12.2, 15.12.3 and 
15.12.4. 
Analyses will be based on all randomised subjects. Subjects for whom the efficacy endpoint is 
missing will be included in the analysis through multiple imputation, where missing data will be 
imputed from the same age group according to the approaches specified in Sections 
15.12.2-15.12.4. Imputation will use the method of unrestricted random sampling with replacement 
(seed=7127) and 1000 multiply imputed datasets will be created. For each dataset, the efficacy 
endpoint will be square root transformed to better approximate the normal distribution and 
analysed using a linear mixed effects model assuming unequal variances in the 2 treatment 
groups. The model will include treatment, pollen season and age group (5-11 years, 12-17 years) 
as fixed effects and geographical location as a random effect. The results will be back-transformed 
to the original scale and Rubin’s rule will be used to combine the results obtained from the multiply 
imputed datasets. Adjusted means for each treatment group, the absolute treatment difference 
with 95% CI, the relative treatment difference with 95% CI and the p-value for the treatment effect 
will be presented. 
15.12.2 
Handling of intercurrent events and missing data for the trial product 
estimand 
For the trial product estimand, diary data occurring after discontinuation of trial treatment will be 
excluded from the derivation of the primary endpoint (see Section 15.9.3 and Section 15.15). 
Subjects for whom the primary endpoint is missing (because of either missing diary data or the 
exclusion of diary data due to discontinuation of trial treatment) will be included in the analysis 
through multiple imputation under the hypothetical situation where subjects continued to take trial 
treatment as planned. 


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Multiple imputation for subjects missing the primary endpoint will be conducted as follows: 
•
For subjects that discontinue trial treatment due to lack of efficacy, multiple imputation of
the missing endpoint will be from the placebo group. This assumes that had the subject
continued to take trial treatment, they would have experienced similar efficacy to subjects in
the placebo arm. Data is assumed to be missing not at random (MNAR).
•
For subjects that discontinue trial treatment due to treatment-related AEs, multiple
imputation of the missing endpoint will be from their own treatment group. This assumes
that the level of efficacy that would have been experienced by the subject if they had
continued to take trial treatment is unrelated to the occurrence of the AE and, if they had
continued to take trial treatment, they would have experienced similar efficacy to subjects in
their own treatment group. Data is assumed to be missing at random (MAR).
•
For subjects that discontinue trial treatment due to any other non-treatment related reason,
multiple imputation of the missing endpoint will be from their own treatment group. This
assumes that the level of efficacy that would have been experienced by the subject had
they continued to take trial treatment is not related to their discontinuation of trial treatment.
Data is assumed to be MAR.
The sensitivity estimator for the trial product estimand will use the multiple imputation policy 
described above for the main estimator except that: 
•
For subjects that discontinue trial treatment due to treatment-related AEs, multiple
imputation of the missing endpoint will be from the placebo group. This assumes subjects
reporting treatment-related AEs would have been experienced a level of efficacy similar to
subjects in the placebo group if they had continued to take trial treatment. Data is assumed
to be MNAR.
Further sensitivity estimator(s) for the trial product estimand may also be considered and will be 
detailed in the SAP. 
15.12.3 
Handling of intercurrent events and missing data for the treatment policy 
estimand 
For subjects discontinuing trial treatment, all diary data (including data collected after 
discontinuation of trial treatment) will be included in the derivation of the primary endpoint 
(see Section 15.9.3 and Section 15.15). Subjects for whom the primary endpoint is missing 
will be included in the analysis through multiple imputation as follows: 
•
For subjects discontinuing trial treatment due to treatment-related AEs or lack of efficacy,
multiple imputation of the missing endpoint will be from the placebo group. This assumes
that missing data following treatment-related discontinuation of trial treatment is MNAR and
that subjects no longer taking active treatment for these reasons would have shown similar
efficacy to subjects receiving placebo.
•
For subjects discontinuing trial treatment due to non-treatment related reasons, multiple
imputation of the missing endpoint will be their own treatment group. This assumes that the
missing data are MAR.
The sensitivity estimator for the treatment policy estimand will use multiple imputation from the 
placebo group for all subjects that discontinue trial treatment regardless of the reason for 


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discontinuation. Further sensitivity estimator(s) for the treatment policy estimand may also be 
considered and will be detailed in the SAP. 
15.12.4 
Estimators for estimands defined for key secondary efficacy objectives 
The key secondary endpoints, average TCS during the TPS, average DSS during the BPS/TPS 
and average DMS during the BPS/TPS will be analysed identically to the primary endpoint using 
the definitions of the trial product estimand and treatment policy estimand (see Section 2.7) and 
the main and sensitivity estimators described in Sections 15.12.2 and 15.12.3. 
15.12.5 
Supportive analyses 
For the primary and key secondary efficacy endpoints, an observed case analysis based on all 
subjects with at least one diary entry in the relevant pollen season will be performed as a 
supportive analysis. This analysis will allow comparison of results both to previous studies where 
the primary efficacy analyses were based on observed cases and also to acknowledged criteria for 
clinical success, which were established based on observed case analyses. 
15.12.6 
Secondary efficacy analyses 
The following secondary endpoints will be analysed identically to the primary endpoint using the 
estimators of the trial product and treatment policy estimands: average TCS, average DSS and 
average DMS during the AHPS and OPS, average TCS (EAACI scoring) 
 
 
Proportion of severe days, proportion of well days, proportion of symptom-free days and patient-
rated global evaluation of treatment efficacy (categorised as improvement versus no improvement) 
will be analysed with a logistic regression model with treatment, pollen season and age group as 
fixed effects and pollen station (or region) as random effects. 
Average weekly overall RQLQ scores during the BPS and TPS, overall PRQLQ scores during the 
BPS and TSQM-9 domain scores will be analysed with a linear mixed model. 
Change from baseline in immunological endpoints will be analysed with a repeated measures 
linear mixed model. 
15.12.7 
Exploratory efficacy analyses 
 
15.13 Safety analyses 
15.13.1 
Evaluation of AEs 
AEs will be summarised by treatment group, MedDRA SOC and PT displaying number of subjects 
in treatment group, number and percentage of subjects having the event as well as number of 
events. Furthermore, the AEs will be summarised according to severity, relationship to IMP, 
outcome and seriousness. 
AEs identified as local administration site reactions, by comparison against a pre-defined list of 
MedDRA PTs, will be summarised separately. 
Further details will be provided in the SAP. 


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15.13.2 
Evaluation of other safety parameters 
Laboratory assessments, physical examination assessments, lung function tests and vital signs will 
be summarised by treatment group displaying number of subjects, mean, standard deviation, 
median, 5-, 25-, 75- and 95-percentiles, minimum and maximum for continuous variables, and 
frequency tables for categorical variables. 
Further details will be provided in the SAP. 
15.14 Interim analyses 
No interim analysis is planned. 
15.15 Handling of missing data and sensitivity analyses 
Efficacy endpoints which are an average of daily diary entries over a defined pollen season will be 
derived provided there is at least one relevant diary entry for that endpoint in the given pollen 
season. Subjects with missing data for an endpoint will be included in the analysis of that endpoint 
through multiple imputation (see Sections 15.12.2, 15.12.3 and 15.12.4). Detailed specification of 
sensitivity analyses to address the assumptions underlying the main estimators of each estimand 
will be provided in the SAP. 
Imputation of missing daily diary data is not considered for the main estimators of the trial product 
and treatment policy estimands. Occasional missing diary values are assumed to be missing 
completely at random (MCAR) and are therefore not a source of bias in the derivation of the 
endpoints. Investigation of patterns of extended periods of missing daily diary data and potential 
sensitivity analyses, however, will be considered in the SAP although appropriate imputation of 
missing daily diary values is a complex problem. Diary entries over the course of a pollen season 
are highly specific to the subject completing the diary; they are a function of the local pollen 
exposure in the immediate environment of the subject and that individual subject’s tolerance to 
allergic rhinoconjunctivitis symptoms and subsequent rescue medication usage. Imputation of 
missing daily data could easily introduce daily data inconsistent with a subject’s individual profile 
and subsequent bias in the derivation of the endpoints. 
16 QUALITY ASSURANCE AND CONTROL 
16.1 Monitoring 
Regular monitoring visits will be performed according to ICH GCP. Data will be evaluated for 
compliance with the protocol and accuracy in relation to source documents. In accordance with 
written standard operating procedures (SOPs), the CRAs will verify that the clinical trial is 
conducted, and data are generated, documented and reported in compliance with the protocol, 
GCP and the applicable regulatory requirements. 
16.2 Source data and access to source documents 
Prior to start of recording of data from subjects, the investigator, with the aid of the CRA, will 
prepare a source data location agreement to document where the first recording of data is done. 


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As a minimum requirement, the following data must be source data-verifiable in source 
documentation other than in the eCRF: 
•
Subject’s month and year of birth
•
Confirmation of participation in the trial (trial ID, subject number/randomisation number,
diagnosis)
•
Date of informed consent and assent for adolescent subjects where this is relevant
•
Confirmation of subject eligibility (in/exclusion criteria)
•
Concomitant diseases and medication
•
Relevant medical history (incl. specific allergy and asthma history and date of diagnosis)
•
Any AEs and SAEs should be described in detail
•
Date and number of each trial visit including signature and/or initials of persons conducting the
trial visit
•
Date and information of any relevant telephone contact with the subject and signature and/or
initials of persons conducting or receiving the call
•
IMP dispensed/returned
•
Subject discontinuation from the trial including reason
Documentation of FEV1, SPT and laboratory results must be kept in the subject’s medical record, 
evaluated, signed and dated by an investigator at the trial site. Documentation on thermo-sensitive 
paper must be copied and signed by the investigator. The copy signed by the investigator should 
be kept together with the original in the subject’s medical record. 
The following data could be recorded directly in the eCRF and is then considered to be source data 
(if acceptable by national legislation and hospital routine): 
•
Demography and body measurements
•
Vital signs
•
Physical examination
•
Smoking habits
The investigator must give the CRA direct access to examine, analyse and verify any medical 
records or reports to procedures, source documentation, data records and reports used, 
referenced or created as part of the conduct of this trial (e.g. relevant hospital or medical records), 
to confirm consistency with eCRF entries. 
The CRA will examine the electronic medical record system and decide one of the following 
options for source data verification: 
•
Option 1
If an audit trail is available, the CRA may choose either to perform source data verification
through a direct comparison of the eCRF and the electronic medical record or may choose to
work according to option 2
•
Option 2
If no audit trail is available, relevant source data from electronic medical records should be
printed out by the investigator or delegate preferably at the day of the monitoring visit. The
investigator or delegate must sign and date the printout to confirm that the print and the
electronic source data are identical. The CRA must verify the original source data at least once
during the trial.
Either option will be agreed with the investigator prior to trial start. 


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All documents must be stored safely under confidential conditions. On all trial-specific documents, 
other than the signed consent, the subject will be referred to by the subject ID number or 
randomisation number. If ALK becomes aware of the identity of a subject, ALK is bound to keep 
this information confidential and to take immediate actions to delete any information received that 
identifies the subject. 
16.3 Investigator site file – and other trial documentation 
The investigator must maintain source documents for each subject in the trial in accordance with 
local legislation. 
The investigator must retain the investigator site file for at least 25 years or according to local 
legislation. 
No trial related documentation may be destroyed by the investigator without prior written 
agreement with ALK. The investigator agrees to adhere to the document retention procedures by 
signing the protocol. 
Should the investigator choose to transfer the trial documents to another physician or institution, 
ALK must be notified. 
16.4 Protocol compliance 
The instructions in the protocol must be followed. If deviations occur, the investigator must inform 
the CRA, and the implications of the deviation must be reviewed and discussed. Deviations must 
be documented (or included in eCRF data). In addition, deviations must be accompanied by a 
description of the deviation, the relevant dates and the action taken. Deviation reports and 
supporting documentation must be kept in the investigator’s file and in the ALK trial master file. 
If a deviation that is likely to affect to a significant degree the safety and rights of a subjects or the 
reliability and robustness of the data generated in the clinical trial (serious breach) has occurred, 
the investigator should inform ALK and the CRO within 24-hours. 
In cases related to COVID-19 where protocol procedures are not carried out as intended, a 
comment should be entered in the eCRF with the prefix 'COVID-19'. In addition, a COVID-19 
protocol deviation must be reported as for all deviations caused by the coronavirus outbreak. 
16.5 Audit 
ALK may conduct audit(s) of clinical research activities in accordance with internal SOPs to 
evaluate compliance with GCP and international and local guidelines and regulations. 
The investigator must be available during the audit and give the auditors direct and unlimited 
access to source documentation and data, records and reports used, referenced or created as part 
of the performance of this trial. 


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17 ETHICS AND REGULATORY PROCEDURES 
17.1 Statement of compliance 
This trial must be carried out in compliance with the protocol, which is designed to ensure 
adherence to the Declaration of Helsinki and the principles of GCP, as described in: 
•
The Declaration of Helsinki (1964, and its amendments and subsequent clarifications) (World
Medical Association 2013)
•
ICH Harmonised Tripartite Guidelines for GCP, 1996 (ICH 1996)
•
EU Directive 2001/20/EC of the European Parliament and of the Council on the Approximation
of the Laws, Regulations and Administrative Provisions of the Member States Relating to the
Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal
Products for Human Use. 2001 (The European parliament 2001)
•
European Commission. Commission Directive 2005/28/EC of 8 April 2005 laying down
principles and detailed guidelines for good clinical practice as regards investigational medicinal
products for human use, as well as the requirements for authorisation of manufacturing or
importation of such products. 2005 (European Commission 2005)
•
FDA regulations relating to GCP and clinical trials, (FDA 2018)
•
GDPR (Regulation (EU) 2016/679) (The European parliament 2016)
17.2 Disclosure and confidentiality 
By signing the protocol, the investigator agrees to keep all information, data and materials whether 
in oral, written, graphic, electronic or other form provided by ALK or a third party acting on behalf of 
or at the instruction of ALK in strict confidentiality. 
Trial documents provided by ALK (protocol, IB, eCRFs and other material) should be stored 
appropriately to ensure their confidentiality. The information provided by ALK to the investigator 
may not be disclosed to others except as expressly authorised by this protocol or the clinical trial 
agreement or with the prior written consent of ALK. 
The investigator may disclose confidential information to employees of the investigator, hospital 
authorities and IECs/IRBs on a need-to-know basis and only if the aforementioned parties are 
bound or obligated by provisions of confidentiality no less strict than imposed upon the investigator 
under this protocol or the clinical trial agreement. Further, the investigator may disclose confidential 
information set out in the protocol to the extent necessary to obtain informed consent from subjects 
who wish to participate in the trial. 
Any data, results, reports, findings, discoveries and any other information developed or collected 
during this trial shall be regarded as ALK's confidential information until published. 
Financial disclosure from the investigators will be obtained before the trial. 
17.3 Subject confidentiality 
The trial staff should ensure that the subject’s anonymity is maintained. The subjects will be 
identified by a subject ID number in the eCRF and any electronic database owned by ALK. All 
documents will be stored securely and only accessible by trial staff and authorised personnel. 


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17.4 Data protection 
All data will be handled and stored according to GDPR (The European parliament 2016). 
Investigator 
By signing this protocol, the investigator recognises that certain personal identifying information 
with respect to the investigator and all sub-investigators and trial site personnel, may be used and 
disclosed for trial management purposes, as part of a regulatory submissions, and as required by 
law. This information may include: 
•
Name, address, telephone number and email address
•
Hospital or clinic address and telephone number
•
Curriculum vitae or other summary of qualifications and credentials
•
Financial disclosure information
•
Other professional documentation
Consistent with the purposes described above, this information may be transmitted to ALK, 
affiliates and ALK representative, in the investigator’s country and other countries, including 
countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included when 
reporting certain SAEs to regulatory authorities or to other investigators. By signing this protocol, 
the investigator expressly consents to these uses and disclosures. 
In order to facilitate contact between investigators, ALK may share an investigator’s name and 
contact information with other participating investigators upon request. 
Subjects 
Subjects will be assigned a unique identifier (a subject number). Any subject records or datasets 
that are transferred to ALK will contain the identifier only; subject names or any information which 
would make the subject identifiable will not be transferred. This way the subject data will be 
pseudonymised, which means that the data cannot be attributed to a specific subject without the 
use of additional information. 
The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out certain 
identifiers will be enforced to protect the identity of subjects as required by local, regional and 
national requirements. 
The subject must be informed that his/her personal trial related data will be used by ALK in 
accordance with local data protection law. The disclosure of the data must also be explained to the 
subject. 
The subject must be informed that his/her medical records may be examined by auditors or other 
authorised personnel appointed by ALK, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
Transfer of data 
If data are transferred to or accessed by third countries, that is, countries outside EU/EEA 
countries, the data will be protected to have an adequate level of data protection principles. 


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Description of arrangements 
To ensure the safekeeping of clinical trial data ALK has SOPs that define how data shall be 
managed including handling of security data breaches. When data is managed by external parties, 
written agreements are in place to ensure that the data is handled according to ALK’s 
instructions/standards. 
17.5 IEC/IRB/regulatory authorities 
Before initiation of this trial, the protocol, the proposed informed consent form and other 
information to subjects as well as other documents required, must be reviewed by a properly 
constituted IEC/IRB and provided to the national (and local, if applicable) regulatory authority. 
A signed and dated statement that the protocol and the subject information sheet/informed consent 
form and any other information to the subjects have been approved by the IEC/IRB and the 
regulatory authority must be obtained before trial initiation. 
17.6 Inspections 
An IEC/IRB or a national or international regulatory authority may also wish to conduct an 
inspection (during the trial or after its completion). If an inspection is requested by a regulatory 
authority, the investigator must inform ALK of the request immediately. The investigator or ALK 
should agree (in accordance with the prevailing law) with the inspectors that ALK shall have the 
right to be present at any inspection or investigation. The investigator or ALK should agree with the 
inspector that ALK may conduct and control applicable action arising from the inspections at ALK’s 
expense. 
The investigator must be available during the inspection and give the inspectors direct and 
unlimited access to source documentation and data, records and reports used, referenced or 
created as part of performance of this trial. 
17.7 Protocol amendments and other changes in trial conduct 
Substantial changes to this protocol require a protocol amendment that must be signed off by ALK 
and the investigator(s) and be approved by IEC/IRB and/or regulatory authorities, as applicable, 
before implementation. 
The requirements for approval of the substantial changes should in no way prevent any immediate 
action from being taken by the investigator or by ALK in the interest of preserving the safety of all 
subjects included in the trial. 
Amendments not considered substantial such as administrative changes will only be submitted to 
the regulatory authorities once another substantial amendment must be submitted or together with 
the end of trial notification unless national legislation requires otherwise. 


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18 REPORTING AND PUBLICATION 
18.1 Clinical trial report 
Data will be reported in an ICTR in compliance with the requirements of the current version of 
ICH E3: Structure and Content of Clinical Trial Report, ICH GCP Guidelines and ALK SOPs. 
The international coordinating investigator will review and sign the ICTR. 
18.2 Publication and disclosure of results 
ALK retains exclusive ownership of all data, results, reports, findings, discoveries and any other 
information developed or collected during this trial and ALK shall have the exclusive right to use all 
such information for any purpose, including, but not limited to, use of the results and data either in 
the form of eCRF (or copies of these), or in the form of a report, with or without comments and with 
or without analysis, in order to submit them to the regulatory authorities of any country. 
By signing the investigator agreement, the investigator agrees that the results of this trial may be 
used for submission to national and/or international registration and supervising authorities. The 
authorities will be notified of the investigator's name, address, qualifications and extent of 
involvement. 
It is envisaged that the findings of this trial, including sub-analysis, and if relevant the epidemiology 
of the screened population and the selection process, will, in due time and by mutual agreement, 
be published in international journals, theses and/or presented at scientific meetings or symposia. 
All presentations and publications must be reviewed by ALK prior to public presentation or 
submission. For multi-site trials, it is mandatory that the primary publication is based on data from 
all trial sites, analysed as stipulated in the protocol and in the SAP. 
Authorship is based on the International Committee of the Medical Journal Editors “Uniform 
Requirements” (Vancouver Declaration). 
If the number of authors is restricted, selection will be based on the degree to which individuals can 
be held accountable for the conduct and reporting of the trial. 
Investigators participating in multi-site trials agree not to present data gathered from one trial site 
or a group of trial sites before the primary publication has been accepted for publication unless 
formally agreed by all other investigators and ALK. 
ALK shall be provided with copies of any proposed publication or presentation at least 60 days in 
advance of the submission of such proposed publication or presentation to a journal, editor, or 
other third party. ALK has the right to review and comment on any such publication or presentation 
within 60 days of receipt but cannot prevent publications of findings. The investigator agrees that 
all reasonable comments made by ALK will be incorporated into the publication. Furthermore, the 
investigator agrees that the investigator shall, at ALK's request exclude or delete any confidential 
information, except trial results generated hereunder, from the proposed publication or 
presentation. 
ALK will review the presentations and publications for accuracy (thus avoiding potential 
discrepancies with submissions to regulatory authorities), verify that the confidential information is 
not being inadvertently divulged, and/or provide any relevant supplementary information. Upon 
ALK's request, the investigator shall delay a publication or presentation for 6 months from ALK's 


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receipt of the publication or presentation to permit ALK to file a patent application or take other 
steps as necessary to protect the confidential information (including trial results of ALK). 
Results of the trial will be posted in the EU Clinical Trials Registry no later than 6 months after 
LSLV. No individual de-identified subject data will be shared. 
Results of the trial, in accordance with the protocol and SAP, will be posted at ClinicalTrials.gov no 
later than 12 months after the primary completion date. No individual de-identified subject data will 
be shared. 
If results are not disclosed on external websites in accordance with international and national 
regulations, a justification must be given. 
19 FINANCE AND INSURANCE 
ALK subscribes to an insurance policy covering, in its terms and provisions, legal liability for 
injuries caused to participating subjects and arising out of these trial assessments performed 
strictly in accordance with this protocol as well as with applicable law and professional standards. 
The compensation to the investigators for work performed under this protocol will be set out in 
separate clinical trial agreements with the investigators. 
20 TRIAL ORGANISATION 
The title, name, address and contact details of vendors, including CROs and subcontractors for 
e.g. project management, monitoring and central laboratory, are listed in Appendix 3.


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21 REFERENCE LIST 
Biedermann,T., Kuna,P., Panzner,P., Valovirta,E., Anderson,M., de Blay,F., Thrane,D., 
Jacobsen,S.H., Stage,B.S. & Winther,L. 2019a. Sublingual immunotherapy with the SQ tree SLIT-
tablet is highly effective and well tolerated: results from a randomized, double-blind, placebo-
controlled phase III trial. JACI, doi: https://doi.org/10.1016/j.jaci.2018.12.1001. 
Biedermann,T., Winther,L., Till,S.J., Panzner,P., Knulst,A. & Valovirta,E. 2019b. Birch pollen 
allergy in Europe. Allergy, 74, 1237-1248. 
Blaiss,M., Maloney,J., Nolte,H., Gawchik,S., Yao,R. & Skoner,D.P. 2011. Efficacy and safety of 
timothy grass allergy immunotherapy tablets in North American children and adolescents. J Allergy 
Clin Immunol, 127, 64-71. 
Blumberga,G., Groes,L. & Dahl,R. 2011. SQ-standardised house dust mite immunotherapy as an 
immunomodulatory treatment in asthma patients. Allergy, 66, 178-185. 
Bousquet,J., Khaltaev,N., Cruz,A.A., Denburg,J., Fokkens,W.J., Togias,A., Zuberbier,T., Baena-
Cagnani,C.E., Canonica,G.W., van,W.C., Agache,I., it-Khaled,N., Bachert,C., Blaiss,M.S., 
Bonini,S., Boulet,L.P., Bousquet,P.J., Camargos,P., Carlsen,K.H., Chen,Y., Custovic,A., Dahl,R., 
Demoly,P., Douagui,H., Durham,S.R., van Wijk,R.G., Kalayci,O., Kaliner,M.A., Kim,Y.Y., 
Kowalski,M.L., Kuna,P., Le,L.T., Lemiere,C., Li,J., Lockey,R.F., Mavale-Manuel,S., Meltzer,E.O., 
Mohammad,Y., Mullol,J., Naclerio,R., O'Hehir,R.E., Ohta,K., Ouedraogo,S., Palkonen,S., 
Papadopoulos,N., Passalacqua,G., Pawankar,R., Popov,T.A., Rabe,K.F., Rosado-Pinto,J., 
Scadding,G.K., Simons,F.E., Toskala,E., Valovirta,E., Van,C.P., Wang,D.Y., Wickman,M., 
Yawn,B.P., Yorgancioglu,A., Yusuf,O.M., Zar,H., nnesi-Maesano,I., Bateman,E.D., Ben,K.A., 
Boakye,D.A., Bouchard,J., Burney,P., Busse,W.W., Chan-Yeung,M., Chavannes,N.H., 
Chuchalin,A., Dolen,W.K., Emuzyte,R., Grouse,L., Humbert,M., Jackson,C., Johnston,S.L., 
Keith,P.K., Kemp,J.P., Klossek,J.M., Larenas-Linnemann,D., Lipworth,B., Malo,J.L., Marshall,G.D., 
Naspitz,C., Nekam,K., Niggemann,B., Nizankowska-Mogilnicka,E., Okamoto,Y., Orru,M.P., 
Potter,P., Price,D., Stoloff,S.W., Vandenplas,O., Viegi,G. & Williams,D. 2008. Allergic Rhinitis and 
its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, 
GA(2)LEN and AllerGen). Allergy, 63 Suppl 86, 8-160. 
Bousquet,J., Lockey,R. & Malling,H.J. 1998a. Allergen immunotherapy: therapeutic vaccines for 
allergic diseases. A WHO position paper. J. Allergy Clin. Immunol., 102, 558-562. 
Bousquet,J., Lockey,R.F. & Malling,H.J. 1998b. WHO Position Paper. Allergen immunotherapy: 
Therapeutic vaccines for allergic diseases. Allergy, 53, 1-42. 
Bufe,A., Eberle,P., Franke-Beckmann,E., Funck,J., Kimmig,M., Klimek,L., Knecht,R., Stephan,V., 
Tholstrup,B., Weisshaar,C. & Kaiser,F. 2009. Safety and efficacy in children of an SQ-standardized 
grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol, 123, 167-173. 
Burbach,G.J., Heinzerling,L.M., Edenharter,G., Bachert,C., Bindslev-Jensen,C., Bonini,S., 
Bousquet,J., Bousquet-Rouanet,L., Bousquet,P.J., Bresciani,M., Bruno,A., Canonica,G.W., 
Darsow,U., Demoly,P., Durham,S., Fokkens,W.J., Giavi,S., Gjomarkaj,M., Gramiccioni,C., 
Haahtela,T., Kowalski,M.L., Magyar,P., Murakozi,G., Orosz,M., Papadopoulos,N.G., Rohnelt,C., 


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Stingl,G., Todo-Bom,A., von,M.E., Wiesner,A., Wohrl,S. & Zuberbier,T. 2009. GA(2)LEN skin test 
study II: clinical relevance of inhalant allergen sensitizations in Europe. Allergy, 64, 1507-1515. 
Canonica,G.W., Baena-Cagnani,C.E., Bousquet,J., Bousquet,P.J., Lockey,R.F., Malling,H.-J., 
Passalacqua,G., Potter,P. & Valovirta,E. 2007. Recommendations for standardization of clinical 
trials with Allergen Specific Immunotherapy for Respiratory allergy. A statement of the World 
Allergy Organization (WAO) taskforce. Allergy, 62, 317-324. 
Canonica,G.W., Bousquet,J., Casale,T., Lockey,R.F., Baena-Cagnani,C.E., Pawankar,R., 
Potter,P.C., Bousquet,P.J., Cox,L.S., Durham,S.R., Nelson,H.S., Passalacqua,G., Ryan,D.P., 
Brozek,J.L., Compalati,E., Dahl,R., Delgado,L., van Wijk,R.G., Gower,R.G., Ledford,D.K., 
Filho,N.R., Valovirta,E.J., Yusuf,O.M., Zuberbier,T., Akhanda,W., Almarales,R.C., Ansotegui,I.J., 
Bonifazi,F., Ceuppens,J., Chivato,T., Dimova,D., Dumitrascu,D., Fontana,L., Katelaris,C.H., 
Kaulsay,R., Kuna,P., Larenas-Linnemann,D., Manoussakis,M., Nekam,K., Nunes,C., O'Hehir,R., 
Olaguibel,J.M., Onder,N.B., Park,J.W., Priftanji,A., Puy,R., Sarmiento,L., Scadding,G.K., Schmid-
Grendelmeier,P., Seberova,E., Sepiashvili,R., Solé,D., Togias,A., Tomino,C., Toskala,E., 
Beever,H.V. & Vieths,S. 2009. Sub-Lingual Immunotherapy: World Allergy Organization Position 
Paper 2009. World Allergy Organization Journal, 2, 233-281. 
Chan-Yeung,M., Anthonisen,N.R., Becklake,M.R., Bowie,D., Sonia,B.A., Dimich-Ward,H., Ernst,P., 
Sears,M.R., Siersted,H.C., Sweet,L., Van,T.L. & Manfreda,J. 2010. Geographical variations in the 
prevalence of atopic sensitization in six study sites across Canada. Allergy, 65, 1404-1413. 
Cox,L., Nelson,H., Lockey,R., Calabria,C., Chacko,T., Finegold,I., Nelson,M., Weber,R., 
Bernstein,D.I., Blessing-Moore,J., Khan,D.A., Lang,D.M., Nicklas,R.A., Oppenheimer,J., 
Portnoy,J.M., Randolph,C., Schuller,D.E., Spector,S.L., Tilles,S. & Wallace,D. 2011. Allergen 
immunotherapy: a practice parameter third update. J. Allergy. Clin. Immunol., 127, S1-55. 
Creticos,P.S., Maloney,J., Bernstein,D.I., Casale,T., Kaur,A., Fisher,R., Liu,N., Murphy,K., 
Nekam,K. & Nolte,H. 2013. Randomized controlled trial of a ragweed allergy immunotherapy tablet 
in North American and European adults. J Allergy Clin Immunol., 131, 1342-1349. 
Demoly,P., Emminger,W., Rehm,D., Backer,V., Tommerup,L. & Kleine-Tebbe,J. 2016. Effective 
treatment of house dust mite-induced allergic rhinitis with 2 doses of the SQ HDM SLIT-tablet: 
Results from a randomized double-blind, placebo-controlled phase III trial. J Allergy Clin Immunol, 
137, 444-451. 
Durham,S.R., Emminger,W., Kapp,A., De Monchy,J.G., Rak,S., Scadding,G.K., Wurtzen,P.A., 
Andersen,J.S., Tholstrup,B., Riis,B. & Dahl,R. 2012. SQ-standardized sublingual grass 
immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a 
randomized trial. J Allergy Clin Immunol, 129, 717-725. 
Durham,S.R., Yang,W.H., Pedersen,M.R., Johansen,N. & Rak,S. 2006. Sublingual immunotherapy 
with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic 
rhinoconjunctivitis. J Allergy Clin Immunol, 117, 802-809. 
Ellis,A.K., Ratz,J.D., Day,A.G. & Day,J.H. 2010. Factors that affect the allergic rhinitis response to 
ragweed allergen exposure. Ann Allergy Asthma Immunol, 104, 293-298. 


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24-May-2020
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EMA. Definition of Investigational Medicinal Products (IMPs) and use of Auxiliary Medicinal 
Products (AMPs). 2016.  
EMA & PDCO. EMA/PDCO Standard Paediatric Investigation Plan for Allergen Products for 
Specific Immunotherapy. EMA/PDCO/737605/2009, Revision 4, 1-13. 2015. 
EMEA. Reflection Paper: Formulations of choice for the paediatric population. 2006. 
EMEA. Guideline on the clinical development of products for specific immunotherapy for the 
treatment of allergic diseases. CHMP/EWP/18504/2006[Final]. 2008. 
European Commission . Commission Directive 2005/28/EC of 8 April 2005 laying down principles 
and detailed guidelines for good clinical practice as regards investigational medicinal products for 
human use, as well as the requirements for authorisation of manufacturing or importation of such 
products. 2005. 
FDA . CRF - Code of Federal Regulations Title 21. 2018. 
GINA Executive Committee . Global Initiative for Asthma; Global Strategy for Asthma Management 
and Prevention (2020 update). 1-211. 2020. 
Heath,M.D., Collis,J., Batten,T., Hutchings,J.W., Swan,N. & Skinner,M.A. 2015. Molecular, 
proteomic and immunological parameters of allergens provide inclusion criteria for new candidates 
within established grass and tree homologous groups. World Allergy Organ. J, 8, 21. 
ICH. ICH Harmonised Tripartite Guideline Topic E6 (R1): Guideline for Good Clinical Practice. 
1996. 
ICH. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline 
on statistical principles for clinical trials (Step 5). 2020. 
Jantunen,J., Sarinen,K. & Rantio-Lehtimaki A 2012. Allergy symptoms in relation to alder and birch 
pollen concentrations in Finland. Aerobiologia, 28, 169-176. 
Juniper,E.F., Howland,W.C., Roberts,N.B., Thompson,A.K. & King,D.R. 1998. Measuring quality of 
life in children with rhinoconjunctivitis. J Allergy Clin Immunol, 101, 163-170. 
Lang,R. & Hawranek,T. 2006. Hymenoptera venom immunotherapy and field stings. J Investig. 
Allergol. Clin Immunol, 16, 224-231. 
Lorenz,A.R., Luttkopf,D., May,S., Scheurer,S. & Vieths,S. 2009. The Principle of Homologous 
Groups in Regulatory Affairs of Allergen Products - A Proposal. Int. Arch. Allergy Immunol., 148, 1-
17. 
Maloney,J., Bernstein,D.I., Nelson,H., Creticos,P., Hebert,J., Noonan,M., Skoner,D., Zhou,Y., 
Kaur,A. & Nolte,H. 2014. Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: 
a large randomized controlled trial. Ann Allergy Asthma Immunol, 112, 146-153. 


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Massie,T. Statistical criteria for establishing safety and efficacy of allergenic products. Allergenics 
Products Advisory Committee, U. S. Food and Drug Administration.  2011.  
Ref Type: Slide 
Meltzer,E.O., Blaiss,M.S., Derebery,M.J., Mahr,T.A., Gordon,B.R., Sheth,K.K., Simmons,A.L., 
Wingertzahn,M.A. & Boyle,J.M. 2009. Burden of allergic rhinitis: results from the Pediatric Allergies 
in America survey. J Allergy Clin Immunol, 124, S43-S70. 
Nelson,H.S., Nolte,H., Creticos,P., Maloney,J., Wu,J. & Bernstein,D.I. 2011. Efficacy and safety of 
timothy grass allergy immunotherapy tablet treatment in North American adults. J Allergy Clin 
Immunol, 127, 72-80. 
Nolte,H., Hebert,J., Berman,G., Gawchik,S., White,M., Kaur,A., Liu,N., Lumry,W. & Maloney,J. 
2013. Randomized controlled trial of ragweed allergy immunotherapy tablet efficacy and safety in 
North American adults. Ann. Allergy Asthma. Immunol., 110, 450-456. 
Pawankar,R., Canonica,G.W., Holgate,S.T. & Lockey,R.F. 2011. WAO White Book on Allergy. 
Milwaukee, Wisconsin: World Allergy Organization. 
Pfaar,O., Demoly,P., Gerth van,W.R., Bonini,S., Bousquet,J., Canonica,G.W., Durham,S.R., 
Jacobsen,L., Malling,H.J., Mosges,R., Papadopoulos,N.G., Rak,S., Rodriguez Del,R.P., 
Valovirta,E., Wahn,U. & Calderon,M.A. 2014. Recommendations for the standardization of clinical 
outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI Position 
Paper. Allergy. 
Quanjer,PH., Borsboom,G., Brunekreef,B., Zach,M., Forche,G., Cotes,J., Sanchis,J. & Paoletti,P. 
1995. Spirometric reference values for white European children and adolescents: Polgar revisited. 
Pediatr. Pulmonol., 19, 135-142. 
Recommendations of the ad hoc group for the development of implementing guidelines for 
Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal 
products for human use . Ethical considerations for clinical trials in the pediatric population. 2008. 
Reddel,H.K., Taylor,D.R., Bateman,E.D., Boulet,L.P., Boushey,H.A., Busse,W.W., Casale,T.B., 
Chanez,P., Enright,P.L., Gibson,P.G., de Jongste,J.C., Kerstjens,H.A., Lazarus,S.C., Levy,M.L., 
O'Byrne,P.M., Partridge,M.R., Pavord,I.D., Sears,M.R., Sterk,P.J., Stoloff,S.W., Sullivan,S.D., 
Szefler,S.J., Thomas,M.D. & Wenzel,S.E. 2009. An official American Thoracic Society/European 
Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for 
clinical asthma trials and clinical practice. Am. J. Respir. Crit Care Med., 180, 59-99. 
Schmitz,R., Ellert,U., Kalcklosch,M., Dahm,S. & Thamm,M. 2013. Patterns of sensitization to 
inhalant and food allergens - findings from the German Health Interview and Examination Survey 
for Children and Adolescents. Int Arch Allergy Immunol, 162, 263-270. 
Stemeseder,T., Klinglmayr,E., Moser,S., Lueftenegger,L., Lang,R., Himly,M., Oostingh,G.J., 
Zumbach,J., Bathke,A.C., Hawranek,T. & Gadermaier,G. 2017. Cross-sectional study on allergic 
sensitization of Austrian adolescents using molecule-based IgE profiling. Allergy, 72, 754-763. 


Clinical trial protocol 
Date: 
24-May-2020
Trial ID: TT-06 
Version: 
3.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
99 of 99 
The European parliament. Directive 2001/20/EC; on the approximation of the laws, regulations and 
administrative provisions of the Member States relating to the implementation of good clinical 
practice in the conduct of clinical trials on medicinal products for human use. 1-19. 2001. 
ec.europa.eu. 
The European parliament . Regulation (EU) No 679/2016 General Data Protection Regulation. 
2016. 
Valovirta,E., Myrseth,S.E. & Palkonen,S. 2008. The voice of the patients: allergic rhinitis is not a 
trivial disease. Curr. Opin. Allergy Clin Immunol, 8, 1-9. 
Winther,L., Malling,H.J. & Mosbech,H. 2000a. Allergen-specific immunotherapy in birch- and 
grass-pollen-allergic rhinitis. II. Side-effects. Allergy, 55, 827-835. 
Winther,L., Malling,H.J., Moseholm,L. & Mosbech,H. 2000b. Allergen-specific immunotherapy in 
birch- and grass-pollen-allergic rhinitis. I. Efficacy estimated by a model reducing the bias of annual 
differences in pollen counts. Allergy, 55, 818-826. 
World Medical Association. Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects. 2013. Adopted by the WMA General Assembly in Helsinki (1964) and 
as amended by the WMA General Assembly. 

SAP_001.pdf: 
Cover page 
Date: 
28-May-2024 
 
Trial ID: TT-06 
Status: 
Final 
     
Version: 
1.0 
CONFIDENTIAL 
Page: 
1 of 1    
 
 
TT-06 STATISTICAL ANALYSIS PLAN COVER PAGE 
Official trial title 
Efficacy and safety of the SQ tree sublingual immunotherapy 
tablet in children and adolescents (5 through 17 years of age) with 
moderate to severe allergic rhinitis and/or conjunctivitis induced 
by pollen from birch and trees belonging to the birch homologous 
group 
NCT number 
NCT04878354 
Document date 
19-Sep-2023 
 
 
 
  
  
 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
1 of 66 
 
 
 
Statistical Analysis Plan  
Trial ID: TT-06 
 
Efficacy and safety of the SQ tree sublingual 
immunotherapy tablet in children and adolescents (5 
through 17 years of age) with moderate to severe allergic 
rhinitis and/or conjunctivitis induced by pollen from birch 
and trees belonging to the birch homologous group  
 
Sponsor:  
ALK A/S 
Bøge Alle 6-8 
DK-2970 Hørsholm 
Investigational medicinal product: SQ tree SLIT-tablet 
Phase: III  
EudraCT No.: 2020-004372-17 
Document status: Final 
Date:19-SEP-2023 
Version number: 1.0 
  
Property of ALK 
May not be used, divulged, published, or otherwise disclosed without the written consent of 
ALK 
 
 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
2 of 66 
 
 
 
 
ALK approval of statistical analysis plan 
Trial statistician: 
  
 
Signature 
 
Date 
Trial manager: 
 
 
Signature 
Date 
 
Medical writer: 
 
 
Signature 
Date 
 
 
Head of biometrics: 
 
 
Signature 
 
Date 
 
 
Head of GPCD: 
 
 
 
 
Signature 
 
Date 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
3 of 66 
 
 
 
 
This document is approved by electronic signature, refer to signature page at the end of this 
document.  


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
4 of 66 
 
 
 
 
Table of Contents    
 
Page 
ALK approval of statistical analysis plan ............................................................................... 2 
Table of Contents ..................................................................................................................... 4 
Table of Figures ........................................................................................................................ 6 
Table of Tables ......................................................................................................................... 7 
1 
List of abbreviations ......................................................................................................... 8 
2 
List of definitions ............................................................................................................ 11 
3 
Introduction ..................................................................................................................... 12 
3.1 
Objectives, endpoints, and estimands ..................................................................... 13 
3.1.1 
Estimands ......................................................................................................... 15 
3.1.1.1 
Primary estimand ............................................................................................................ 15 
3.1.1.2 
Secondary Estimand ....................................................................................................... 16 
3.1.1.3 
Intercurrent events .......................................................................................................... 16 
3.1.1.4 
Estimands for key secondary objectives ........................................................................ 16 
3.2 
Trial design ............................................................................................................. 16 
3.2.1 
Flow chart ......................................................................................................... 19 
3.2.2 
Actual trial timelines .......................................................................................... 26 
3.2.3 
Randomisation .................................................................................................. 26 
4 
Statistical hypotheses..................................................................................................... 26 
4.1.1 
Multiplicity adjustment ....................................................................................... 26 
5 
Analysis sets ................................................................................................................... 27 
6 
Statistical analyses ......................................................................................................... 28 
6.1 
General considerations ........................................................................................... 28 
6.2 
Overall strategy of efficacy analyses ....................................................................... 28 
6.3 
Primary endpoint analysis ....................................................................................... 29 
6.3.1 
Definition of endpoint ......................................................................................... 29 
6.3.2 
Main estimator, sensitivity estimator(s) and statistical analysis for the trial product 
and treatment policy estimands ......................................................................................... 29 
6.3.3 
Handling of intercurrent events and missing data .............................................. 30 
6.3.3.1 
Handling of intercurrent events and missing data for the trial product estimand ........... 30 
6.3.3.2 
Handling of intercurrent events and missing data for the treatment policy estimand ..... 31 
6.3.3.3 
Sensitivity analyses......................................................................................................... 31 
6.3.3.4 
Sensitivity analysis for the product trial estimand ........................................................... 31 
6.3.3.5 
Sensitivity analysis for the treatment policy estimand .................................................... 32 
6.3.4 
Supportive analyses .......................................................................................... 32 
6.3.5 
Supplementary analyses ................................................................................... 32 
6.4 
Key secondary endpoint analyses .......................................................................... 32 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
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6.4.1 
Estimators for estimands defined for key secondary efficacy objectives ............ 32 
6.5 
Summary of primary and key secondary endpoints analyses and figures ............... 33 
6.5.1 
Figures for primary and key secondary endpoints ............................................. 37 
6.6 
Additional endpoints analyses................................................................................. 37 
6.7 
Secondary endpoints .............................................................................................. 37 
6.7.1 
Questionnaires .................................................................................................. 38 
6.7.2 
Immunology....................................................................................................... 38 
 
 .............................................................................. 39 
6.9 
Safety analyses ...................................................................................................... 39 
6.9.1 
Extent of exposure ............................................................................................ 39 
6.9.1.1 
Exposure ......................................................................................................................... 39 
6.9.1.2 
Treatment duration.......................................................................................................... 40 
6.9.1.3 
IMP compliance .............................................................................................................. 40 
6.9.1.4 
eDiary compliance .......................................................................................................... 40 
6.9.2 
Adverse events ................................................................................................. 40 
6.9.2.1 
Events of special interest ................................................................................................ 40 
6.9.2.2 
Reporting of adverse events ........................................................................................... 40 
6.9.2.3 
Local administration site TEAEs ..................................................................................... 41 
6.9.3 
Additional safety assessments .......................................................................... 42 
6.10 
Interim analysis ....................................................................................................... 42 
6.11 
Changes and/or deviations to protocol-planned analyses ....................................... 42 
7 
Sample size determination ............................................................................................. 43 
8 
Demographics and baseline characteristics ................................................................. 44 
8.1 
Screening failures ................................................................................................... 44 
8.2 
Protocol deviations ................................................................................................. 44 
8.3 
Subject disposition .................................................................................................. 44 
8.4 
Baseline characteristics .......................................................................................... 44 
8.5 
Medical history ........................................................................................................ 45 
8.6 
Prior and concomitant therapy ................................................................................ 45 
9 
Supporting documentation ............................................................................................. 45 
9.1 
Definition of pollen seasons .................................................................................... 45 
9.2 
Derivations for the trial ............................................................................................ 47 
9.2.1 
Derivations of endpoints .................................................................................... 47 
9.2.1.1 
Definition of DSS and DMS ............................................................................................ 47 
9.2.1.2 
DSS ................................................................................................................................. 47 
9.2.1.3 
DMS ................................................................................................................................ 47 
9.2.1.4 
TCS ................................................................................................................................. 48 
 
 ................................................................................................................... 48 
9.2.1.6 
Daily EAACI medication score ........................................................................................ 49 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
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EudraCT No: 2020-004372-17 
Status: 
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CONFIDENTIAL 
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9.2.1.7 
TCS with EAACI medication scoring (TCSEAACI) ......................................................... 49 
9.2.2 
Derivation of average symptom and medication scores ..................................... 50 
9.2.2.1 
Average Daily Rhinoconjuctivitis Symptom Score (average DSS) ................................. 50 
9.2.2.2 
Average Daily Rhinoconjuctivitis Medication Score (average DMS) .............................. 50 
9.2.2.3 
Average Daily Rhinoconjuctivitis Total Combined score (average TCS) ....................... 50 
 
 .............................................. 50 
9.2.2.5 
Average Daily Total Combined Score with EAACI medication scoring (average 
TCSEAACI) .................................................................................................................................... 50 
9.2.3 
Derivation of daily binary variables .................................................................... 50 
9.2.3.1 
Proportion of well days ................................................................................................... 50 
9.2.3.2 
Proportion of severe days ............................................................................................... 50 
9.2.3.3 
Proportion of symptom-free days .................................................................................... 51 
 
 ................................................................................... 51 
 
 ....................................................................................... 51 
 
 ................................. 51 
9.2.4 
Other derivations of endpoints ........................................................................... 51 
9.2.4.1 
RQLQ .............................................................................................................................. 51 
9.2.4.2 
PRQLQ ........................................................................................................................... 52 
9.2.4.3 
TSQM-9 .......................................................................................................................... 52 
9.2.4.4 
Patient-rated global evaluation of treatment efficacy...................................................... 52 
9.2.4.5 
Lung function .................................................................................................................. 52 
9.2.5 
Imputation of dates ............................................................................................ 52 
9.2.5.1 
Partial dates in adverse event reporting ......................................................................... 52 
9.2.5.2 
Incomplete date for last IMP ........................................................................................... 53 
10 
References ..................................................................................................................... 54 
11 
Appendices .................................................................................................................... 55 
Appendix A Local administration site TEAEs: ................................................................................ 55 
Appendix B Further details to statistical analyses .......................................................................... 56 
Appendix C Examples of SAS code ............................................................................................... 58 
Appendix D Final pollen season ..................................................................................................... 59 
 
Table of Figures    
 
Page 
Figure 1: Overall trial design ................................................................................................. 17 
 
 ............................................ 18 
Figure 3: Example of tree pollen season with non-continuous period ................................... 46 
 


Statistical Analysis Plan 
Date: 
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Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
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CONFIDENTIAL 
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Table of Tables    
 
Page 
Table 1: Objective and endpoints ......................................................................................... 13 
Table 2: Flow chart ............................................................................................................... 19 
Table 3:Schedule of cohorts ................................................................................................. 26 
Table 4: Analysis set definitions ........................................................................................... 27 
Table 5: Overall overview of strategies for efficacy analyses ................................................ 29 
Table 6: Overview of analyses for the primary and key secondary endpoints ....................... 33 
Table 7: Power to meet regulatory criteria for FAS and Observed Case Analyses ................ 44 
Table 8: Scoring for allergic rhinoconjunctivitis rescue medication usage ............................. 48 
Table 9: EAACI scoring for allergic rhinoconjunctivitis rescue medication usage .................. 49 
Table 10: LME analyses ....................................................................................................... 56 
Table 11: SAS code for primary efficacy analysis ................................................................. 58 
Table 12: Example for calculating proportion endpoints........................................................ 58 
 
 
 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
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Version History 
This SAP for the trial TT-06 is based on the CTP version 3.0 dated 24-MAY-2022.  
 
SAP 
Version 
Date 
Change 
Rationale 
1 
19-SEP-2023 
Not applicable 
Original version 
 
1 
List of abbreviations 
AE 
adverse event 
AHPS 
alder-hazel pollen season 
AR/C 
allergic rhinoconjunctivitis 
BPS 
birch pollen season  
eCRF 
electronic case report form 
CTP 
clinical trial protocol 
DMS 
daily rhinoconjunctivitis medication score 
DSS 
daily rhinoconjunctivitis symptom score 
DPS 
data point sets  
E 
exclusion criteria 
EAACI 
European Academy of Allergy and Clinical Immunology 
EOE 
eosinophilic oesophagitis 
EOT 
end of treatment 
ESI 
event of special interest 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FAS 
full analysis set 
 
  
 
  
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GLMM 
generalized linear mixed model 
 
 
H 
hypothesis 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
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ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IE 
intercurrent event 
IgE 
immunoglobulin E 
IgE-BF 
IgE-blocking factor  
IgG4 
immunoglobulin G4 
IMP 
investigational medicinal product 
IRT 
interactive response technology 
LME 
linear mixed effects 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNAR 
missing not at random  
OPS 
oak pollen season 
PD 
protocol deviation 
PT 
preferred term 
RQLQ  
rhinitis quality of life questionnaire 
SABA 
short-acting β2-agonist 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SAS 
statistical analysis system 
SD 
standard deviation 
SOC 
system organ class 
SPT 
skin prick test 
SLIT 
sublingual immunotherapy 
SLIT-tablet 
sublingual immunotherapy tablet 
SUB 
subgroup analysis set 
TAS 
total analysis set 
TC 
telephone call 
TCS 
total combined score 
TEAE 
treatment-emergent adverse event 
TPS 
tree pollen season 
UV 
unscheduled visit 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
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CONFIDENTIAL 
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V 
visit  
WHO 
World Health Organisation 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
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2 
List of definitions 
Cohort  
A group of subjects receiving treatment during the pollen seasons of 
a particular calendar year (e.g., cohort 1 was treated during the 
pollen seasons of 2022) 
Completed subject 
 
A randomised subject is considered completed if he/she has not 
discontinued the trial before visit 6. 
Concomitant 
medication 
All medications continued by a subject on entry to the trial and all 
medications initiated during the trial including ALK rescue 
medication. 
Date of last contact 
 
Date of the last contact, either by telephone or in a visit. 
End of trial 
The overall end of the trial is defined as the date of last follow-up 
phone visit (TC4) for the last subject in the trial globally. 
 
Estimand 
A precise description of the treatment effect reflecting the clinical 
question of interest posed by the trial objective. It summarises at a 
population-level what the outcomes would be in the same patients 
under different treatment conditions being compared (ICH 2020). 
 
ESI 
ESIs are selected AEs that are considered critical for the 
evaluation of the product’s safety profile and for which additional 
data will be collected. 
 
IMP 
A pharmaceutical form of an active substance or placebo being 
tested or used as a reference in a clinical trial, including products 
already with a marketing authorisation but used or assembled 
(formulated or packaged) in a way different from the authorised form, 
or when used for an unauthorised indication, or when used to gain 
further information about the authorised form. 
 
IE  
Events occurring after treatment initiation that affect either the 
interpretation or existence of the measurements associated with the 
clinical question of interest. It is necessary to address IEs when 
describing the clinical question of interest in order to precisely define 
the treatment effect that is to be estimated (ICH 2020). 
 
IRT 
Automated system that can be used for managing randomisation, 
subject enrolment, and trial supply management in a clinical trial. 
 
Rescue medication 
Medicinal products provided by ALK when the efficacy of the IMP is 
not sufficient or likely to cause an adverse event to the subject or to 
manage an emergency situation in relation to allergy symptoms in 
agreement with the EMA Definition of IMPs and use of AMPs 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
12 of 66 
 
 
 
 
consultation document (EMA 2016). 
 
TEAEs 
An adverse event with start date on or after the time of first IMP 
administration and no later than 7 days after last IMP administration. 
 
Trial discontinuation 
date 
Date of subject trial discontinuation. In case of subjects lost to follow-
up, the trial discontinuation date is defined as the date the 
investigator/sponsor decides to discontinue the subject from the trial. 
 
3 
Introduction 
The statistical analysis plan is a supplement to the statistical section in the CTP and provides 
additional details regarding estimands (where applicable), analysis sets, endpoints, and the 
statistical analyses.  
Changes to the analyses and changes that might impact the analyses described in the CTP are 
documented in section 6.11. 
Supporting documentation is provided in section 9. Section 9.1 ‘Definition of pollen seasons’ 
contains the definition of start and end dates for the different pollen seasons used in the trial. 
Section 9.2 ‘Derivations for the trial’ contains details about the derivations used in the trial.  
In addition to above, the SAP includes several appendices (section 11). Appendix A includes a 
list of terms used to identify local administration site TEAEs, further details about the statistical 
analyses are provided in Appendix B, examples of SAS code are listed in Appendix C, and 
Appendix D includes the start and end dates of the pollen station.  
This SAP has been written and approved before database lock and unblinding. 
 
 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
13 of 66 
 
 
 
 
3.1 
Objectives, endpoints, and estimands 
Table 1: Objective and endpoints 
▪ Objectives 
▪ Endpoints 
▪ Primary 
 
To compare the efficacy of the SQ tree SLIT-tablet 
to placebo in the treatment of moderate to severe 
AR/C induced by pollen from birch and trees 
belonging to the birch homologous group in children 
and adolescents (5 through 17 years of age) based 
on the average TCS1 during the BPS. 
• 
Average TCS during the BPS 
▪ Key secondary 
 
To compare the efficacy of the SQ tree SLIT-tablet 
to placebo based on average TCS during the TPS, 
and average rhinoconjunctivitis daily symptom 
score and average rhinoconjunctivitis daily 
medication score during the BPS and TPS. 
• 
Average TCS during the TPS 
• 
Average DSS during the BPS 
• 
Average DSS during the TPS 
• 
Average DMS during the BPS 
• 
Average DMS during the TPS 
▪ Secondary 
 
To compare the safety and tolerability of the SQ 
tree SLIT-tablet to placebo. 
• 
TEAEs 
• 
ESIs 
o 
Systemic allergic reactions 
including anaphylaxis 
o 
Events treated with 
adrenaline/epinephrine 
o 
Severe local swelling or oedema 
of the mouth and/or throat 
o 
EoE 
o 
Oral allergy syndrome 
o 
Asthma exacerbations 
• 
Vital signs, physical examination, lung 
function tests and clinical laboratory 
values during treatment and at the end-of-
treatment visit 
• 
Treatment-related local administration site 
TEAEs (defined according to a pre-
specified list of MedDRA preferred terms) 
                                               
1 daily total combined score = daily symptom score + daily medication score 


Statistical Analysis Plan 
Date: 
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Trial ID: TT-06 
Version: 
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EudraCT No: 2020-004372-17 
Status: 
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To compare the efficacy of the SQ tree SLIT-tablet 
to placebo using additional endpoints based on 
daily allergic rhinoconjunctivitis symptoms and 
rescue medication use. 
• 
Average TCS, average DSS and average 
DMS during the AHPS and seasons OPS 
• 
Average TCS (EAACI scoring) during the 
BPS and TPS 
• 
Number of severe days during the BPS 
and TPS 
• 
Number of well days during the BPS and 
TPS 
• 
Number of symptom-free days during the 
BPS and TPS 
• 
Percentage of patients free of 
symptoms/signs and with no use of rescue 
medication during the BPS and TPS 
To compare the efficacy of the SQ tree SLIT-tablet 
to placebo based on assessments of quality of life. 
• 
Average weekly overall RQLQ score 
during the BPS and TPS (12-17 years 
only) 
• 
Overall PRQLQ score during the BPS (5-
11 years only) 
• 
TSQM-9 evaluations 
To compare the efficacy of the SQ tree SLIT-tablet 
to placebo based on patient treatment satisfaction. 
• 
Patient-rated global evaluation of 
treatment efficacy 
To compare the effect of the SQ tree SLIT-tablet to 
placebo on immunological parameters to birch, 
alder, hazel and oak pollen. 
• 
Change from baseline in birch specific IgE, 
and IgG4 
• 
Change from baseline in alder, hazel and 
oak specific IgE and IgG4 (for a subgroup 
of randomised subjects only) 
• 
Change from baseline in birch, alder and 
hazel specific IgE-BF (for a subgroup of 
randomised subjects only) 
▪ Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Date: 
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Trial ID: TT-06 
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EudraCT No: 2020-004372-17 
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3.1.1 
Estimands 
A primary and secondary estimand is defined for each of the primary and key secondary 
endpoints. 
3.1.1.1 
Primary estimand  
The primary estimand will be referred to as the ‘trial product estimand’. The trial product 
estimand assesses the anticipated effect of the SQ tree SLIT-tablet if it is taken as instructed. 
This estimand is considered to be of most relevance to the patient, as it describes the potential 
benefit they could obtain from the SQ tree SLIT-tablet if they adhere to treatment for the 
planned duration. Adherence to treatment is considered important in allergy immunotherapy 
since the optimal effect of allergy immunotherapy is expected when taken consistently for a 
longer period. 
Using the framework proposed in the ICH E9 (R1) addendum, the trial product estimand can be 
described by: 
A. Treatment: SQ tree SLIT-tablet or placebo, with rescue medication taken as required 
B. Population: Children and adolescents (5-17 years of age) with moderate to severe 
AR/C caused by pollen from birch 
C. Variable: Average TCS during the BPS 
D. How to account for intercurrent events: under the hypothetical situation where all 
subjects have completed treatment for the planned duration (hypothetical strategy) 
E. Population summary: Absolute difference between treatments 
A hypothetical strategy will be used to address the intercurrent event of discontinuation of trial 
treatment. As such, if a subject discontinues trial treatment, only diary data up until the time of 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
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EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
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discontinuation will be included in the analysis. Any diary data recorded after discontinuation of 
trial treatment will be excluded from the analysis. Details of the handling of IEs and missing data 
are provided in section 6.3.3.1. 
3.1.1.2 
Secondary Estimand 
The secondary estimand will be referred to as the ‘treatment policy estimand’. The treatment 
policy estimand assesses the treatment effect regardless of adherence to treatment and 
provides a broad perspective of the treatment effect in clinical practice in the selected 
population of patients. This estimand is in line with to the ‘intention to treat’ principle and 
provides a robust assessment of the efficacy of the SQ tree SLIT-tablet. 
The treatment policy estimand can similarly be described by: 
A. Treatment: SQ tree SLIT-tablet or placebo, with rescue medication taken as required 
B. Population: children and adolescents (5-17 years of age) with moderate to severe AR/C 
caused by pollen from birch 
C. Variable: Average TCS during the BPS 
D. How to account for intercurrent events: regardless of whether subjects complete 
treatment for the planned duration (treatment policy strategy) 
E. Population summary: Absolute difference between treatments 
A treatment policy strategy will be used to address the intercurrent event of discontinuation of 
trial treatment. As such, if a subject discontinues trial treatment, all available diary data will be 
included in the analysis, regardless of adherence to treatment. Details of the handling of IEs 
and missing data are provided in section 6.3.3.2. 
3.1.1.3 
Intercurrent events 
The IE that has been identified as relevant is discontinuation of trial treatment. No additional IEs 
were identified to have an impact on the overall efficacy assessment.  
Due to the long duration of allergy immunotherapy clinical trials, rescue medication is dispensed 
to every subject for ethical reasons. The use of rescue medication is, therefore, part of the 
treatment policy and as such, it is not classified as an IE for this trial.   
The number of IEs will be summarised by reason for discontinuation of trial treatment and 
treatment.  
3.1.1.4 
Estimands for key secondary objectives 
The trial product estimand and treatment policy estimand, specified for the primary objective in 
sections 3.1.1.1 and 3.1.1.2 respectively, are defined similarly for each of the key secondary 
objectives, where the relevant key secondary endpoint of interest is specified in attribute C. 
3.2 
Trial design 
This is a phase III, randomised, parallel-group, double-blind, placebo-controlled, multi-regional 
trial in children (5-11 years) and adolescents (12-17 years) with AR/C, with or without asthma, 
induced by pollen from birch. Based on previous trials, it is anticipated that most subjects 
allergic to birch will also have AR/C induced by pollen from the birch homologous group. 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
17 of 66 
 
 
 
 
Approximately 1000 subjects were to be randomised (1:1) and receive treatment with the SQ 
tree SLIT-tablet or placebo. The randomisation was stratified by geographical location (country) 
and by age group (5-11 years and 12-17 years).  
The trial consisted of 3 periods: a screening period, a treatment period, which included pre-
seasonal and co-seasonal treatment, and a follow-up period (Figure 1). The trial consisted of 2 
cohorts; subjects in cohort 1 were randomised in 2021 and received treatment during the pollen 
seasons of 2022; subjects in cohort 2 were randomised in 2022 and received treatment during 
the pollen seasons of 2023. 
 
Figure 1: Overall trial design 
 
 
The screening visit took place up to approximately 6 months prior to randomisation. Once 
randomised, subjects were treated for at least 12 weeks prior to the start of the TPS. Treatment 
continued until 1 week after the end of the TPS, corresponding to up to approximately 12 
months of treatment. 
 
 
Open-label rescue medication for allergic rhinoconjunctivitis was 
provided during the TPS 
. Open-label asthma medication was provided to subjects 
with asthma during the TPS 
. A follow-up phone visit was planned 1 week after the 
final treatment. 
 


Statistical Analysis Plan 
Date: 
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Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
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Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
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3.2.1 
Flow chart 
The flow chart of the trial assessments by visits are shown below in Table 2.  
Table 2: Flow chart 
Visit ID: 
V1 
TC12 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV3 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off 
season 
Pre-TPS Start of 
TPS 
Pre-BPS 
In 
season 
BPS 
Only for 
cohort 1 
subjects 
also 
 
 
 
End-of-treatment Follow-
up 
Unsched-
uled 
Scheduled week 
1-26 
weeks 
prior to 
V2 
4-12 
weeks 
prior to 
V2 
At least 
12 weeks 
prior to 
expected 
start of 
TPS4 
4 weeks 
after V2 
2 weeks 
prior to 
expected 
start of 
TPS 
 
 
2 weeks 
prior to 
expected 
start of 
BPS 
2 weeks 
after 
expected 
start of 
BPS5 
1 week 
after 
expected 
end of TPS 
1 week after 
expected end of 
TPS 
1 week 
after V6 
 
Cohort 1 subjects 
also 
 
 
1 week after 
expected end of 
6 
Visit window 
 
 
 
+7 days -14 to +7 
days 
-4 days 
+7 days +7 days 
+7 days 
+7 days 
+7 
days 
 
Administrative procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed consent7 
X 
 
 
 
 
 
 
 
 
 
 
 
                                               
2 Only required if V1 (screening) is performed more than 12 weeks prior to randomisation. 
3 Unscheduled visits should be conducted as necessary. The evaluations/examinations listed with brackets should only be performed if deemed necessary by the investigator. 
4 Randomisation (V2) must be performed at least 12 weeks prior to expected TPS but no later than 31 October. 
5 Visit 5 can be scheduled based on the actual BPS start date. 
6 In cohort 1 subjects also 
 V6 is to be performed 1 week after the expected end of 
. End of 
 can be no later than 31 August 2022. 
7 Obtain written informed consent for the trial, storage of serum samples in the ALK Research Biobank, and for pharmacogenetics testing before any other trial procedures are 
performed. 


Statistical Analysis Plan 
Date: 
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Trial ID: TT-06 
Version: 
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Status: 
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CONFIDENTIAL 
Page: 
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Visit ID: 
V1 
TC12 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV3 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off 
season 
Pre-TPS Start of 
TPS 
Pre-BPS 
In 
season 
BPS 
Only for 
cohort 1 
subjects 
also 
 
 
 
End-of-treatment Follow-
up 
Unsched-
uled 
Inclusion/exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
Smoking habit 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
Record prior and 
concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TC to ensure that subject 
is still interested in the trial 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense IMP 
 
 
X 
 
X 
 
 
X 
 
 
 
(X) 
Instruct the subject in use 
of IMP 
 
 
X 
 
 
 
 
 
 
 
 
(X) 
Collect IMP and perform 
drug accountability 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Perform IMP compliance 
check 
 
 
 
X 
X 
 
 
X 
 
X 
 
 
Dispense 
rhinoconjunctivitis and 
asthma rescue medication 
 
 
 
 
X 
 
 
X 
 
 
 
(X) 
Collect rescue medication 
and perform drug 
accountability 
 
 
 
 
 
 
 
X 
 
X 
 
 
Handout eDiary 
 
 
 
 
X 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Date: 
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Trial ID: TT-06 
Version: 
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EudraCT No: 2020-004372-17 
Status: 
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CONFIDENTIAL 
Page: 
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Visit ID: 
V1 
TC12 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV3 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off 
season 
Pre-TPS Start of 
TPS 
Pre-BPS 
In 
season 
BPS 
Only for 
cohort 1 
subjects 
also 
 
 
 
End-of-treatment Follow-
up 
Unsched-
uled 
Instruct in the use of the 
eDiary incl. training in 
symptom scoring 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Show and/or discuss trial 
video 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Inform that TPS is starting  
 
 
 
 
 
X 
 
 
 
 
 
 
Clinical procedures/assessments 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
 
 
 
 
X 
 
(X) 
Height  
 
 
X 
 
 
 
 
 
 
X 
 
(X) 
Weight 
X 
 
X 
 
 
 
 
 
 
X 
 
(X) 
Vital signs 
X 
 
 
 
 
 
 
 
 
X 
 
(X) 
Lung function test8 
 
 
X 
 
 
 
 
 
 
X 
 
(X) 
SPT9 
X 
 
(X) 
 
 
 
 
 
 
 
 
 
Assess AEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess symptoms of 
eosinophilic oesophagitis 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intake of IMP at clinic 
 
 
X 
 
 
 
 
 
 
 
 
 
                                               
8 Measure FVC and FEV1 while subject is on their usual asthma medication (if applicable) following at least a 6 hour washout of SABA.  
9 To be taken after a urine pregnancy test (if applicable). A positive SPT is defined in the SPT guideline. Briefly, a positive SPT is defined as a wheal size of ≥3 mm. If medication that 
could interfere with the SPT, according to prohibited and restricted medication table, has not been washed out, the SPT must be performed at V2 after the interfering medication has 
been washed out. 


Statistical Analysis Plan 
Date: 
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Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
22 of 66 
 
 
 
 
Visit ID: 
V1 
TC12 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV3 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off 
season 
Pre-TPS Start of 
TPS 
Pre-BPS 
In 
season 
BPS 
Only for 
cohort 1 
subjects 
also 
 
 
 
End-of-treatment Follow-
up 
Unsched-
uled 
All subjects (except for 
cohort 1 subjects with 
) 
Daily eDiary recording: 
• AR/C symptoms 
• AR/C medication 
•
 
 
 
 
 
 
•
 
 
 
 
Weekly eDiary 
recording: 
• RQLQ(S)10 
 
 
 
 
 
X --------------------------------------------------------------------------X 
 
 
Cohort 1 subjects with 
 
 
 
 
 
 
X --------------------------------------------------------------------------X 
 
 
                                               
10 RQLQ(S) should be performed only for subjects who were 12-17 years at the randomisation visit. 


Statistical Analysis Plan 
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Trial ID: TT-06 
Version: 
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EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
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Visit ID: 
V1 
TC12 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV3 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off 
season 
Pre-TPS Start of 
TPS 
Pre-BPS 
In 
season 
BPS 
Only for 
cohort 1 
subjects 
also 
 
 
 
End-of-treatment Follow-
up 
Unsched-
uled 
Daily eDiary recording: 
• AR/C symptoms 
AR/C medication  
Cohort 1 subjects with 
 
Daily eDiary recording: 
•
 
•
 
 
 
•
 
•
 
•
 
 
 
 
Weekly eDiary 
recording: 
RQLQ(S)10 
 
 
 
 
 
X --------------------------------------------------X 
 
 
 
Review eDiary recordings 
and compliance 
 
 
 
 
 
X------------------------------------------------------------------------------X 
 
 
Collect eDiary 
 
 
 
 
 
 
 
 
 
X 
 
 


Statistical Analysis Plan 
Date: 
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Trial ID: TT-06 
Version: 
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Status: 
Final 
CONFIDENTIAL 
Page: 
24 of 66 
 
 
 
 
Visit ID: 
V1 
TC12 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV3 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off 
season 
Pre-TPS Start of 
TPS 
Pre-BPS 
In 
season 
BPS 
Only for 
cohort 1 
subjects 
also 
 
 
 
End-of-treatment Follow-
up 
Unsched-
uled 
PRQLQ11  
 
 
 
 
 
 
 
X 
 
 
 
 
All subjects (except for 
cohort 1 subjects with 
): 
• Global evaluation of 
treatment efficacy 
• TSQM-9 
 
 
 
 
 
 
 
 
 
X 
 
 
Cohort 1 subjects with 
: 
• Global evaluation of 
treatment efficacy 
TSQM-9 
 
 
 
 
 
 
 
 
X 
 
 
 
Laboratory 
procedures/assessments 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for specific 
IgE against Bet v 
X 
 
 
 
 
 
 
 
 
 
 
(X) 
Blood and urine samples 
for safety laboratory 
assessments 
X 
 
 
 
 
 
 
 
 
X 
 
(X) 
Urine pregnancy test12 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
(X) 
                                               
11 Perform PRQLQ interview, only for subjects who were 5-11 years at the randomisation visit. 
12 For female subjects of childbearing potential only, additional urine pregnancy tests should be performed during the trial, if a menstrual period is missed. 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
25 of 66 
 
 
 
 
Visit ID: 
V1 
TC12 
V2 
V3 
V4 
TC2 
TC3 
V5 
TC 
 
V6 
TC4 
UV3 
Name of visit 
Screen-
ing 
Retention Randomi-
sation 
Off 
season 
Pre-TPS Start of 
TPS 
Pre-BPS 
In 
season 
BPS 
Only for 
cohort 1 
subjects 
also 
 
 
 
End-of-treatment Follow-
up 
Unsched-
uled 
Blood sample for 
Immunological 
assessments 
X 
 
 
 
X 
 
 
 
 
X 
 
(X) 
Blood sample for 
biobank13 
X 
 
 
 
X 
 
 
 
 
X 
 
(X) 
Blood sample for 
pharmacogenetics14 
 
 
 
 
 
 
 
 
 
X 
 
(X) 
 
 
 
 
 
                                               
13 Only for subjects where informed consent for biobank sampling has been obtained. 
14 Only for subjects where informed consent for pharmacogenetics sampling has been obtained. 


Statistical Analysis Plan 
Date: 
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Trial ID: TT-06 
Version: 
1.0 
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Status: 
Final 
CONFIDENTIAL 
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3.2.2 
Actual trial timelines 
For cohort 2 the randomisation window was extended based on regional pollen data instead of 
dates for national pollen data used for cohort 1. 
The schedule of cohorts is presented in Table 3. 
Table 3:Schedule of cohorts 
 
Cohort 1 
Cohort 2 
First subject first visit  
08-Apr-2021 
10-Mar-2022 
Last subject randomised 
01-Nov-2021 
21-Dec-2022 
Last subject last visit  
24-Oct-2022 
31-July-2023 
 
3.2.3 
Randomisation 
The randomisation list has been generated by the IRT provider and will not be accessible to trial 
personnel involved in the conduct of the trial, until the database has been locked. The 
randomisation was administered centrally via IRT and was stratified based on country and age 
group.  
The randomisation codes will only be made available for data analysis when the clinical 
database has been locked and all PDs have been identified, evaluated, categorised, and 
closed. 
4 
Statistical hypotheses 
4.1.1 
Multiplicity adjustment 
For the trial product estimand based on the primary efficacy endpoint and the key secondary 
efficacy endpoints, the analyses for the main estimators will be controlled for multiplicity to 
ensure a maximum overall type I error rate of 5% in the hypothesis testing of these endpoints.  
The control for multiplicity will be performed through hierarchical testing, using a pre-specified 
order of hypothesis to be tested. For each endpoint, the null hypothesis to be tested is the 
hypothesis of no difference between placebo and active SQ tree SLIT-tablet. Let µ1 denote the 
mean in the SQ tree SLIT-tablet group, and µ2 denote the mean in the placebo group. Then the 
null hypothesis (H0) and the alternative hypothesis (HA) are given as follows:  
H0: µ1 = µ2  and HA: µ1 ≠ µ2   
The order of the hypotheses to be tested is: 
1. The primary efficacy analysis of average TCS during BPS 
2. The key secondary efficacy analysis of average TCS during TPS 
3. The key secondary efficacy analysis of average DSS during BPS 
4. The key secondary efficacy analysis of average DSS during TPS 
5. The key secondary efficacy analysis of average DMS during BPS 
6. The key secondary efficacy analysis of average DMS during TPS 


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CONFIDENTIAL 
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The first hypothesis in the hierarchy will be tested at a two-sided 5% significance level. Testing 
will proceed to the second hypothesis only if the first test is statistically significant (p<0.05). 
Similarly, testing will proceed to the next level of the hierarchy, only if the previous comparison 
is statistically significant at the 5% level. If a test is not statistically significant (p >0.05) then no 
further testing within the hierarchy will be conducted. Thus, the 2nd, 3rd, 4th, 5th, and 6th 
hypothesis tests in the hierarchy will only be conducted if all previously tested hypotheses are 
statistically significant at the 5% level. 
Furthermore, analysis of the quality of life endpoints will be included as the final steps in the 
testing hierarchy, where the order of the hypotheses to be tested is: 
7. The secondary efficacy analysis of average weekly overall RQLQ score during the BPS 
8. The secondary efficacy analysis of average weekly overall RQLQ score during the TPS 
9. The secondary efficacy analysis of overall PRQLQ score during the BPS 
Additional endpoints and analyses are supportive in nature and are not controlled for 
multiplicity. 
5 
Analysis sets 
For the purposes of analysis, the analysis sets presented in  
Table 4 are defined. 
Table 4: Analysis set definitions 
Participant 
analysis set 
Description 
Application 
TAS 
All subjects who signed informed consent and thus 
includes screening failures.  
Outputs related to 
disposition.  
FAS 
All randomised subjects. Subjects will be analysed as 
randomised i.e., according to their randomised 
assignment of treatment.   
Outputs related to baseline 
and efficacy outputs. 
 
 
 
 
  
 
 
 
 
 
SAF 
All randomised subjects who received at least one dose 
of IMP. Subjects will be analysed as treated i.e., 
according to treatment they actually received.  
Outputs related to safety 
reporting. 
SUB 
Subjects in a random subset sample stratified by 
treatment group and age group for cohort 1. 
Endpoints related to alder, 
hazel and oak specific IgE 
and IgG4, and birch, alder, 
and hazel specific IgE-BF. 
 
 
 


Statistical Analysis Plan 
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CONFIDENTIAL 
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Statistical Analysis Plan 
Date: 
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Status: 
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CONFIDENTIAL 
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The following DPS are defined: 
 
DPS1: For subjects who complete the trial treatment, all data is included.  
For subjects who discontinue trial treatment, all data collected after the time of trial 
treatment discontinuation will not be included for the trial product estimand. 
DPS2: All data is included.  
FAS and DPS1 are used to estimate the trial product estimand, FAS and DPS2 are used to 
estimate the treatment policy estimand and observed case.  
6 
Statistical analyses 
Statistical analyses will be carried out by ALK, Biometrics, Hørsholm, Denmark. All computation 
will be performed using SAS, SAS® version 9.4 or later. 
The analyses described in this section along with the supporting information supplied in section 
9 and Appendix B specify the statistical analyses.  
6.1 
General considerations 
Continuous data will be summarised by treatment group using mean, standard deviation, 
median, minimum, and maximum. Categorical data will be summarised by treatment using 
frequency tables displaying numbers and percentages. For the tabulations of data by visit an 
observed case approach is used.   
All the statistical tests described in this document use a significance level of 5% and all tests 
and confidence intervals are two-sided. The null hypothesis is the hypothesis of no difference 
between treatment groups and the alternative to the null hypothesis is the hypothesis of 
difference. For each analysis the specific test is described in more detail. 
The number of imputations will be increased from 1000 to 10000 if the actual significance level 
of the performed test is estimated to be between 4%-6%. This will be done to ensure the 
precision of estimated standard error, and thus the right hypothesis testing conclusion will be 
made. 
Baseline values are defined as the latest available observation at or prior to the date of the first 
administration of IMP, unless otherwise defined.  
Collected age at randomisation will be used to derive the medication score throughout the 
pollen season.  
6.2 
Overall strategy of efficacy analyses 
An overall overview of the strategies for efficacy analyses is listed in Table 5 . A detailed 
description of each endpoint will be described in following sections.  
 
 


Statistical Analysis Plan 
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Table 5: Overall overview of strategies for efficacy analyses 
 
Hypothetical strategy 
Treatment policy strategy  
observed case 
Primary endpoint 
- Main estimator 
- Sensitivity estimator 
- Sensitivity estimator 
(tipping point) 
- Main estimator 
- Sensitivity estimator 
 
√ 
Key secondary 2-61 
- Main estimator 
- Sensitivity estimator 
 
- Main estimator 
- Sensitivity estimator 
 
√ 
Secondary 7-91 
- Main estimator 
- Sensitivity estimator 
 
√ 
Secondary endpoints2 
- Main estimator 
 
 
Immunology 
parameters 
 
 
√ 
1 Key secondary and secondary endpoints in the testing hierarchy 
2 Binomial endpoints will be analysed under the hypothetical strategy using the same imputation rules as 
for the primary endpoints, however the estimator is different.      
6.3 
Primary endpoint analysis 
6.3.1 
Definition of endpoint 
The primary endpoint is the average TCS during the BPS. The average TCS during the BPS is 
the average of the daily sum of the DSS and DMS during the BPS. 
6.3.2 
Main estimator, sensitivity estimator(s) and statistical analysis for the trial 
product and treatment policy estimands 
The main estimator for both estimands will be the absolute treatment difference.  
The main estimator for both estimands will be based on an identical method of statistical 
analysis (specified below), although the actual data used in each analysis may vary according 
to the different strategies taken for the handling of intercurrent events and missing data. Further 
details of the different strategies for each estimand are provided in sections 6.3.3.1, 6.3.3.2, and 
6.4.1. 
Analyses will be based on all randomised subjects. Subjects for whom the efficacy endpoint is 
missing will be included in the analysis through multiple imputation, where missing data will be 


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Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
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CONFIDENTIAL 
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imputed from the same age group according to the approaches specified in sections 6.3.3.1, 
6.3.3.2, and 6.4.1. Imputation will use the method of unrestricted random sampling with 
replacement (seed=7127) and 1000 multiply imputed datasets will be created. For each dataset, 
the efficacy endpoint will be square root transformed in order for the residuals to fulfil the 
underlying assumption of following the so-called statistical normal distribution and analysed 
using a linear mixed effects model assuming unequal variances in the 2 treatment groups. The 
model will include treatment, cohort (1, 2), and age group (5-11 years, 12-17 years) as fixed 
effects and pollen station within cohort as a random effect, with different residual errors 
specified for each treatment group. The model will be estimated using REML, and the 
denominator degrees of freedom will be calculated using the Kenward and Roger’s 
approximation (Kenward and Roger 1997).  
Rubin’s rule is used to combine the 1000 analysis results across the multiple imputed datasets. 
The p-value for the absolute difference is reported as the test result.  
The results are back-transformed as follows; after Rubin's rule is used to combine results 
across imputations, estimated least square means on the square root transformed scale are 
output along with the associated covariance matrix. The absolute difference is calculated by 
squaring the adjusted means, and then calculating the difference. For the absolute difference 
the SE is approximated by using the first order Delta method (first order Taylor approximation), 
and from this the 95% CI is calculated. For the relative difference, Fieller’s theorem (Fieller 
1954) is used to calculate the 95% CI. More details can be found in Appendix B. 
6.3.3 
Handling of intercurrent events and missing data 
Subjects for whom the endpoint is missing because of missing diary data or missing pollen 
exposure (see Section 9.1), multiple imputation will be from own treatment group in case of no 
intercurrent event has occurred, otherwise below imputation rules will be applied. Data is 
assumed to be MAR. 
Subjects with imputed endpoint, will be included in the statistical model with their original 
treatment group, age group, cohort, and pollen station. 
6.3.3.1 
Handling of intercurrent events and missing data for the trial product estimand 
For the trial product estimand, diary data occurring after discontinuation of trial treatment will be 
excluded from the derivation of the primary endpoint (see section 9.2.2.3). Subjects for whom 
the primary endpoint is missing (because of either missing diary data or the exclusion of diary 
data due to discontinuation of trial treatment) will be included in the analysis through multiple 
imputation under the hypothetical situation where subjects continued to take trial treatment as 
planned. 
Multiple imputation for subjects missing the primary endpoint will be conducted as follows: 
• 
For subjects that discontinue trial treatment due to lack of efficacy, multiple imputation of 
the missing endpoint will be from the placebo group. This assumes that had the subject 
continued to take trial treatment, they would have experienced similar efficacy to 
subjects in the placebo arm. Data is assumed to be MNAR. 
• 
For subjects that discontinue trial treatment due to treatment-related AEs, multiple 
imputation of the missing endpoint will be from their own treatment group. This assumes 
that the level of efficacy that would have been experienced by the subject if they had 


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continued to take trial treatment is unrelated to the occurrence of the AE and, if they had 
continued to take trial treatment, they would have experienced similar efficacy to 
subjects in their own treatment group. Data is assumed to be MAR. 
• 
For subjects that discontinue trial treatment due to any other non-treatment related 
reason, multiple imputation of the missing endpoint will be from their own treatment 
group. This assumes that the level of efficacy that would have been experienced by the 
subject had they continued to take trial treatment is not related to their discontinuation of 
trial treatment. Data is assumed to be MAR. 
6.3.3.2 
Handling of intercurrent events and missing data for the treatment policy estimand 
For subjects discontinuing trial treatment, all diary data (including data collected after 
discontinuation of trial treatment) will be included in the derivation of the primary endpoint (see 
section 9.2.1.4). Subjects for whom the primary endpoint is missing will be included in the 
analysis through multiple imputation as follows: 
• 
For subjects discontinuing trial treatment due to treatment-related AEs or lack of 
efficacy, multiple imputation of the missing endpoint will be from the placebo group. This 
assumes that missing data following treatment-related discontinuation of trial treatment 
is MNAR and that subjects no longer taking active treatment for these reasons would 
have shown similar efficacy to subjects receiving placebo. 
• 
For subjects discontinuing trial treatment due to non-treatment related reasons, multiple 
imputation of the missing endpoint will be their own treatment group. This assumes that 
the missing data are MAR. 
6.3.3.3 
Sensitivity analyses 
The sensitivity estimator for both estimands will be the absolute treatment difference.  
The sensitivity estimator for both estimands will be based on an identical method of statistical 
analysis although the actual data used in each analysis may vary according to the different 
strategies taken for the handling of intercurrent events and missing data. Further details of the 
different strategies for each estimand are provided in sections 6.3.3.4 and 6.3.3.5. 
6.3.3.4 
Sensitivity analysis for the product trial estimand 
The sensitivity estimator for the trial product estimand will use the multiple imputation policy 
described for the main estimator (see section 6.3.3.1) except that: 
• 
For subjects that discontinue trial treatment due to treatment-related AEs, multiple 
imputation of the missing endpoint will be from the placebo group. This assumes 
subjects reporting treatment-related AEs would have been experienced a level of 
efficacy similar to subjects in the placebo group if they had continued to take trial 
treatment. Data is assumed to be MNAR. 
An additional sensitivity estimator will be performed to investigate the MAR assumption for the 
imputation in the sensitivity estimator above. The analysis will be performed as follows: a 
penalty (a number) is added to all imputed values in the active treatment group, and the 
analysis is repeated on the FAS population for the trial product estimand. The penalty is 
gradually increased until the point, the tipping point, where the null hypothesis is no longer 


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rejected. If the tipping point is considered a clinical plausible difference, the tipping-point 
analysis does not support the sensitivity estimator.  
6.3.3.5 
Sensitivity analysis for the treatment policy estimand 
The sensitivity estimator for the treatment policy estimand will use multiple imputation from the 
placebo group for all subjects that discontinue trial treatment regardless of the reason for 
discontinuation. Data is assumed to be MNAR.  
6.3.4 
Supportive analyses 
For the primary and key secondary efficacy endpoints, an observed case analysis based on all 
subjects with at least one diary entry in the relevant pollen season will be performed as a 
supportive analysis. This analysis will allow comparison of results both to previous trials where 
the primary efficacy analyses were based on observed cases and also to acknowledged criteria 
for clinical success, which were established based on observed case analyses. 
6.3.5 
Supplementary analyses 
A supplementary analysis for the primary endpoint will be performed using the main estimator of 
the trial product estimand (see section  6.3.2). Subjects with potential data issues listed in (VV-
CLIN-005043) will be excluded from the analysis.  
6.4 
Key secondary endpoint analyses 
6.4.1 
Estimators for estimands defined for key secondary efficacy objectives 
The key secondary endpoints, average TCS during the TPS, average DSS during the BPS and 
TPS, and average DMS during the BPS and TPS will be analysed identically to the primary 
endpoint using the definitions of the trial product estimand and treatment policy estimand (see 
sections 3.1.1.1 and 3.1.1.2 respectively) and the main, sensitivity, and supportive estimators 
described in section 6.3.3, except for the tipping point analysis.  
 
 


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CONFIDENTIAL 
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6.5 
Summary of primary and key secondary endpoints analyses and figures 
An overview of analyses for the primary and key secondary endpoints are presented in Table 6. 
Table 6: Overview of analyses for the primary and key secondary endpoints 
Endpoint 
 
Description 
 
Population 
 
Model 
 
Analysis name 
Multiple imputation 
Reason for IMP 
discontinuation' and not 'IE 
handling 
Imputation group 
Assumption 
Average 
TCS 
during 
BPS 
Trial product 
estimand 
FAS 
LME with MI 
Main estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Own treatment 
group 
• 
Own treatment 
group 
• 
MNAR 
• 
MAR 
• 
MAR 
Sensitivity estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Sensitivity (tipping 
point) 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group (penalty 
on active group) 
• 
MNAR 
• 
MNAR 
• 
MAR 
Supplementary 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Own treatment 
group 
• 
Own treatment 
group 
• 
MNAR 
• 
MAR 
• 
MAR 
Treatment 
policy 
estimand 
LME with MI Main estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Sensitivity estimator 
• 
All reasons 
• 
Placebo 
• 
MNAR 


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Observed 
case 
LME 
Supportive 
- 
- 
- 
Average 
TCS 
during 
TPS  
Trial product 
estimand 
FAS 
LME with MI 
Main estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Own treatment 
group 
• 
Own treatment 
group 
• 
MNAR 
• 
MAR 
• 
MAR 
Sensitivity estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Treatment 
policy 
estimand 
LME with MI Main estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Sensitivity estimator 
• 
All reasons 
• 
Placebo 
• 
MNAR 
Observed 
case 
LME 
Supportive 
- 
 
- 
- 
Average 
DSS 
during 
BPS 
Trial product 
estimand 
FAS 
LME with MI 
Main estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reason 
• 
Placebo 
• 
Own treatment 
group 
• 
Own treatment 
group 
• 
MNAR 
• 
MAR 
• 
MAR 
Sensitivity estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Treatment 
policy 
estimand 
LME with MI Main estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Sensitivity estimator 
• 
All reasons 
• 
Placebo 
• 
MNAR 


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Observed 
case 
LME 
Supportive 
- 
- 
- 
Average 
DSS 
during 
TPS 
Trial product 
estimand 
FAS 
LME with MI 
Main estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Own treatment 
group 
• 
Own treatment 
group 
• 
MNAR 
• 
MAR 
• 
MAR 
Sensitivity estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Treatment 
policy 
estimand 
LME with MI Primary 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Sensitivity estimator 
• 
All reasons 
• 
Placebo 
• 
MNAR 
Observed 
case 
LME 
Supportive 
- 
- 
- 
Average 
DMS 
during 
BPS 
Trial product 
estimand 
FAS 
LME with MI 
Main Estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Own treatment 
group 
• 
Own treatment 
group 
• 
MNAR 
• 
MAR 
• 
MAR 
Sensitivity estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Treatment 
policy 
estimand 
LME with MI Main estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Sensitivity estimator 
• 
All reasons 
• 
Placebo 
• 
MNAR 


Statistical Analysis Plan 
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Status: 
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Observed 
case 
LME 
Supportive 
- 
- 
- 
Average 
DMS 
during 
TPS 
Trial product 
estimand 
FAS 
LME with MI 
Main estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Own treatment 
group 
• 
Own treatment 
group 
• 
MNAR 
• 
MAR 
• 
MAR 
Sensitivity estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Treatment 
policy 
estimand 
LME with MI Main estimator 
• 
Lack of efficacy 
• 
Treatment-related AEs 
• 
Other non treatment-related 
reasons 
• 
Placebo 
• 
Placebo 
• 
Own treatment 
group 
• 
MNAR 
• 
MNAR 
• 
MAR 
Sensitivity estimator 
• 
All reasons 
• 
Placebo 
• 
MNAR 
Observed 
case 
LME 
Supportive 
- 
- 
- 


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6.5.1 
Figures for primary and key secondary endpoints 
A plot with the results from the statistical analyses in the testing hierarchy will be presented. In 
addition, plots with 2 y-axes will be presented (the daily pollen count and average TCS, DSS 
and DMS) relative to day from TPS start for each cohort. 
6.6 
Additional endpoints analyses 
6.7 
Secondary endpoints 
The following secondary endpoints will be analysed identically to the primary endpoint using the 
main estimator for the trial product estimand: 
• 
Average TCS during the AHPS and OPS 
• 
Average DSS during the AHPS and OPS 
• 
Average DMS during the AHPS and OPS 
• 
Average TCS (EAACI scoring) during BPS and TPS 
Following endpoints will be analysed under the hypothetical strategy using the same 
intercurrent events and imputation approach defined for the main estimator.  
• 
Proportion of severe days during BPS and TPS 
• 
Proportion of well days during BPS and TPS  
• 
Proportion of symptom-free days during BPS and TPS  
The proportion of severe days during BPS will be analysed using a GLMM with a logit link 
function. For the proportion of severe days during BPS the model will includes “number of 
severe days/total number of days in BPS” as the response variable and treatment, cohort and 
age group as fixed effects and pollen station within cohort as random effects. From the GLMM 
model, the odds ratio of having a severe day of active treatment relative to placebo will be 
presented together with the corresponding p-values and 95% confidence limits. The endpoints 
proportion of severe days during TPS, proportion of well days during BPS and TPS, and 
symptom-free days during BPS and TPS will be analysed using the same model as for severe 
days during BPS. The imputation of missing data of aforementioned endpoints, will be done by 
using unrestricted random sampling method, which utilise selection with equal probability and 
with replacement. For each subject with missing data, the number of days in pollen season as 
well as the number of days with the endpoint of interest will be replaced from the pool of 
completed subjects with non-missing data in the same age group and the treatment group 
according to hypothetical strategy.  
A plot with the results from the statistical analyses of the endpoints proportion of severe days, 
proportion of well days and proportion of symptom-free days during BPS will be presented. The 
plot will include estimated proportions of having a severe day, well day and symptom free days, 
the relative difference including 95% CI, and a p-values.   
The endpoint percentage of patients free of symptoms and with no use of rescue medication 
during the BPS and TPS will be summarised. The endpoint will be categorised as a binary 
variable (0/1). A subject will be considered as responder if he/she has no symptoms and has 
not used rescue medication during an entire season (BPS or TPS).  


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6.7.1 
Questionnaires 
The endpoint average weekly overall RQLQ(S) score during the BPS and TPS respectively will 
be analysed using the same model as for the main estimator and sensitivity estimator for the 
trial product estimand and supportive analysis, except for not square rooting the endpoint and 
including age group as a fixed effect, i.e., the model will include treatment, and cohort as fixed 
effects and pollen station within cohort as a random effect, with different residual errors 
specified for each treatment group. The overall PRQLQ will be analysed using the same 
approach and model as for RQLQ.  
In addition to above the average weekly overall RQLQ(S) score during the BPS and TPS will be 
summarised.  
The endpoint patient-rated global evaluation of treatment efficacy at EOT categorised as a 
binary variable (improvement versus no improvement) will be analysed by using a GLIMM with a 
logit link function, under the hypothetical strategy using the same intercurrent event and 
imputation approach defined for the main estimator. The assessment is made at EOT and each 
subjects had to respond to the question using the 5-point scale: much better, better, the same, 
worse, much worse. A subject is considered as responder if she/he feels better or much better 
(improvement=1), otherwise it’s considered as a non-responder (improvement=0). The model 
includes the binary endpoint (improvement/no improvement) as response variable and 
treatment, cohort and age group as fixed effects and pollen station within cohort as random 
effects. From the GLMM model, the odds ratio of having an improvement at EOT of active 
treatment relative to placebo will be presented together with the corresponding p-values and 
95% CI.  
TSQM-9 using the convenience domain for subjects 5 to less than 12 years at EOT will be 
analysed similar to average weekly overall RQLQ(S) score and overall PRQLQ using the main 
estimator for trial product estimand. 
Summary of TSQM-9 by domains (effectiveness, convenience, global satisfaction) and 
treatment will be presented.   
6.7.2 
Immunology 
The following immunology endpoints will be summarised by visit and treatment including 
change from baseline: 
• 
Birch specific IgE, log10(IgE), log10(IgG4). 
• 
Alder, hazel and oak specific log10(IgE) and log10(IgG4) (SUB) 
• 
Birch, alder, and hazel specific IgE-BF (SUB)  
Change from baseline in birch specific log10(IgE) and log10(IgG4) at visit 4 and 6 will be 
analysed using repeated measures linear mixed model. The model includes change from 
baseline of the log-transformed immunological parameter as response variable and the log-
transformed immunological parameter at baseline, treatment, visit and treatment*visit interaction 
as fixed effects, and subject as random effect. The active group will be compared to placebo at 
each visit using a t-test in the linear mixed model. The corresponding difference in adjusted 
means (placebo vs active) will be calculated together with the associated p-value and 95% CI. 
In addition, the back-transformed adjusted mean and relative difference in back-transformed 
adjusted means including 95% CI will be listed. The analysis will be based on observed case 
and FAS. 


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The birch specific IgE-BF will be analysed using the same model as for IgE and IgG4, without 
log transforming the endpoint and the fixed effect IgE-BF parameter at baseline. The analysis 
will be based on observed case and SUB.  
Plots of change from baseline in birch specific log10(IgE), log10(IgG4), and IgE-BF in adjusted 
means will be displayed by treatment with 95% CI.  
When taking the logarithm, values below the LLOQ of IgE and IgG4 will be given the minimum 
value measured above 0 for IgE and IgG4 and. Otherwise, data is used as measured. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
   
6.9 
Safety analyses 
All safety summary tables, figures, and listings will be based on the SAF unless otherwise 
specified.  
6.9.1 
Extent of exposure 
6.9.1.1 
Exposure 
Exposure is a priori defined as the difference between the number of tablets dispensed and the 
number of tablets returned or lost. However, for a substantial number of subjects the information 


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about tablets lost is missing and is therefore assumed to be 0. To account for this, exposure will 
be calculated as the minimum of the difference between the number of tablets dispensed and 
the number of tablets returned or lost, and the treatment duration.   
The number of tablets taken will be summarised by treatment group.   
6.9.1.2 
Treatment duration 
The duration of treatment for each subject will be calculated from the date of first dose up until 
(and including) the date of last IMP administration.  
Treatment duration (days) will be summarised by treatment group.   
6.9.1.3 
IMP compliance  
IMP compliance (%) will be calculated for each subject as number of tablets taken divided by 
the treatment duration (days) multiplied by 100.  
IMP compliance (%) will be summarised by treatment group.    
Percentage IMP compliance will be summarised by treatment group. 
6.9.1.4 
eDiary compliance 
eDiary compliance (%) for the TPS will be calculated as the number of non-missing eDiary 
entries in the TPS divided by total number of days in the TPS. 
 eDiary compliance (%) will be summarised by treatment group.  
6.9.2 
Adverse events 
MedDRA version 23.1 will be used for reporting of AEs. 
6.9.2.1 
Events of special interest  
Events of special interest for this trial are:  
• 
Systemic allergic reactions including anaphylaxis 
• 
Events treated with adrenaline/epinephrine 
• 
Severe local swelling or oedema of the mouth and/or throat 
• 
Oral allergy syndrome 
• 
Eosinophilic oesophagitis 
• 
Asthma exacerbations 
6.9.2.2 
Reporting of adverse events 
AE is considered a TEAE if the time of onset is after the time of first dose of IMP and at most 7 
days after last dose of IMP. 
All TEAEs will be summarised by treatment group according to causality, severity (mild, 
moderate, severe), seriousness, action taken, outcome, and whether the event led to IMP 
discontinuation. The number of subjects in each treatment group, the number and frequency of 


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subjects having the event, as well as the number of events and proportion of events will be 
displayed. A similar summary table will be produced for all IMP-related TEAEs.  
All TEAEs and all IMP-related TEAEs will be summarised (in separate tables) by treatment 
group, SOC, and PT, displaying number of subjects in treatment group, and number and 
frequency of subjects having the event. The tables will be sorted according to most frequent 
SOC and PT in the active treatment group, and the most common TEAEs (preferred term from 
MedDRA) defined as those that are present in at least 5% of subjects in the active treatment 
group will be marked. 
Severe TEAEs will be listed only, if there are fewer than 10 events in total. Otherwise, severe 
TEAEs will also be summarised similar to how TEAEs are presented. The same applies for 
SAEs, IMP-related SAEs, TEAEs leading to IMP interruption, and TEAEs leading to IMP 
discontinuation.  
For most frequent IMP-related TEAEs (present in at least 5% of subject in the active treatment 
group) onset and duration will be presented as follows: Average time to onset and average 
duration both in days, will be presented by PT and treatment. In addition, for day 1 of treatment 
average time to onset in day and minutes will be presented by SOC, PT, and treatment.  
For the most frequent IMP-related TEAEs which are recurrent, the average daily duration and 
the average duration in days from first to last occurrence will be presented by SOC, PT and 
treatment. 
Most frequent non-serious TEAEs in any arm (≥1 and ≥5%) will be summarised by system 
organ class and preferred term.  
A table with the overall summary of the safety profile will be produced showing subjects with 
TEAEs, IMP-related TEAEs, IMP-related severe TEAEs, IMP-related treatment-emergent SAEs, 
IMP-related TEAEs leading to IMP discontinuation, and each type of IMP-related treatment-
emergent ESI by treatment group.  
Serious TEAEs, severe TEAEs, TEAEs leading to discontinuation, individual ESIs, and all non-
treatment emergent adverse events will be listed.  
The 6 different types of ESIs will be summarised by SOC, PT, and treatment group.  
Medication errors, including overdose, abuse and misuse of the IMP will be listed.  
In addition to above a plot of the most frequent (≥5%, in active arm) IMP-related TEAS by SOC 
and PT will be produced. Furthermore, plots of the median duration in days and time to onset in 
days of most frequently (≥5%) reported IMP-related AEs of subjects in active treatment group.  
6.9.2.3 
Local administration site TEAEs 
The AEs identified as local administration site TEAEs, by comparison against a pre-defined list 
of MedDRA PTs, will be summarised separately. The pre-defined list of PTs is given in section 
Appendix A. 
IMP-related local administration site reactions TEAEs will be summarised similar to all TEAEs 
by treatment group according to causality, severity (mild, moderate, severe), seriousness, 
action taken, outcome, and whether the event led to IMP discontinuation. 


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6.9.3 
Additional safety assessments  
Shift tables will be produced for physical examination, and laboratory assessments (chemistry, 
haematology, and urinalysis) for baseline to EOT.   
In addition to above laboratory assessments (chemistry and haematology), vital signs and the 
pulmonary function test parameters (FVC, FVC percent predicted, FEV1, and FEV1 percent 
predicted) will be summarised by visit and treatment group. 
Results from the pregnancy test for female subjects of child-bearing potential will be listed.  
6.10 Interim analysis 
No interim analysis was planned. 
6.11 Changes and/or deviations to protocol-planned analyses 
In addition to the analyses specified in the CTP a supplementary analysis for the primary 
endpoint has been added where subjects with potential data issues will be excluded from the 
main analysis.  
The secondary endpoints (average TCS during the AHPS and OPS, average DSS during the 
AHPS and OPS, average DMS during the AHPS and OPS, and average TCS (EAACI scoring) 
during BPS and TPS) will be analysed by using the hypothetical estimand and main estimator 
only.  
Local administration site reactions are specified as 'treatment-related local administration site 
TEAEs.  
The reasons for IMP discontinuation will be visualised by a band plot, instead of a Kaplan-Meier 
plot as the band plot also shows the different reasons for discontinuation. 
Physical examination will not be summarized by visit as stated in the CTP, instead a shift table 
will be made from baseline to end of treatment. 5-, 25-, 75-, and 95 percentiles will not be 
presented for tabulation of data by visit as stated in the CTP.  
The exploratory assessment of the levels of serum antibodies/serum components/serum 
markers to relevant allergens will not be performed nor reported in a separate document as 
stated in CTP.  
Due to the amount of missing pollen data, it was deemed necessary to perform a visual 
inspection of all species by pollen station instead of the pollen plots (pollen grains/m3 versus 
time) as the approach chosen is more precise. 


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7 
Sample size determination 
Sample size calculations are based on the primary endpoint, the average TCS during the BPS, 
which will be square root transformed prior to analysis in order to better approximate the normal 
distribution. Based on previous ALK SLIT-tablet studies in both adult and paediatric populations, 
it is assumed that the mean of the square root transformed average TCS during the BPS in the 
placebo group is 2.5 with corresponding common standard deviation of 1.4 in both placebo and 
active groups. 
Analyses for the primary and secondary estimands will include all randomised subjects and use 
different multiple imputation strategies to account for missing data. For the purposes of sample 
size estimation, it is assumed that 5% of observations in the active arm are imputed from the 
placebo arm. A true relative treatment effect of 25% is assumed, which corresponds to an 
effective relative treatment effect of 23.75% after placebo imputation. 
For a range of sample sizes and a 1:1 randomisation ratio between active and placebo groups, 
1000 trial datasets were simulated under the above assumptions and each trial was analysed 
using a linear model with a fixed term for treatment. For each choice of sample size, the 
probability of the trial fulfilling the regulatory requirements of both the EMA and FDA for the 
primary endpoint was assessed over all the simulated trials. 
The following regulatory requirements were considered: 
1. Statistical significance of the absolute treatment effect (EMA) 
2. Point estimate of the absolute treatment effect greater than 1 (EMA) 
3. Point estimate of the relative treatment effect greater than 15% (FDA) 
4. Lower limit of the 95% CI for the relative treatment effect greater than 10% (FDA) 
Based on the results of the simulation trial, 500 randomised subjects per arm (1000 subjects in 
total) was chosen to provide at least 85% power to satisfy regulatory requirements 1, 2 and 3 for 
the analyses based on all randomised subjects (assuming 5% imputation of placebo in the 
active arm for missing data). Assuming 10% of the 1000 randomised subjects do not have any 
diary data during the BPS, the power for an observed case (OC) analysis to meet the 
requirements is also presented. 


Statistical Analysis Plan 
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Table 7: Power to meet regulatory criteria for FAS and Observed Case Analyses 
 
Statistical 
significance of 
absolute treatment 
effect 
Point estimate 
of absolute 
treatment effect 
>1 
Point estimate 
of relative 
treatment 
effect >15% 
Lower limit of 95% 
CI for relative 
treatment effect 
>10% 
FAS analysis1,3 
n=5002 per arm 
95.0% 
88.3% 
92.8% 
60.2% 
OC analysis1,4 
n=4502 per 
arm3 
94.7% 
89.9% 
93.9% 
62.2% 
1 FAS analysis includes all randomised subjects, OC analysis includes all randomised subjects with diary data in the 
BPS 
2 n=number of subjects included in the analysis 
3 Assumptions: placebo mean=2.5, SD=1.4 (active & placebo), true relative treatment effect=25%, 5% of active arm 
imputed from placebo 
4 Assumptions: placebo mean=2.5, SD=1.4 (active and placebo), true relative treatment effect=25%, no MI, 10% of 
1000 randomised subjects excluded due to missing data 
8 
Demographics and baseline characteristics 
8.1 
Screening failures 
A summary of reasons for screening failure will be presented for the total analysis set.  
8.2 
Protocol deviations 
Overall important PDs will be summarised by trial-, country-, site- and subject-level. 
Furthermore, the important PDs will be summarized by the subject-level deviations and 
treatment.   
A listing with all important PDs will be presented. In addition, a listing with subjects who had 
TC4 before V6 will be presented.  
8.3 
Subject disposition 
Subject disposition will be summarised by number and percentage of subjects screened, 
randomised, included in the analysis sets, completed trial, discontinued trial, reason of 
discontinuation of trial, completed IMP, discontinued IMP, and reason for IMP discontinuation by 
treatment group.   
IMP discontinuations over time by different reasons will be visualised by a band plot showing 
proportions on treatment, having discontinued treatment due to AE, withdrawal by subject, and 
all other reasons (pooled).  
Screening failures will be summarised by reason.  
8.4 
Baseline characteristics 
Demographic variables (age, age group, sex, race, ethnic origin, and country) will be 
summarised by treatment group. 


Statistical Analysis Plan 
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Baseline characteristics (mono/poly sensitised, duration of AR/C induced by birch pollen, skin 
prick test results, skin prick test wheal sizes (birch), specific IgE to birch, and asthma status) will 
be summarised by treatment group. 
8.5 
Medical history 
Medical history is coded using the MedDRA version 23.1 and will be summarised by treatment 
group. 
Separate tables will be created for allergy or asthma history and other medical history.  In 
addition, the other medical history will also be summarised by PT and SOC.  
8.6 
Prior and concomitant therapy 
Prior and concomitant medication will be coded according to the WHO drug dictionary and 
summarised separately by treatment group. 
9 
Supporting documentation 
9.1 
Definition of pollen seasons 
Each site was allocated to a pollen region prior to unblinding. 
The different pollen seasons varied across the selected pollen regions both in intensity and 
duration.  
BPS  
For each pollen region and year the BPS were defined as follows:  
Start date:  
The start date of the BPS is defined as the first day of 3 consecutive days 
with pollen count larger than or equal to 30 grains/m3 
Stop date:  
 
The stop date of the BPS is defined as the last day in the last occurrence 
of 3 consecutive days with pollen count larger than or equal to 30 
grains/m3 
 
Alder, Hazel and Oak  
The alder, hazel, oak pollen seasons were defined as the days included in any of the alder, 
hazel, and oak pollen seasons: 
Start date:  
The start date of the pollen season is defined as the first day of 3 consecutive 
days with pollen count larger than or equal to 10 grains/m3 
Stop date:  
The stop date of the pollen season is defined as the last day in the last 
occurrence of 3 consecutive days with pollen count larger than or equal to 
10 grains/m3 


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Based on experience from trial TT-04, it is anticipated that there will be a high degree of overlap 
between the alder and hazel seasons. As such, a combined alder-hazel season is defined for 
each pollen station as follows: 
Start date:  
The start date of the alder-hazel pollen season is the earliest of the alder season 
start date and hazel season start date 
Stop date:  
The stop date of the alder-hazel pollen season is the latest of the alder season 
stop date and the hazel season stop date 
TPS 
The TPS is defined as all days included in any of the alder, birch, hazel, oak pollen seasons. 
The TPS is not necessarily a continuous period, an example is illustrated in Figure 3 .  
Figure 3: Example of tree pollen season with non-continuous period 
 
 
 
 
  
 
 
  
 
 
 
  
In case of missing pollen counts for specific pollen stations one of the 3 approaches was 
applied prior to unblinding: 
• 
For pollen stations with missing data between observed start and stop date of the 
season LOCF was applied. 
• 
For pollen stations with either very sparse data or completely missing data, each station 
was assigned a neighboring station as close as possible to the original station where 
data was available. Pollen counts from the backup station was used and in addition a 
sanity check was made by looking into the historical pollen data for the original pollen 
station.  
• 
For pollen stations where data was missing for a short period of time and it was deemed 
realistic that seasons had started or not yet ended LOCF was applied.  


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Due to the Ukraine crisis data from the pollen station RUMOSC (Moscow, Russia) was not 
retrievable. Start and stop dates for all pollen seasons in Russia in the season 2022 have been 
estimated by Uwe Berger15 based on the past 5 years of pollen data. 
In addition, a visual inspection of the pollen count for all species is made to validate the pollen 
counts in the season based on the criteria described below. This procedure can identify long 
periods with low pollen counts within the season. 
The final pollen seasons are listed in Appendix D. 
9.2 
Derivations for the trial 
9.2.1 
Derivations of endpoints 
9.2.1.1 
Definition of DSS and DMS 
During the diary completion period, symptoms and medication use are recorded daily by the 
subject in the e-diary. In addition, missed school days for patient, missed workdays for 
caregiver, and school days where performance is affected by AR/C are collected in the e-diary.  
9.2.1.2 
DSS  
The 6 symptoms of AR/C DSS consist of 4 rhinitis symptoms (runny nose, blocked nose, 
sneezing, itchy nose) and 2 conjunctivitis symptoms (gritty feeling/red/itchy eyes, watery eyes). 
The subject rates each symptom as none, mild, moderate, or severe. Each rating is then 
assigned to a score from 0 to 3 based on the subject’s daily rate: 
0 = no symptoms 
1 = mild symptoms 
2 = moderate symptoms  
3 = severe symptoms 
The DSS is the sum of the 6 individual rhinoconjunctivitis symptom scores each day and ranges 
from 0 to 18.  
9.2.1.3 
DMS  
The AR/C DMS is derived using the scoring system in Table 8 and takes values between 0 and 
20 (maximum allowable daily rescue medication used). Note that the recommended dose of 
Desloratadine is scored 6, and that doses below are scored proportionally, i.e. if a 12-year-old 
takes 5 ml once daily, this is scored as 3. Similarly lower doses than recommended use of 
Loratadine tablets, Olopatadine eye drops, and Mometasone furoate nasal spray is also scored 
proportionally based on the recommended daily dose. Subjects taking Loratadine tablets, 
although they should have taken Desloratadine oral solution are scored the same as if they 
should have taken tablets, i.e. a score of 6 for 1 tablet, and a score of 3 for half a tablet. Even if 
a subject takes more than the allowed dosage, then it cannot score more than the max daily 
score for that type of rescue medication. The following rules will be applied: 
• 
A half tablet will be scored to 0.5 x “tablet score”. 
                                               
15 Uwe E. Berger, Head of Aerobiology and Pollen, Information Research Unit, AZ Pollen Research, GmbH, Friedrich Schoeffel-G. 
6, 2000 Stockerau, Austria 
 


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• 
A maximum daily score of 20 will be ensured by capping individual items scores.  
Table 8: Scoring for allergic rhinoconjunctivitis rescue medication usage 
Rescue medication 
Dosage  
Score/ 
Dose unit 
Max 
daily 
score 
Loratadine, 10 mg 
 
Or 
 
Desloratadine, oral 
solution 0.5 mg/mL 
6-12 years old and >30 kg: 1 tablet once 
daily as needed 
6 per tablet 
6 
>12 years old: 1 tablet once daily as needed 
5 years old: 2.5 mL solution once daily as 
needed 
6 per 2.5mL 
6-11 years old: 5.0 mL solution once daily as 
needed  
6 per 5 mL 
≥12 years old: 10 mL solution once daily as 
needed  
6 per 10 mL 
Olopatadine eye 
drops, 1 mg/mL 
1 drop in the affected eye(s) twice daily, 
morning and evening as needed 
1.5 pr. drop 
6 
Mometasone nasal 
spray, 50 µg/dose 
5-11 years old: 1 puff in each nostril once 
daily as needed (max 2 puffs) 
4 per puff 
8 
≥12 years old: 2 puffs in each nostril once 
daily as needed (max 4 puffs) 
2 per puff 
Maximum allergic rhinoconjunctivitis daily medication score (DMS) 
20 
 
9.2.1.4 
TCS 
The AR/C daily TCS is the sum of the daily DSS and DMS (that is, daily TCS=DSS+DMS) and 
takes values between 0 and 38. 
 
 
 
 
  
 
 
 
 
 


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9.2.1.6 
Daily EAACI medication score 
The daily EAACI medication score (DMSEAACI) is defined according to the use of symptom 
relieving medication as follows:   
Table 9: EAACI scoring for allergic rhinoconjunctivitis rescue medication usage 
Rescue medication 
Dosage 
EAACI 
component score 
if medication is 
used 
(0 otherwise) 
Loratadine, 10 mg 
 
Or 
 
Desloratadine, oral 
solution 0.5 mg/mL 
6-12 years old and >30 kg: 1 tablet once daily as 
needed 
1 
>12 years old: 1 tablet once daily as needed 
5 years old: 2.5 mL solution once daily as 
needed 
6-11 years old: 5.0 mL solution once daily as 
needed  
≥12 years old: 10 mL solution once daily as 
needed  
Olopatadine eye 
drops, 1 mg/mL 
1 drop in the affected eye(s) twice daily, morning 
and evening as needed 
1 
Mometasone nasal 
spray, 50 µg/dose 
5-11 years old: 1 puff in each nostril once daily 
as needed (max 2 puffs) 
2 
≥12 years old: 2 puffs in each nostril once daily 
as needed (max 4 puffs) 
Maximum allergic rhinoconjunctivitis daily medication score (DMSEAACI) 
2 
DMSEAACI is defined as the greatest of the EAACI components for each rescue medication type i.e., DMSEAACI 
can takes values of 0, 1, or 2. 
Note that in DMSEAACI can take a value of 3 if a subject uses “Oral corticosteroids with/without INS, with/without 
H1A” (Pfaar et al. 2014). This is not relevant for this trial as oral corticosteroids are not supplied as rescue 
medication.  
9.2.1.7 
TCS with EAACI medication scoring (TCSEAACI) 
The TCS with EAACI medication scoring (TCSEAACI) is the sum of DSS/6 and DMSEAACI and 
ranges from 0 to 5.  


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9.2.2 
Derivation of average symptom and medication scores 
9.2.2.1 
Average Daily Rhinoconjuctivitis Symptom Score (average DSS) 
The average DSS during a given pollen season is the mean of all non-missing DSS over all 
days in the selected pollen season. Average DSS will be derived for the BPS, TPS, AHPS, OPS 
 
9.2.2.2 
Average Daily Rhinoconjuctivitis Medication Score (average DMS) 
The average DMS during a given pollen season is the mean of all non-missing DMS over all 
days in the selected pollen season. Average DMS will be derived for the BPS, TPS, AHPS, 
OPS 
 
9.2.2.3 
Average Daily Rhinoconjuctivitis Total Combined score (average TCS) 
The average TCS during a given pollen season is the mean of all non-missing daily TCS over 
all days in the selected pollen season. Average TCS will be derived for the BPS, TPS, AHPS, 
OPS 
 The definitions of the pollen 
seasons are provided in section 9.1. 
 
 
 
 
 
9.2.2.5 
Average Daily Total Combined Score with EAACI medication scoring (average 
TCSEAACI) 
The average TCS (EAACI scoring) is the mean of the daily non-missing values of the AR/C 
daily TCS with EAACI scoring.  
 
The average TCS (EAACI scoring) will be derived in the BPS and TPS. 
9.2.3 
Derivation of daily binary variables 
9.2.3.1 
Proportion of well days 
A well day is defined as a day with no use of AR/C rescue medication (i.e., DMS=0) and DSS 
less than or equal to 2. A day that meets the definition of well day will take the value 1, and 0 
otherwise. 
The proportion of well days during BPS and TPS is the number of well days/total number of 
days in a season (BPS or TPS). 
9.2.3.2 
Proportion of severe days 
A severe day is a day with a DSS greater than or equal to 6 and at least 2 moderate symptoms 
or 1 severe symptom. A day that meets the definition of severe day will take the value 1, and 0 
otherwise. 
The proportion of severe days during BPS and TPS is the number of severe days/total number 
of days in a season (BPS or TPS). 


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9.2.3.3 
Proportion of symptom-free days 
A symptom-free day is defined as a day with no symptoms and with no use of rescue 
medication (i.e., daily TCS=0). A day that meets the definition of symptom-free day will take the 
value 1, and 0 otherwise.  
The proportion of symptom-free days during BPS and TPS is the number of symptom-free 
days/total number of days in a season (BPS or TPS). 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
9.2.4 
Other derivations of endpoints 
9.2.4.1 
RQLQ 
The RQLQ(S) consists of 28 items covering 7 domains (activities, sleep, no-nose/eye 
symptoms, practical problems, nasal symptoms, eye symptoms, emotional). Each item is scored 
on a 7-point (0-6) scale, where lower scores indicate better quality of life and all items within 
each domain are weighted equally. The domain scores are derived as the mean of all item 
scores within each domain. The overall RQLQ score is the mean of the 28 item scores. 
The RQLQ(S) is completed weekly in the eDiary during TPS by subjects aged 12-17 years at 
randomisation.  


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9.2.4.2 
PRQLQ 
The PRQLQ consists of 23 items covering 5 domains (nasal symptoms, eye symptoms, 
practical problems, activity limitation and other symptoms). Each item is scored on a 7-point (0-
6) scale, where lower scores indicate better quality of life and all items within each domain are 
weighted equally. The domain scores are derived as the mean of all item scores within each 
domain. The overall PRQLQ score is the mean of the 23 item scores. 
The PRQLQ is completed once during the BPS by subjects aged 5-11 years at randomisation. 
9.2.4.3 
TSQM-9 
The TSQM-9 consists of 9 items covering 3 domains (Effectiveness, Convenience, Global 
satisfaction). Items are scored on either a 5-point (1-5) scale or 7-point (1-7) scale, where 
higher scores indicate greater treatment satisfaction. For each domain, item scores are 
summed and normalised to a 0-100 scale, where 0 is the worst possible level of satisfaction and 
100 is the best possible level of satisfaction. The calculations specific to each domain are 
presented in detail in the Treatment Satisfaction Questionnaire for Medication (TSQM) User 
Manual, version 1.8, 08Jun2020.  
9.2.4.4 
Patient-rated global evaluation of treatment efficacy 
Subjects will be asked the following question regarding their perception of the efficacy of the 
treatment they received during the birch/tree pollen season: “Compared to your rhinitis and/or 
conjunctivitis symptoms in the previous birch/tree pollen season, how have you felt overall in 
this birch/tree pollen season?” 
Subjects will respond to the question using the 5-point scale: much better, better, the same, 
worse, much worse. 
‘Better’ or “much better” will be categorised as “improved”, and “much worse”, “worse” or “the 
same” will be categorised as “not-improved”. 
9.2.4.5 
Lung function 
Measurements of FVC, FVC percent predicted, FEV1 and FEV1 percent predicted will be 
recorded by the trial sites. The formulae used for calculating predicted FVC and predicted FEV1 
can vary slightly depending on the spirometer used at each site. Therefore, for reporting 
purposes, FVC percent predicted and FEV1 percent predicted will be recalculated using values 
of predicted FVC and predicted FEV1 calculated from the Quanjer equations (Quanjer et al. 
1995). This is to ensure a standard approach to the derivation of the endpoints. The Quanjer 
formulae for predicted FVC and FEV1 are a function of age, height, and race. 
9.2.5 
Imputation of dates 
9.2.5.1 
Partial dates in adverse event reporting 
Partial dates and time for start of AEs are handled in the following way: 
• 
Missing day is imputed as maximum of first day of month and day of first IMP 
• 
Missing month is imputed as maximum of first day in January and date of first IMP 
Partial dates and time for end of AEs are handled in the following way: 


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• 
Missing day is imputed as minimum of last day in month and day of last contact 
• 
Missing month is imputed as minimum last day of December and date of last contact 
With these imputation rules, AEs are considered treatment emergent when dates are partial, 
and the existing information does not exclude the possibility of the event being treatment 
emergent.  
9.2.5.2 
Incomplete date for last IMP 
Any partial date of last dose is imputed to as late as possible but no later than the date of last 
contact. Missing dates of last dose are imputed as the date of last contact.


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10 References 
EMA & PDCO. EMA/PDCO Standard Paediatric Investigation Plan for Allergen Products for 
Specific Immunotherapy. EMA/PDCO/737605/2009, Revision 4, 1-13. 2015 
 
Fieller, EC. (1954). "Some problems in interval estimation". Journal of the Royal Statistical 
Society, Series B. 16 (2): 175–185 
ICH E9 Statistical Principles for clinical Trials, Feb 1998 
ICH E9 (R1) Addendum on estimands and sensitivity analysis in clinical trials to the guideline on 
statistical Principles for Clinical Trials, November 2019 
 
Kenward, M. G., and Roger, J. H. (1997). “Small Sample Inference for Fixed Effects from 
Restricted Maximum Likelihood.” Biometrics 53:983–997. 
Pfaar,O., Demoly,P., Gerth van,W.R., Bonini,S., Bousquet,J., Canonica,G.W., Durham,S.R., 
Jacobsen,L., Malling,H.J., Mosges,R., Papadopoulos,N.G., Rak,S., Rodriguez Del,R.P., 
Valovirta,E., Wahn,U. & Calderon,M.A. 2014. Recommendations for the standardization of 
clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an 
EAACI Position Paper. Allergy. 
 
 


Statistical Analysis Plan 
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11 Appendices  
Appendix A 
Local administration site TEAEs: 
 
 
 
 
 
High-Level Group Terms (HLGTs) 
- 
Oral soft tissue conditions 
- 
Salivary gland conditions 
- 
Tongue conditions 
High-Level Terms (HLTs) 
- 
Gingival disorders, signs, and symptoms NEC 
- 
Gingival haemorrhages 
- 
Dental and oral soft tissue infections 


Statistical Analysis Plan 
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Appendix B 
Further details to statistical analyses 
Table 10: LME analyses  
LME output 
Adjusted means for each treatment group, the absolute treatment difference 
(Placebo – Active) with 95% confidence interval and p-value, and the relative 
treatment difference (Placebo – Active/ Placebo) with 95% confidence interval will be 
presented. 
Without multiple imputation  
Endpoint  
The endpoint is analysed as the response variable in a LME model which includes 
relevant fixed and random effects, and with different residual errors specified for 
each treatment group. The model will be estimated using REML, and the Kenward 
and Roger’s approximation (Kenward and Roger 1997) is used to calculate the 
denominator degrees of freedom.  
The p-value for the absolute difference is reported as the test result. The 95% CI for 
the relative difference will be calculated using Fieller’s theorem (Fieller 1954).  
Square root 
transformed 
endpoint  
The square root transformed endpoint is analysed as the response variable in a LME 
model which includes relevant fixed and random effects, and with different residual 
errors specified for each treatment group. The model will be estimated using REML, 
and the Kenward and Roger’s approximation (Kenward and Roger 1997) is used to 
calculate the denominator degrees of freedom.  
The results are back-transformed as follows: estimated least square means of the 
square root transformed endpoint are output along with the associated covariance 
matrix. The absolute difference is calculated by squaring the adjusted means, and 
then calculating the difference. For the absolute difference the SE is approximated 
by using the first order Delta method (first order Taylor approximation), and from this 
the 95% CI is calculated. For the relative difference, Fieller’s theorem (Fieller 1954) 
is used to calculate the 95% CI for X/Y, and then the 95% confidence bounds for (Y2-
X2)/Y2 = 1 - (X/Y)2 are found by applying the monotone transformation f(r)= 1 - r2 to 
the confidence interval. 
With multiple imputation  
Imputation will be done using the method of unrestricted random sampling with replacement 
(seed=7127) and 1000 multiple imputed datasets will be created. 
Endpoint 
Each of the 1000 multiple imputed datasets is analysed using the model specified for 
the endpoint. The endpoint is analysed as the response variable in a LME model 
which includes relevant fixed and random effects. The model will be estimated using 
REML, and the Kenward and Roger’s approximation (Kenward and Roger 1997) is 
used to calculate the denominator degrees of freedom.  
Rubin’s rule is used to combine the 1000 analysis results across the multiple imputed 
datasets. The p-value for the absolute difference is reported as the test result. The 
95% confidence interval for the relative difference is calculated using Fieller’s 
theorem (Fieller 1954). 


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Square root 
transformed 
endpoint  
Each of the 1000 multiple imputed datasets is analysed using the model specified for 
square root transformed endpoint. The square root transformed endpoint is analysed 
as the response variable in a LME model which includes relevant fixed and random 
effects, and with different residual errors specified for each treatment group. The 
model will be estimated using REML, and the Kenward and Roger’s approximation 
(Kenward and Roger 1997) is used to calculate the denominator degrees of freedom.  
Rubin’s rule is used to combine the 1000 analysis results across the multiple imputed 
datasets. The p-value for the absolute difference is reported as the test result.  
The results are back-transformed as follows; after Rubin's rule is used to combine 
results across imputations, estimated least square means on the square root 
transformed scale are output along with the associated covariance matrix. The 
absolute difference is calculated by squaring the adjusted means, and then 
calculating the difference. For the absolute difference the SE is approximated by 
using the first order Delta method (first order Taylor approximation), and from this the 
95% CI is calculated. For the relative difference, Fieller’s theorem (Fieller 1954) is 
used to calculate the 95% CI for X/Y, and then the 95% confidence bounds for (Y2-
X2)/Ys2 = 1 - (X/Y)2 are found by applying the monotone transformation f(r)= 1 - r2 to 
the confidence interval. 
Convergence issues:  
If the model does not converge due, then the random effect pollen station will be pooled into larger 
groups. If the model still does not converge, the random effect of pollen within cohort will be removed 
from the model.  
Model checking:  
The assumption of normally distributed residuals underlying the LME model will be evaluated by visual 
inspection of quantile-quantile plots for the primary and key secondary endpoints 
Square root transformation:  
The LME relies on the assumption of normally distributed residuals. Therefore, the square root 
transformation is generally applied, as this usually results in a good approximation to the so-called 
normal distribution. In addition, the square root transformation is used as the DMS scores are skewed 
with a lot if 0’s, which is the reason for not using a log transformation.  
Mean and SE 
Let 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜, 𝜇𝐴𝑐𝑡𝑖𝑣𝑒, 𝜎2
𝑃𝑙𝑎𝑐𝑒𝑏𝑜, and 𝜎2
𝐴𝑐𝑡𝑖𝑣𝑒 be the resulting means and variances for placebo and active 
treatment and 𝑐𝑜𝑣 be the covariance. Then the back-transformed means are given by:  
• 
𝜇̂𝑃𝑙𝑎𝑐𝑒𝑏𝑜= (𝜇𝑃𝑙𝑎𝑐𝑒𝑏𝑜)2 
• 
𝜇̂𝐴𝑐𝑡𝑖𝑣𝑒= (𝜇𝐴𝑐𝑡𝑖𝑣𝑒)2 
• 
𝜇̂𝐷𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒= (𝜇𝑃𝑙𝑎𝑐𝑒𝑏𝑜)2 −(𝜇𝐴𝑐𝑡𝑖𝑣𝑒)2 
and the back-transformed standard errors are given by  
• 
𝑆𝐸𝐴𝑐𝑡𝑖𝑣𝑒= √(2𝜇𝐴𝑐𝑡𝑖𝑣𝑒)2𝜎𝐴𝑐𝑡𝑖𝑣𝑒 
• 
𝑆𝐸𝑃𝑙𝑎𝑐𝑒𝑏𝑜= √(2𝜇𝑃𝑙𝑎𝑐𝑒𝑏𝑜)2𝜎𝑃𝑙𝑎𝑐𝑒𝑏𝑜 
• 
𝑆𝐸𝐷𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒= √(2𝜇𝑃𝑙𝑎𝑐𝑒𝑏𝑜)2𝜎𝑃𝑙𝑎𝑐𝑒𝑏𝑜+ (−2𝜇𝐴𝑐𝑡𝑖𝑣𝑒)2𝜎𝐴𝑐𝑡𝑖𝑣𝑒+ 2(2𝜇𝑃𝑙𝑎𝑐𝑒𝑏𝑜)(−2𝜇𝐴𝑐𝑡𝑖𝑣𝑒)𝑐𝑜𝑣 


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Appendix C 
Examples of SAS code 
Table 11: SAS code for primary efficacy analysis 
SAS code 
proc mixed data= method=reml plots=studentpanel(marginal conditional); 
  class treatment cohort age_group  pollen_station; 
  model TCSqrt= treatment cohort age_group / ddfm = KenwardRogers residual; 
  random pollen_station (cohort); 
  repeated/group=treatment; 
   lsmeans treatment / cl cov diff;  
run; 
TCSsqrt is the square root of the average TCS. 
Table 12: Example for calculating proportion endpoints 
SAS code 
 proc glimmix data =; 
   class treatment cohort age_group pollen_station; 
   model aval / datadays = treatment cohort agegroup / dist=binomial link=logit; 
   random pollen_station(cohort); 
   lsmeans treatment / diff ilink  oddsratio cl; 
 run; 
 
 
 
 
 
 
 
 
 
 


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Appendix D 
Final pollen season 
pollen_ 
station 
Season Cohort 
Start_date 
End_date 
Average 
grains/m3 
Neighbouring 
comments 
ATWIEN 
ALDER 
1 
05-02-2022 
30-03-2022 
95,6   
  
CZTRIN 
ALDER 
1 
13-02-2022 
30-03-2022 
110,1   
  
DEAACH 
ALDER 
1 
09-02-2022 
08-03-2022 
47   
  
DEBOCH 
ALDER 
1 
07-02-2022 
13-03-2022 
54,7   
  
DEBORS 
ALDER 
1 
27-01-2022 
25-03-2022 
109,8   
  
DEDRES 
ALDER 
1 
12-02-2022 
24-03-2022 
55   
  
DELEVE 
ALDER 
1 
07-02-2022 
13-03-2022 
27,2   
  
DELOEW 
ALDER 
1 
04-02-2022 
22-03-2022 
52,8   
  
DEMARB 
ALDER 
1 
08-02-2022 
23-03-2022 
64,7   
  
DEMOEN 
ALDER 
1 
07-02-2022 
13-03-2022 
34,7   
  
DKCOPE 
ALDER 
1 
12-02-2022 
15-03-2022 
20   
  
FRSTRA 
ALDER 
1 
02-02-2022 
28-03-2022 
324,8   
  
HUGYOE 
ALDER 
1 
03-02-2022 
26-03-2022 
84,7   
  
HUMISK 
ALDER 
1 
05-02-2022 
01-05-2022 
36,3   
  
HUPEST 
ALDER 
1 
04-02-2022 
30-03-2022 
118,2   
  
HUSALG 
ALDER 
1 
05-02-2022 
03-04-2022 
107,4   
  
HUSZE2 
ALDER 
1 
15-02-2022 
29-03-2022 
65,2   
  
LTSIAU 
ALDER 
1 
24-02-2022 
28-03-2022 
82,3   
  
LTVILN 
ALDER 
1 
25-02-2022 
05-04-2022 
63,5   
  
PLBYDG 
ALDER 
1 
13-02-2022 
06-04-2022 
171,7   
  
PLCRAC 
ALDER 
1 
13-02-2022 
28-03-2022 
156,3   
  
PLKATO 
ALDER 
1 
08-02-2022 
04-04-2022 
126,5   
  
PLLODZ 
ALDER 
1 
13-02-2022 
02-04-2022 
180,8   
  
PLLUBL 
ALDER 
1 
15-02-2022 
29-03-2022 
120,6   
  
PLPTRY 
ALDER 
1 
08-02-2022 
05-04-2022 
175,1   
  
PLSZCZ 
ALDER 
1 
05-02-2022 
14-03-2022 
51,5   
  
RUMOSC 
ALDER 
1 
14-03-2022 
12-04-2022   
  
  
SKBRAT 
ALDER 
1 
09-02-2022 
09-04-2022 
113,6   
  
ATWIEN 
ALDER 
2 
20-02-2023 
11-03-2023 
19,3   
  
BEBRUS 
ALDER 
2 
08-02-2023 
23-03-2023 
133,4 NLLEID 
completely missing 
BEMARC 
ALDER 
2 
07-02-2023 
24-03-2023 
153,8 DEMOEN 
completely missing 
CZTRIN 
ALDER 
2 
07-03-2023 
10-03-2023 
27,5   
  
DEBOCH 
ALDER 
2 
13-02-2023 
22-03-2023 
141,2   
  
DEDRES 
ALDER 
2 
16-02-2023 
03-03-2023 
71,8   
  
DELEVE 
ALDER 
2 
07-02-2023 
24-03-2023 
153,8 DEMOEN 
partially missing 
DELIPP 
ALDER 
2 
16-02-2023 
21-03-2023 
83,1   
  


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
61 of 66 
 
 
 
 
DELOEW 
ALDER 
2 
15-02-2023 
06-03-2023 
76,5   
  
DEMARB 
ALDER 
2 
22-02-2023 
18-03-2023 
63,4   
  
DEMOEN 
ALDER 
2 
07-02-2023 
24-03-2023 
153,8   
  
DEMUNC 
ALDER 
2 
16-02-2023 
10-03-2023 
38   
  
DKCOPE 
ALDER 
2 
11-02-2023 
03-04-2023 
41,8   
  
DKVIBO 
ALDER 
2 
01-03-2023 
03-04-2023 
12,8   
  
FRSTRA 
ALDER 
2 
02-02-2023 
14-03-2023 
127,7   
  
HUGYOE 
ALDER 
2 
17-02-2023 
10-03-2023 
45,3   
  
HUMISK 
ALDER 
2 
21-02-2023 
05-03-2023 
18,9   
  
HUPEST 
ALDER 
2 
17-02-2023 
10-03-2023 
25,3   
  
HUSALG 
ALDER 
2 
18-02-2023 
17-03-2023 
25,3   
  
HUSZE2 
ALDER 
2 
17-02-2023 
02-03-2023 
35,6   
  
LTSIAU 
ALDER 
2 
19-03-2023 
11-04-2023 
46   
  
LTVILN 
ALDER 
2 
14-03-2023 
25-03-2023 
138,5   
  
MONTREAL ALDER 
2 
09-04-2023 
11-05-2023 
35,8   
  
NLLEID 
ALDER 
2 
08-02-2023 
23-03-2023 
133,4   
  
PLBIAL 
ALDER 
2 
10-03-2023 
24-03-2023 
93,5   
  
PLBYDG 
ALDER 
2 
17-02-2023 
16-04-2023 
24,3   
  
PLCRAC 
ALDER 
2 
26-02-2023 
14-03-2023 
33,5   
  
PLKATO 
ALDER 
2 
10-03-2023 
14-03-2023 
44,8   
  
PLLODZ 
ALDER 
2 
03-03-2023 
20-03-2023 
54   
  
PLLUBL 
ALDER 
2 
18-02-2023 
31-03-2023 
18,9 PLPTRY 
completely missing 
PLPTRY 
ALDER 
2 
18-02-2023 
31-03-2023 
18,9   
  
PLSZCZ 
ALDER 
2 
17-02-2023 
16-04-2023 
24,3 PLBYDG 
completely missing 
PLWROC 
ALDER 
2 
01-03-2023 
14-03-2023 
46,5   
  
QUEBEC 
ALDER 
2 
13-04-2023 
09-05-2023 
20,4   
  
SKBRAT 
ALDER 
2 
17-02-2023 
11-03-2023 
43,2   
  
SKNITR 
ALDER 
2 
17-02-2023 
11-03-2023 
43,2 SKBRAT 
completely missing 
ATWIEN 
BIRCH 
1 
28-03-2022 
03-05-2022 
367,9   
LOCF 
CZTRIN 
BIRCH 
1 
14-04-2022 
15-05-2022 
378,4   
  
DEAACH 
BIRCH 
1 
23-03-2022 
26-04-2022 
260,5 DEMOEN 
completely missing 
DEBOCH 
BIRCH 
1 
23-03-2022 
29-04-2022 
323,5   
  
DEBORS 
BIRCH 
1 
16-04-2022 
11-05-2022 
324,8   
  
DEDRES 
BIRCH 
1 
06-04-2022 
11-05-2022 
463,6   
  
DELEVE 
BIRCH 
1 
22-03-2022 
24-04-2022 
221,4   
  
DELOEW 
BIRCH 
1 
28-03-2022 
09-05-2022 
132,1   
  
DEMARB 
BIRCH 
1 
09-04-2022 
11-05-2022 
556,8   
  
DEMOEN 
BIRCH 
1 
23-03-2022 
26-04-2022 
260,5   
  
DKCOPE 
BIRCH 
1 
27-04-2022 
30-04-2022 
41   
  


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
62 of 66 
 
 
 
 
FRSTRA 
BIRCH 
1 
24-03-2022 
04-05-2022 
228,2   
  
HUGYOE 
BIRCH 
1 
28-03-2022 
03-05-2022 
185,2   
  
HUMISK 
BIRCH 
1 
05-04-2022 
14-05-2022 
250,1   
  
HUPEST 
BIRCH 
1 
26-03-2022 
10-05-2022 
175,5   
  
HUSALG 
BIRCH 
1 
07-04-2022 
12-05-2022 
257,3   
  
HUSZE2 
BIRCH 
1 
29-03-2022 
14-05-2022 
131,4   
  
LTSIAU 
BIRCH 
1 
21-04-2022 
24-05-2022 
560,2   
  
LTVILN 
BIRCH 
1 
26-04-2022 
24-05-2022 
389,2   
  
MONTREAL BIRCH 
1 
08-05-2022 
13-05-2022 
150,9   
  
PLBYDG 
BIRCH 
1 
13-04-2022 
15-05-2022 
1053,9   
  
PLCRAC 
BIRCH 
1 
12-04-2022 
13-05-2022 
601   
  
PLKATO 
BIRCH 
1 
08-04-2022 
23-05-2022 
1049,2   
  
PLLODZ 
BIRCH 
1 
13-04-2022 
14-05-2022 
972,1   
  
PLLUBL 
BIRCH 
1 
14-04-2022 
13-05-2022 
632,8   
  
PLPTRY 
BIRCH 
1 
13-04-2022 
14-05-2022 
1002,3   
  
PLSZCZ 
BIRCH 
1 
18-04-2022 
03-05-2022 
78,3   
  
QUEBEC 
BIRCH 
1 
09-05-2022 
14-05-2022 
198,7   
  
RUMOSC 
BIRCH 
1 
21-04-2022 
13-05-2022   
  
  
SKBRAT 
BIRCH 
1 
27-03-2022 
12-05-2022 
441,6   
  
ATWIEN 
BIRCH 
2 
24-03-2023 
24-04-2023 
64,3   
  
BEBRUS 
BIRCH 
2 
12-04-2023 
01-05-2023 
143,2 NLLEID 
completely missing 
BEMARC 
BIRCH 
2 
02-04-2023 
05-05-2023 
329,1 DEMOEN 
completely missing 
CZTRIN 
BIRCH 
2 
13-04-2023 
06-05-2023 
189,6   
  
DEBOCH 
BIRCH 
2 
10-04-2023 
05-05-2023 
615,5   
  
DEDRES 
BIRCH 
2 
17-04-2023 
01-05-2023 
68,2 DEMARB 
partially missing 
DELEVE 
BIRCH 
2 
05-04-2023 
14-04-2023 
172,1   
LOCF 
DELIPP 
BIRCH 
2 
17-04-2023 
02-05-2023 
212,9   
  
DELOEW 
BIRCH 
2 
17-04-2023 
05-05-2023 
81,4   
  
DEMARB 
BIRCH 
2 
17-04-2023 
01-05-2023 
68,2   
  
DEMOEN 
BIRCH 
2 
02-04-2023 
05-05-2023 
329,1   
  
DEMUNC 
BIRCH 
2 
21-04-2023 
05-05-2023 
158,5   
  
DKCOPE 
BIRCH 
2 
19-04-2023 
05-05-2023 
248,4   
  
DKVIBO 
BIRCH 
2 
20-04-2023 
14-05-2023 
250,4   
  
FRSTRA 
BIRCH 
2 
22-03-2023 
05-05-2023 
80,4   
  
HUGYOE 
BIRCH 
2 
23-03-2023 
24-04-2023 
80,8   
  
HUMISK 
BIRCH 
2 
16-04-2023 
26-04-2023 
338,8   
LOCF 
HUPEST 
BIRCH 
2 
24-03-2023 
26-04-2023 
151,4   
  
HUSALG 
BIRCH 
2 
12-04-2023 
24-04-2023 
613,4   
  
HUSZE2 
BIRCH 
2 
24-03-2023 
24-04-2023 
141,3   
  


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
63 of 66 
 
 
 
 
LTSIAU 
BIRCH 
2 
19-04-2023 
17-05-2023 
162,7   
  
LTVILN 
BIRCH 
2 
18-04-2023 
15-05-2023 
880,5   
  
MONTREAL BIRCH 
2 
28-04-2023 
24-05-2023 
195,5   
  
NLLEID 
BIRCH 
2 
12-04-2023 
01-05-2023 
143,2   
  
PLBIAL 
BIRCH 
2 
17-04-2023 
07-05-2023 
277,5   
  
PLBYDG 
BIRCH 
2 
17-04-2023 
06-05-2023 
283,7   
  
PLCRAC 
BIRCH 
2 
13-04-2023 
04-05-2023 
260,2   
  
PLLODZ 
BIRCH 
2 
16-04-2023 
06-05-2023 
464,1   
  
PLLUBL 
BIRCH 
2 
16-04-2023 
07-05-2023 
327,4 PLPTRY 
completely missing 
PLPTRY 
BIRCH 
2 
16-04-2023 
07-05-2023 
327,4   
  
PLSZCZ 
BIRCH 
2 
17-04-2023 
06-05-2023 
283,7 PLBYDG 
completely missing 
PLWROC 
BIRCH 
2 
15-04-2023 
02-05-2023 
409,7   
  
QUEBEC 
BIRCH 
2 
05-05-2023 
29-05-2023 
243   
LOCF 
SKBRAT 
BIRCH 
2 
25-03-2023 
24-04-2023 
138   
  
SKNITR 
BIRCH 
2 
25-03-2023 
24-04-2023 
138 SKBRAT 
completely missing 
ATWIEN 
HAZEL 
1 
30-01-2022 
17-03-2022 
30   
  
CZTRIN 
HAZEL 
1 
10-02-2022 
23-03-2022 
100,4   
  
DEAACH 
HAZEL 
1 
09-02-2022 
21-02-2022 
81,1   
  
DEBOCH 
HAZEL 
1 
28-01-2022 
15-02-2022 
55,3   
  
DEBORS 
HAZEL 
1 
27-01-2022 
24-02-2022 
25,1   
  
DEDRES 
HAZEL 
1 
28-01-2022 
19-02-2022 
31,9   
  
DELEVE 
HAZEL 
1 
12-02-2022 
18-02-2022 
26,3   
  
DELOEW 
HAZEL 
1 
28-01-2022 
14-03-2022 
23,2   
  
DEMARB 
HAZEL 
1 
27-01-2022 
13-03-2022 
20,4   
  
DEMOEN 
HAZEL 
1 
31-12-2021 
15-02-2022 
14,4   
  
FRSTRA 
HAZEL 
1 
02-01-2022 
13-03-2022 
71,4   
  
HUGYOE 
HAZEL 
1 
02-02-2022 
24-03-2022 
21,8   
  
HUMISK 
HAZEL 
1 
05-02-2022 
28-03-2022 
53,9   
  
HUPEST 
HAZEL 
1 
29-01-2022 
31-03-2022 
41,8   
  
HUSALG 
HAZEL 
1 
05-02-2022 
03-04-2022 
69,3   
  


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
64 of 66 
 
 
 
 
HUSZE2 
HAZEL 
1 
03-02-2022 
31-03-2022 
47,1   
  
LTSIAU 
HAZEL 
1 
12-03-2022 
28-03-2022 
64,2   
  
LTVILN 
HAZEL 
1 
15-03-2022 
26-03-2022 
65,7   
  
PLBYDG 
HAZEL 
1 
07-02-2022 
24-03-2022 
20,7   
  
PLCRAC 
HAZEL 
1 
09-02-2022 
21-03-2022 
49   
  
PLKATO 
HAZEL 
1 
09-02-2022 
21-03-2022 
46,2   
  
PLLODZ 
HAZEL 
1 
12-02-2022 
22-03-2022 
22,3   
LOCF 
PLLUBL 
HAZEL 
1 
13-02-2022 
24-03-2022 
42,1   
  
PLPTRY 
HAZEL 
1 
09-02-2022 
24-03-2022 
31,4   
  
PLSZCZ 
HAZEL 
1 
28-01-2022 
30-01-2022 
20,7   
  
RUMOSC 
HAZEL 
1 
18-03-2022 
12-04-2022   
  
  
SKBRAT 
HAZEL 
1 
02-02-2022 
01-05-2022 
21,5   
  
ATWIEN 
HAZEL 
2 
16-02-2023 
10-03-2023 
19,4   
  
BEBRUS 
HAZEL 
2 
06-01-2023 
18-02-2023 
6 NLLEID 
completely missing 
BEMARC 
HAZEL 
2 
31-12-2022 
12-04-2023 
28,9 DEMOEN 
completely missing 
CZTRIN 
HAZEL 
2 
11-01-2023 
26-02-2023 
29,5   
  
DEBOCH 
HAZEL 
2 
05-01-2023 
23-02-2023 
58,1   
  
DEDRES 
HAZEL 
2 
03-02-2023 
02-03-2023 
37,3   
  
DELEVE 
HAZEL 
2 
05-01-2023 
07-01-2023 
29,3   
  
DELIPP 
HAZEL 
2 
13-02-2023 
27-02-2023 
39,9   
  
DELOEW 
HAZEL 
2 
15-02-2023 
06-03-2023 
42,7   
  
DEMARB 
HAZEL 
2 
05-01-2023 
12-03-2023 
10,3   
  
DEMOEN 
HAZEL 
2 
31-12-2022 
12-04-2023 
28,9   
  
DEMUNC 
HAZEL 
2 
04-01-2023 
10-03-2023 
31,7   
  
DKCOPE 
HAZEL 
2 
11-02-2023 
21-02-2023 
25,1   
  
FRSTRA 
HAZEL 
2 
02-01-2023 
10-03-2023 
89,6   
  
HUGYOE 
HAZEL 
2 
13-01-2023 
21-02-2023 
5,8   
  
HUMISK 
HAZEL 
2 
17-02-2023 
13-03-2023 
29,3   
LOCF 
HUPEST 
HAZEL 
2 
01-01-2023 
16-03-2023 
17,4   
  
HUSALG 
HAZEL 
2 
27-01-2023 
16-03-2023 
22,1   
  
HUSZE2 
HAZEL 
2 
07-01-2023 
10-03-2023 
14,5   
  
LTSIAU 
HAZEL 
2 
19-03-2023 
22-03-2023 
43,7   
  
LTVILN 
HAZEL 
2 
18-03-2023 
24-03-2023 
51,4   
  
NLLEID 
HAZEL 
2 
06-01-2023 
18-02-2023 
6   
  
PLBYDG 
HAZEL 
2 
10-01-2023 
19-03-2023 
14   
  
PLCRAC 
HAZEL 
2 
10-01-2023 
14-03-2023 
11,3   
  
PLKATO 
HAZEL 
2 
21-02-2023 
19-03-2023 
18,7   
  
PLLODZ 
HAZEL 
2 
17-03-2023 
19-03-2023 
14,7   
  
PLLUBL 
HAZEL 
2 
06-02-2023 
15-03-2023 
15,6 PLPTRY 
completely missing 


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
65 of 66 
 
 
 
 
PLPTRY 
HAZEL 
2 
06-02-2023 
15-03-2023 
15,6   
  
PLSZCZ 
HAZEL 
2 
10-01-2023 
19-03-2023 
14 PLBYDG 
completely missing 
SKBRAT 
HAZEL 
2 
17-02-2023 
11-03-2023 
25,6   
  
SKNITR 
HAZEL 
2 
17-02-2023 
11-03-2023 
25,6 SKBRAT 
completely missing 
ATWIEN 
OAK 
1 
24-04-2022 
20-05-2022 
134,2   
  
CZTRIN 
OAK 
1 
02-05-2022 
22-05-2022 
84,9   
  
DEAACH 
OAK 
1 
14-04-2022 
17-05-2022 
253,3 DEMOEN 
completely missing 
DEBOCH 
OAK 
1 
18-04-2022 
14-05-2022 
353,4   
  
DEBORS 
OAK 
1 
01-05-2022 
22-05-2022 
786,7   
  
DEDRES 
OAK 
1 
28-04-2022 
11-05-2022 
582,1   
  
DELEVE 
OAK 
1 
14-04-2022 
11-05-2022 
193   
  
DELOEW 
OAK 
1 
14-04-2022 
13-05-2022 
89,7   
  
DEMARB 
OAK 
1 
03-05-2022 
20-05-2022 
430,1   
  
DEMOEN 
OAK 
1 
14-04-2022 
17-05-2022 
253,3   
  
DKCOPE 
OAK 
1 
11-05-2022 
22-05-2022 
60,5   
  
FRSTRA 
OAK 
1 
13-04-2022 
20-05-2022 
136   
  
HUGYOE 
OAK 
1 
30-04-2022 
12-05-2022 
32,2   
  
HUMISK 
OAK 
1 
29-04-2022 
22-05-2022 
65,3   
  
HUPEST 
OAK 
1 
24-04-2022 
22-05-2022 
91,3   
  
HUSALG 
OAK 
1 
24-04-2022 
23-05-2022 
196,2   
  
HUSZE2 
OAK 
1 
14-04-2022 
19-05-2022 
42,9   
  
LTSIAU 
OAK 
1 
17-05-2022 
28-05-2022 
25,1   
  
LTVILN 
OAK 
1 
19-05-2022 
27-05-2022 
40,4   
  
MONTREAL OAK 
1 
13-05-2022 
19-05-2022 
32,6   
LOCF 
PLBYDG 
OAK 
1 
28-04-2022 
24-05-2022 
74,9   
  
PLCRAC 
OAK 
1 
28-04-2022 
16-05-2022 
101,2   
  
PLKATO 
OAK 
1 
15-04-2022 
21-05-2022 
57,9   
  
PLLODZ 
OAK 
1 
05-05-2022 
21-05-2022 
124,5   
  
PLLUBL 
OAK 
1 
05-05-2022 
21-05-2022 
76,1   
  
PLPTRY 
OAK 
1 
30-04-2022 
23-05-2022 
97,3   
  
PLSZCZ 
OAK 
1 
07-05-2022 
13-05-2022 
24,3   
  
QUEBEC 
OAK 
1 
18-05-2022 
26-05-2022 
94,2   
  
RUMOSC 
OAK 
1 
07-05-2022 
22-05-2022   
  
  
SKBRAT 
OAK 
1 
25-03-2022 
22-05-2022 
115,4   
  
ATWIEN 
OAK 
2 
21-04-2023 
11-05-2023 
39,5   
  
BEBRUS 
OAK 
2 
03-05-2023 
21-05-2023 
46,1 NLLEID 
completely missing 
BEMARC 
OAK 
2 
10-04-2023 
21-05-2023 
63,5 DEMOEN 
completely missing 
CZTRIN 
OAK 
2 
11-05-2023 
14-05-2023 
29,8   
  
DEBOCH 
OAK 
2 
09-04-2023 
16-05-2023 
89,2   
  


Statistical Analysis Plan 
Date: 
19-SEP-2023 
 
Trial ID: TT-06 
Version: 
1.0 
EudraCT No: 2020-004372-17 
Status: 
Final 
CONFIDENTIAL 
Page: 
66 of 66 
 
 
 
 
DEDRES 
OAK 
2 
17-05-2023 
25-05-2023 
30,7 DEMARB 
partially missing 
DELEVE 
OAK 
2 
25-04-2023 
21-05-2023 
83,7 DEMOEN 
partially missing 
DELIPP 
OAK 
2 
28-04-2023 
22-05-2023 
112,1   
LOCF 
DELOEW 
OAK 
2 
22-04-2023 
10-05-2023 
28,1   
  
DEMARB 
OAK 
2 
17-05-2023 
25-05-2023 
30,7   
  
DEMOEN 
OAK 
2 
10-04-2023 
21-05-2023 
63,5   
  
DEMUNC 
OAK 
2 
03-05-2023 
23-05-2023 
33,1   
  
DKCOPE 
OAK 
2 
10-05-2023 
23-05-2023 
27,5   
  
DKVIBO 
OAK 
2 
12-05-2023 
26-05-2023 
91,8   
  
FRSTRA 
OAK 
2 
23-03-2023 
21-05-2023 
31,9   
  
HUGYOE 
OAK 
2 
22-04-2023 
10-05-2023 
12,4   
  
HUPEST 
OAK 
2 
16-04-2023 
09-05-2023 
36,4   
  
HUSALG 
OAK 
2 
28-04-2023 
22-05-2023 
76,7   
  
HUSZE2 
OAK 
2 
11-04-2023 
04-05-2023 
55,7   
  
LTSIAU 
OAK 
2 
11-05-2023 
23-05-2023 
39,7   
  
LTVILN 
OAK 
2 
10-05-2023 
16-05-2023 
39,1   
  
MONTREAL OAK 
2 
11-05-2023 
22-05-2023 
121,5   
  
NLLEID 
OAK 
2 
03-05-2023 
21-05-2023 
46,1   
  
PLBYDG 
OAK 
2 
23-04-2023 
23-05-2023 
18   
  
PLCRAC 
OAK 
2 
23-04-2023 
14-05-2023 
49,1   
  
PLKATO 
OAK 
2 
05-05-2023 
18-05-2023 
28,6   
  
PLLODZ 
OAK 
2 
02-05-2023 
18-05-2023 
89,6   
  
PLLUBL 
OAK 
2 
27-04-2023 
23-05-2023 
44,4 PLPTRY 
completely missing 
PLPTRY 
OAK 
2 
27-04-2023 
23-05-2023 
44,4   
  
PLSZCZ 
OAK 
2 
23-04-2023 
23-05-2023 
18 PLBYDG 
completely missing 
PLWROC 
OAK 
2 
21-04-2023 
18-05-2023 
49,5   
  
QUEBEC 
OAK 
2 
19-05-2023 
29-05-2023 
253,3   
LOCF 
SKBRAT 
OAK 
2 
22-03-2023 
11-05-2023 
23,2   
  
SKNITR 
OAK 
2 
22-03-2023 
11-05-2023 
23,2 SKBRAT 
completely missing 
 


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